Tuesday, March 31, 2009
AF atrial fibrillation
Original Article
Published at www.nejm.org March 31, 2009 (10.1056/NEJMoa0901301)
Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation
The ACTIVE Investigators
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ABSTRACT
Background Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation.
Methods A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K–antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non–central nervous system systemic embolism, or death from vascular causes.
Results At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001).
Conclusions In patients with atrial fibrillation for whom vitamin K–antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00243178 [ClinicalTrials.gov] .)
Atrial fibrillation is a common cardiac arrhythmia that increases the risk of stroke by a factor of five.1 Adjusted-dose vitamin K antagonists and antiplatelet agents reduce the risk of stroke by 64% and 22%, respectively.2 As compared with aspirin, vitamin K antagonists reduce the risk of stroke by 38% but more than double the risk of intracranial hemorrhage and increase the risk of major extracranial hemorrhage by 70%. They do not reduce mortality from any cause or from vascular causes.2,3 On the basis of these data, vitamin K antagonists are recommended for patients at higher risk for stroke, and aspirin for patients at lower risk.4,5
Vitamin K antagonists have a narrow window for a therapeutic benefit and require regular monitoring of the international normalized ratio (INR).6 Several surveys in North America and Europe indicate that only about 50% of patients with atrial fibrillation who are at increased risk for stroke receive vitamin K antagonists.7,8,9,10 Patients may not be treated with a vitamin K antagonist for any number of reasons, including concern about interactions with other drugs, the increased risk of hemorrhage, inadequate compliance with INR monitoring, and a desire by the patient to avoid vitamin K–antagonist therapy. Most of these patients are treated with aspirin.
The benefit of combining clopidogrel with aspirin has been proven in patients with acute coronary syndromes.11 The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) was initiated to evaluate the role of clopidogrel plus aspirin for the prevention of stroke and other vascular events in patients with atrial fibrillation. ACTIVE W, which has previously been reported,12 compared clopidogrel plus aspirin with a vitamin K antagonist. ACTIVE A, reported here, compared clopidogrel plus aspirin with aspirin alone in patients with atrial fibrillation who were at increased risk for stroke and for whom therapy with a vitamin K antagonist was considered unsuitable.
Published at www.nejm.org March 31, 2009 (10.1056/NEJMoa0901301)
Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation
The ACTIVE Investigators
This Article
- Abstract
Tools and Services
- Add to Personal Archive
- Add to Citation Manager
- Notify a Friend
- E-mail When Cited
More Information
ABSTRACT
Background Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation.
Methods A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K–antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non–central nervous system systemic embolism, or death from vascular causes.
Results At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001).
Conclusions In patients with atrial fibrillation for whom vitamin K–antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00243178 [ClinicalTrials.gov] .)
Atrial fibrillation is a common cardiac arrhythmia that increases the risk of stroke by a factor of five.1 Adjusted-dose vitamin K antagonists and antiplatelet agents reduce the risk of stroke by 64% and 22%, respectively.2 As compared with aspirin, vitamin K antagonists reduce the risk of stroke by 38% but more than double the risk of intracranial hemorrhage and increase the risk of major extracranial hemorrhage by 70%. They do not reduce mortality from any cause or from vascular causes.2,3 On the basis of these data, vitamin K antagonists are recommended for patients at higher risk for stroke, and aspirin for patients at lower risk.4,5
Vitamin K antagonists have a narrow window for a therapeutic benefit and require regular monitoring of the international normalized ratio (INR).6 Several surveys in North America and Europe indicate that only about 50% of patients with atrial fibrillation who are at increased risk for stroke receive vitamin K antagonists.7,8,9,10 Patients may not be treated with a vitamin K antagonist for any number of reasons, including concern about interactions with other drugs, the increased risk of hemorrhage, inadequate compliance with INR monitoring, and a desire by the patient to avoid vitamin K–antagonist therapy. Most of these patients are treated with aspirin.
The benefit of combining clopidogrel with aspirin has been proven in patients with acute coronary syndromes.11 The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) was initiated to evaluate the role of clopidogrel plus aspirin for the prevention of stroke and other vascular events in patients with atrial fibrillation. ACTIVE W, which has previously been reported,12 compared clopidogrel plus aspirin with a vitamin K antagonist. ACTIVE A, reported here, compared clopidogrel plus aspirin with aspirin alone in patients with atrial fibrillation who were at increased risk for stroke and for whom therapy with a vitamin K antagonist was considered unsuitable.
polypill
'Polypill' promises to bring low cost primary CVD prevention to the masses
30 March 2009
MedWire News: A 'polypill' (Polycap) containing five generic drugs reduced blood pressure and was well tolerated in a large, international, randomized, double-blind study. Results of The Indian Polycap Study (TIPS) were reported at a late-breaking clinical trial session during the 58th Annual Scientific Session of the American College of Cardiology and was published simultaneously online in The Lancet.
“If this pill is shown to be effective, safe and tolerable - and it is - it will make a huge difference in how we treat people for primary prevention. We estimate that the polypill will reduce coronary heart disease by 50% and stroke by 60%,” said Dr. Salim Yusuf (McMaster University, Hamilton, Ontario, Canada). “We estimate that the daily cost of the polypill will be less than a cup of Starbucks coffee,” he added.
Polycap contains generic versions of hydrochlorothiazide, atenolol, ramipril, a statin, and an aspirin and is made by Cadila Pharmaceuticals in India, which sponsored the study but did not participate in data collection or analysis. The study randomized 2053 non-hypertensive participants to Polycap (n=400) or to one of eight other study arms, each with about 200 participants. The other arms included aspirin alone, simvastatin alone, hydrochlorothiazide alone, three combinations of the two blood pressure-lowering drugs (atenolol and ramipril), three blood pressure-lowering drugs alone, and an arm with three blood pressure-lowering drugs plus aspirin.
Subjects were recruited from 50 centers in India between March 5, 2007 and August 5, 2008. Mean age was 54 years and one third of subjects had diabetes. At baseline, mean baseline blood pressure was 134/85 mm Hg, mean cholesterol was 180 mg/dL, mean HDL cholesterol was 44 mg/dL and mean LDL cholesterol was 117 mg/dL.
“Side effect profiles in the different arms of the study were identical. The side effects of one drug tended to counteract another, for example, ACE inhibitors and thiazides counteract each other’s side effects,” Dr. Yusuf told listeners at an official Press Conference.
Compared with groups not receiving blood pressure lowering drugs, the polypill reduced systolic blood pressure by 7.4 mm Hg and diastolic blood pressure by 5.6 mm Hg. A similar reduction was achieved with three blood pressure lowering drugs with or without aspirin, he said.
The reductions in blood pressure increased along with the number of blood pressure lowering drugs, he said. For example, one drug achieved a reduction of -2.2/1.3 mmHg; two drugs, 4.7/3.6 mm Hg; and three drugs, 6.3/4.5 mm Hg.
Dr. Yusuf said that the polypill should be used in people who already take these drugs, such as those with coronary heart disease and stroke. “The bigger question is should high-risk people use it for primary prevention, and I think that is where the field is going. The final question is should we put it in the drinking water. The answer to that is I don’t know, and will withhold judgment for 5 or 10 years,” he said.
MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009
30 March 2009
MedWire News: A 'polypill' (Polycap) containing five generic drugs reduced blood pressure and was well tolerated in a large, international, randomized, double-blind study. Results of The Indian Polycap Study (TIPS) were reported at a late-breaking clinical trial session during the 58th Annual Scientific Session of the American College of Cardiology and was published simultaneously online in The Lancet.
“If this pill is shown to be effective, safe and tolerable - and it is - it will make a huge difference in how we treat people for primary prevention. We estimate that the polypill will reduce coronary heart disease by 50% and stroke by 60%,” said Dr. Salim Yusuf (McMaster University, Hamilton, Ontario, Canada). “We estimate that the daily cost of the polypill will be less than a cup of Starbucks coffee,” he added.
Polycap contains generic versions of hydrochlorothiazide, atenolol, ramipril, a statin, and an aspirin and is made by Cadila Pharmaceuticals in India, which sponsored the study but did not participate in data collection or analysis. The study randomized 2053 non-hypertensive participants to Polycap (n=400) or to one of eight other study arms, each with about 200 participants. The other arms included aspirin alone, simvastatin alone, hydrochlorothiazide alone, three combinations of the two blood pressure-lowering drugs (atenolol and ramipril), three blood pressure-lowering drugs alone, and an arm with three blood pressure-lowering drugs plus aspirin.
Subjects were recruited from 50 centers in India between March 5, 2007 and August 5, 2008. Mean age was 54 years and one third of subjects had diabetes. At baseline, mean baseline blood pressure was 134/85 mm Hg, mean cholesterol was 180 mg/dL, mean HDL cholesterol was 44 mg/dL and mean LDL cholesterol was 117 mg/dL.
“Side effect profiles in the different arms of the study were identical. The side effects of one drug tended to counteract another, for example, ACE inhibitors and thiazides counteract each other’s side effects,” Dr. Yusuf told listeners at an official Press Conference.
Compared with groups not receiving blood pressure lowering drugs, the polypill reduced systolic blood pressure by 7.4 mm Hg and diastolic blood pressure by 5.6 mm Hg. A similar reduction was achieved with three blood pressure lowering drugs with or without aspirin, he said.
The reductions in blood pressure increased along with the number of blood pressure lowering drugs, he said. For example, one drug achieved a reduction of -2.2/1.3 mmHg; two drugs, 4.7/3.6 mm Hg; and three drugs, 6.3/4.5 mm Hg.
Dr. Yusuf said that the polypill should be used in people who already take these drugs, such as those with coronary heart disease and stroke. “The bigger question is should high-risk people use it for primary prevention, and I think that is where the field is going. The final question is should we put it in the drinking water. The answer to that is I don’t know, and will withhold judgment for 5 or 10 years,” he said.
MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009
polypill
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One Pill Might Prevent Heart Disease
Ads by Google
High Quality BP Monitors
Clinical grade ambulatory, spot & cardiac stress BP devices.
www.SunTechMed.com
Restore Heart & Arteries
Fight heart disease, hypertension. Improve coronary circulation!
cardiofy.com
MONDAY, March 30 -- Create a single pill that contains a statin, three blood pressure drugs and aspirin, and you have an inexpensive medication that can reduce the risk of heart attack, stroke and other cardiovascular problems.
Or so researchers hope.
A first trial of the polypill (which already has a brand name, Polycap), has been successful, according to a report that was to be presented Monday at the American College of Cardiology annual meeting in Orlando, Fla., and online in The Lancet.
The polypill contains generic versions of the blood pressure medications atenolol, hydrochlorothiazide and rampiril, as well as simvastatin (Zocor) and aspirin. It is designed to attack three major risk factors of cardiovascular disease -- high blood pressure, high blood cholesterol and formation of artery-blocking blood clots. It is being tested by an Indian company, Cadila Pharma.
The idea was originated by a group of physicians trained in India and now at McMaster University in Canada, said Dr. Koon Teo, a professor of medicine at McMaster and a member of the research team.
"We know that there are many medications that are beneficial," Teo said. "But often people don't like to take many pills, and doctors don't give patients all the pills they might need."
The first trial enrolled 2,053 people with one risk factor, such as high blood pressure, but no cardiovascular disease. They were divided into nine groups, one taking the polypill, the others various combinations of the medications.
The study, done at 50 centers in India, was designed to answer several questions:
Would the five-drug polypill deliver the same effect as individual pills? What reduction in blood pressure and cholesterol could it achieve? Would there be harmful interactions between the ingredients? Would aspirin reduce the blood-pressure-lowering effect?
The answers were favorable. The polypill reduced systolic blood pressure (the higher of the 120/80 reading) by 7.4 points and diastolic blood pressure by 5.6 points, better than the reduction produced by individual medications. LDL cholesterol reductions were almost as great as those produced by individual doses of simvastatin, the statin in the polypill. Readings showed a reduction in urinary levels of a clot-associated molecule. There was no indication of harmful interactions for those taking the polypill.
The blood pressure reduction caused by the polypill would lower the risk of heart disease by 24 percent and lower stroke risk by 33 percent, the researchers estimated. The cholesterol-lowering effect would reduce heart disease risk by 27 percent and stroke risk by 8 percent, they estimated.
And putting those benefits into one pill would increase the possibility that healthy people would actually take the medications needed to keep them healthy, they said.
"I think this is a good idea, in that even though all these drugs are available in separate pills, people don't take them for lots of reasons -- logistics, costs, availability," said Dr. Christopher P. Cannon, an associate professor of medicine at Harvard Medical School, who wrote an accompanying commentary in The Lancet. "If one had a simple, inexpensive pill, it could open cardiovascular protection to many people."
Millions of Americans who are at risk of cardiovascular disease because of common conditions, such as obesity and high blood pressure, are potential beneficiaries of a polypill, Cannon said. "They should be taking cardiovascular medications, but don't, because they are otherwise healthy," he said. "If there were one, simple pill, they might be open to taking it."
More studies obviously are needed, Cannon said, and physician care would be necessary if the pill became available. "You can't just give it and walk away," he said. "You would have to monitor for side effects, but once you get past that hurdle, one simple pill would help."
Some major regulatory changes by the U.S. Food and Drug Administration would be necessary for the polypill to be available in the United States, Cannon added. "The current mandates of the FDA are that a combination pill would have to be tested for every combination of every drug included in that pill. That obviously would not be feasible in this case. It would require a re-looking at the rules by the FDA, and for that, one needs larger and longer studies."
Even with those hurdles to overcome, a polypill would be "a major step forward in trying to simplify and broaden the applicability of all the medications that reduce cardiovascular risk," Cannon said.
The next step would be a major trial of the polypill among people with clear risk of cardiovascular disease, Teo said. If such a trial succeeded, the hope is that a drug company would pick up the idea, he said.
"The concept is important, and we are testing the concept," Teo said. "Once the concept is proved, we hope that a company in Europe or the United States could see that something can be done with it."
One Pill Might Prevent Heart Disease
Ads by Google
High Quality BP Monitors
Clinical grade ambulatory, spot & cardiac stress BP devices.
www.SunTechMed.com
Restore Heart & Arteries
Fight heart disease, hypertension. Improve coronary circulation!
cardiofy.com
MONDAY, March 30 -- Create a single pill that contains a statin, three blood pressure drugs and aspirin, and you have an inexpensive medication that can reduce the risk of heart attack, stroke and other cardiovascular problems.
Or so researchers hope.
A first trial of the polypill (which already has a brand name, Polycap), has been successful, according to a report that was to be presented Monday at the American College of Cardiology annual meeting in Orlando, Fla., and online in The Lancet.
The polypill contains generic versions of the blood pressure medications atenolol, hydrochlorothiazide and rampiril, as well as simvastatin (Zocor) and aspirin. It is designed to attack three major risk factors of cardiovascular disease -- high blood pressure, high blood cholesterol and formation of artery-blocking blood clots. It is being tested by an Indian company, Cadila Pharma.
The idea was originated by a group of physicians trained in India and now at McMaster University in Canada, said Dr. Koon Teo, a professor of medicine at McMaster and a member of the research team.
"We know that there are many medications that are beneficial," Teo said. "But often people don't like to take many pills, and doctors don't give patients all the pills they might need."
The first trial enrolled 2,053 people with one risk factor, such as high blood pressure, but no cardiovascular disease. They were divided into nine groups, one taking the polypill, the others various combinations of the medications.
The study, done at 50 centers in India, was designed to answer several questions:
Would the five-drug polypill deliver the same effect as individual pills? What reduction in blood pressure and cholesterol could it achieve? Would there be harmful interactions between the ingredients? Would aspirin reduce the blood-pressure-lowering effect?
The answers were favorable. The polypill reduced systolic blood pressure (the higher of the 120/80 reading) by 7.4 points and diastolic blood pressure by 5.6 points, better than the reduction produced by individual medications. LDL cholesterol reductions were almost as great as those produced by individual doses of simvastatin, the statin in the polypill. Readings showed a reduction in urinary levels of a clot-associated molecule. There was no indication of harmful interactions for those taking the polypill.
The blood pressure reduction caused by the polypill would lower the risk of heart disease by 24 percent and lower stroke risk by 33 percent, the researchers estimated. The cholesterol-lowering effect would reduce heart disease risk by 27 percent and stroke risk by 8 percent, they estimated.
And putting those benefits into one pill would increase the possibility that healthy people would actually take the medications needed to keep them healthy, they said.
"I think this is a good idea, in that even though all these drugs are available in separate pills, people don't take them for lots of reasons -- logistics, costs, availability," said Dr. Christopher P. Cannon, an associate professor of medicine at Harvard Medical School, who wrote an accompanying commentary in The Lancet. "If one had a simple, inexpensive pill, it could open cardiovascular protection to many people."
Millions of Americans who are at risk of cardiovascular disease because of common conditions, such as obesity and high blood pressure, are potential beneficiaries of a polypill, Cannon said. "They should be taking cardiovascular medications, but don't, because they are otherwise healthy," he said. "If there were one, simple pill, they might be open to taking it."
More studies obviously are needed, Cannon said, and physician care would be necessary if the pill became available. "You can't just give it and walk away," he said. "You would have to monitor for side effects, but once you get past that hurdle, one simple pill would help."
Some major regulatory changes by the U.S. Food and Drug Administration would be necessary for the polypill to be available in the United States, Cannon added. "The current mandates of the FDA are that a combination pill would have to be tested for every combination of every drug included in that pill. That obviously would not be feasible in this case. It would require a re-looking at the rules by the FDA, and for that, one needs larger and longer studies."
Even with those hurdles to overcome, a polypill would be "a major step forward in trying to simplify and broaden the applicability of all the medications that reduce cardiovascular risk," Cannon said.
The next step would be a major trial of the polypill among people with clear risk of cardiovascular disease, Teo said. If such a trial succeeded, the hope is that a drug company would pick up the idea, he said.
"The concept is important, and we are testing the concept," Teo said. "Once the concept is proved, we hope that a company in Europe or the United States could see that something can be done with it."
Saturday, March 28, 2009
dementia alzheimer
Publication Logo
AD/PD 2009: Are We Experiencing an Alzheimer's Epidemic?
Pauline Anderson
Medscape Medical News 2009. © 2009 Medscape
March 25, 2009 (Prague, Czech Republic) — The world may be experiencing an epidemic of Alzheimer's disease (AD) that is not entirely attributable to an aging population, new research suggests.
Presented here at AD/PD 2009: 9th International Conference on Alzheimer's and Parkinson's Diseases, Murray Waldman, MD, from St. John's Rehabilitation Hospital, in Toronto, Ontario, found that while citations in the medical literature for femur fractures rose from 1706 to 3730 between 1996 and 2000, citations for AD and other dementias shot up from 1274 to 21 569 during the same time period.
Femur fractures make a good comparison for AD because both increase with age and treatment for both conditions has not changed significantly in the past 40 years, said Dr. Murray.
Little Mention Of AD Before 1960
Although AD is one of the most common diseases of the elderly, Dr. Waldman could find little mention of it before the 1960s. "I looked everywhere. I looked on 3 continents and in every medical library I could find, including the Library of Congress and the British Museum library," Dr. Waldman told Medscape Psychiatry.
"I also looked at psychiatric literature and at the pathology literature, but no matter where I looked, I couldn't find anything that indicated there was very much AD prior to the 1960s."
This lack of reference may indicate that AD did exist but nobody noticed it, "which I don't believe for a second, because of all diseases, Alzheimer's is one of the most difficult to miss," said Dr. Waldman. The only other plausible explanation, he said, is that it was less frequent then than it is now.
After 1960, the number of femur fractures rose in a linear fashion, reflecting the aging population. There were 1706 citations for these fractures from 1966 through 1970; 2077 from 1971 through 1975; 2356 from 1981 through 1985; 3235 from 1990 through 1995; and 3730 from 1996 through 2000.
In contrast, the number for AD and other dementias rose exponentially: 1274 citations from 1966 through 1970; 1733 from 1971 through 1975; 5465 from 1981 through 1985; 16 204 from 1991 through 1995; and 21 569 from 1996 through 2000.
This dramatic spike over 40 or so years, he said, cannot be accounted for by an aging population, "because what we were looking at was incidence, not prevalence."
Incidence Has Soared
Epidemiological data collected over a 25-year period shows the incidence of AD in the 1960s was 2% in people over the age of 85 years, whereas today, most experts accept that the incidence of AD in this population is 50%. It is 20% over the age of 75 years and 10% in individuals over the age of 65 years, he added.
"So the incidence seems to have soared enormously in this brief period."
The "exponential curve" pattern showing the rise in incidence of AD is similar to that of AIDS, said Dr. Waldman. Both patterns seem to fit the conditions of an epidemic. For example, the increased AD incidence began in Europe, moved to North America, then to Japan, China, and finally to India. India, he added, just started reporting AD cases in the past 5 years.
Dr. Waldman has his own theory of what might explain this spike in AD cases and wrote about it in his book Dying for a Hamburger (Toronto, ON: McClelland & Stewart, 2004). He's convinced that AD is due to prions, extraordinarily rare but extremely infectious agents. Prions apparently caused an outbreak of bovine spongiform encephalopathy in England over a decade ago.
He added he was disappointed that the AD/PD conference where he presented his work did not seem to feature research probing the causes of AD. "I didn't hear anything new," he said. "Nobody seems to be looking at what's causing this. No one seems to be asking the most fundamental question: Where does this disease come from?"
AD/PD 2009: 9th International Conference on Alzheimer's and Parkinson's Diseases: Abstract 90. Presented March 12-13, 2009
AD/PD 2009: Are We Experiencing an Alzheimer's Epidemic?
Pauline Anderson
Medscape Medical News 2009. © 2009 Medscape
March 25, 2009 (Prague, Czech Republic) — The world may be experiencing an epidemic of Alzheimer's disease (AD) that is not entirely attributable to an aging population, new research suggests.
Presented here at AD/PD 2009: 9th International Conference on Alzheimer's and Parkinson's Diseases, Murray Waldman, MD, from St. John's Rehabilitation Hospital, in Toronto, Ontario, found that while citations in the medical literature for femur fractures rose from 1706 to 3730 between 1996 and 2000, citations for AD and other dementias shot up from 1274 to 21 569 during the same time period.
Femur fractures make a good comparison for AD because both increase with age and treatment for both conditions has not changed significantly in the past 40 years, said Dr. Murray.
Little Mention Of AD Before 1960
Although AD is one of the most common diseases of the elderly, Dr. Waldman could find little mention of it before the 1960s. "I looked everywhere. I looked on 3 continents and in every medical library I could find, including the Library of Congress and the British Museum library," Dr. Waldman told Medscape Psychiatry.
"I also looked at psychiatric literature and at the pathology literature, but no matter where I looked, I couldn't find anything that indicated there was very much AD prior to the 1960s."
This lack of reference may indicate that AD did exist but nobody noticed it, "which I don't believe for a second, because of all diseases, Alzheimer's is one of the most difficult to miss," said Dr. Waldman. The only other plausible explanation, he said, is that it was less frequent then than it is now.
After 1960, the number of femur fractures rose in a linear fashion, reflecting the aging population. There were 1706 citations for these fractures from 1966 through 1970; 2077 from 1971 through 1975; 2356 from 1981 through 1985; 3235 from 1990 through 1995; and 3730 from 1996 through 2000.
In contrast, the number for AD and other dementias rose exponentially: 1274 citations from 1966 through 1970; 1733 from 1971 through 1975; 5465 from 1981 through 1985; 16 204 from 1991 through 1995; and 21 569 from 1996 through 2000.
This dramatic spike over 40 or so years, he said, cannot be accounted for by an aging population, "because what we were looking at was incidence, not prevalence."
Incidence Has Soared
Epidemiological data collected over a 25-year period shows the incidence of AD in the 1960s was 2% in people over the age of 85 years, whereas today, most experts accept that the incidence of AD in this population is 50%. It is 20% over the age of 75 years and 10% in individuals over the age of 65 years, he added.
"So the incidence seems to have soared enormously in this brief period."
The "exponential curve" pattern showing the rise in incidence of AD is similar to that of AIDS, said Dr. Waldman. Both patterns seem to fit the conditions of an epidemic. For example, the increased AD incidence began in Europe, moved to North America, then to Japan, China, and finally to India. India, he added, just started reporting AD cases in the past 5 years.
Dr. Waldman has his own theory of what might explain this spike in AD cases and wrote about it in his book Dying for a Hamburger (Toronto, ON: McClelland & Stewart, 2004). He's convinced that AD is due to prions, extraordinarily rare but extremely infectious agents. Prions apparently caused an outbreak of bovine spongiform encephalopathy in England over a decade ago.
He added he was disappointed that the AD/PD conference where he presented his work did not seem to feature research probing the causes of AD. "I didn't hear anything new," he said. "Nobody seems to be looking at what's causing this. No one seems to be asking the most fundamental question: Where does this disease come from?"
AD/PD 2009: 9th International Conference on Alzheimer's and Parkinson's Diseases: Abstract 90. Presented March 12-13, 2009
tonsillitis keelpijn pharingitis
*
Management of Streptococcal Pharyngitis Reviewed CME/CE
News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd
Disclosures
Release Date: March 10, 2009; Valid for credit through March 10, 2010
Credits Available
Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians;
Nurses - 0.25 ANCC contact hours (0.25 contact hours are in the area of pharmacology)
To participate in this internet activity: (1) review the target audience, learning objectives, and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation; (4) view/print certificate View details.
Learning Objectives
Upon completion of this activity, participants will be able to:
1. Describe the prevalence, presentation, and diagnosis of group A beta-hemolytic streptococcus pharyngitis.
2. Describe treatment and follow up guidelines for acute, chronic, and recurrent group A beta-hemolytic streptococcus pharyngitis
Authors and Disclosures
Laurie Barclay, MD
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
Désirée Lie, MD, MSEd
Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.
Laurie Scudder, MS, NP
Disclosure: Laurie Scudder, MS, NP, has disclosed no relevant financial information.
Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.
March 10, 2009 — Best practices to diagnose and treat streptococcal pharyngitis in the primary care setting are reviewed in an article published in the March 1 issue of American Family Physician.
"Pharyngitis is diagnosed in 11 million patients in U.S. emergency departments and ambulatory settings annually," writes Beth A. Choby, MD, from University of Tennessee College of Medicine in Chattanooga. "Group A beta-hemolytic streptococcus (GABHS), the most common bacterial etiology, accounts for 15 to 30 percent of cases of acute pharyngitis in children and 5 to 20 percent in adults....The infection is transmitted via respiratory secretions, and the incubation period is 24 to 72 hours."
In addition to sore throat, signs and symptoms frequently associated with streptococcal pharyngitis include fever with temperature greater than 100.4°F (38°C), tonsillar exudates, and cervical adenopathy. Viral pharyngitis is more likely than streptococcal pharyngitis to be associated with cough, coryza, and diarrhea.
The gold standard for streptococcal pharyngitis is throat culture. However, there have been significant improvements in sensitivity and specificity of rapid antigen detection testing (RADT). To facilitate management, the modified Centor score can help clinicians determine which patients should need no testing, throat culture/RADT, or empiric treatment with antibiotics.
The Centor clinical decision rule allowing clinicians to determine appropriate management of patients with sore throat assigns 1 point for each of the following: absence of cough, swollen and tender anterior cervical nodes, elevated temperature of more than 100.4°F (38°C), tonsillar exudates or swelling, and ages 3 to 14 years. One point is subtracted for age 45 years and older.
For a score of 0 to 1, the risk for GABHS pharyngitis is 1% to 2.5% (score ≤ 0) or 5% to 10% (score 1), and no further testing or antibiotics are indicated, although throat culture or RADT may be performed for a score of 1. Other factors should be considered, such as recent family contact with documented streptococcal infection, which would lower the threshold for testing and/or treatment.
For a score of 2 or 3, the risk for GABHS pharyngitis is 11% to 18% (score 2) up to 28% to 35% (score 3), and throat culture or RADT should be performed and antibiotics given if culture results are positive.
For a score of 4 or more, the risk for GABHS pharyngitis is 51% to 53%, and empiric treatment with antibiotics should be considered.
"Although GABHS pharyngitis is common, the ideal approach to management remains a matter of debate," the review authors write. "U.S. guidelines differ in whether they recommend using clinical prediction models versus diagnostic testing. Several international guidelines recommend not testing for or treating GABHS pharyngitis at all."
Complications of GABHS pharyngitis may be either suppurative or nonsuppurative. The suppurative complications may include bacteremia, cervical lymphadenitis, endocarditis, mastoiditis, meningitis, otitis media, peritonsillar or retropharyngeal abscess, and/or pneumonia. Nonsuppurative complications may include poststreptococcal glomerulonephritis or rheumatic fever.
The treatment of choice for streptococcal pharyngitis is penicillin (10 days of oral treatment or 1 injection of intramuscular benzathine penicillin) because of cost, narrow spectrum of activity, and efficacy. However, amoxicillin tastes better and is equally effective. In patients with penicillin allergy, reasonable options are erythromycin and first-generation cephalosporins.
There have been reports of increased GABHS treatment failure with penicillin. Therefore, some guidelines recommend use of cephalosporins in all nonallergic patients, and not just in persons with penicillin allergy, because of improved eradication of GABHS and greater efficacy against chronic carriage of GABHS.
Despite appropriate antibiotic treatment, chronic GABHS colonization is common. There is generally no need to treat chronic carriers because they are thought to be at low risk of transmitting disease or developing invasive GABHS infections.
Persons or situations in which antibiotic treatment of chronic GABHS colonization may be appropriate include recurrent GABHS infection within a family; personal history of or close contact with a person with acute rheumatic fever or acute poststreptococcal glomerulonephritis; close contact with a person with group A streptococcal infection; community outbreak of acute rheumatic fever, poststreptococcal glomerulonephritis, or invasive group A streptococcal infection; healthcare workers or patients in hospitals, chronic care facilities, or nursing homes; families who cannot be reassured without antibiotic treatment; and children who are at risk for tonsillectomy for repeated GABHS pharyngitis.
It is still unclear whether tonsillectomy or adenoidectomy reduces the incidence of GABHS pharyngitis, but the potential benefits are thought to be too small to outweigh the associated costs and surgical risks.
Specific clinical recommendations for practice, and their accompanying level of evidence rating, are as follows:
* Use of clinical decision rules to diagnose GABHS pharyngitis is associated with better quality of care, less unnecessary treatment, and lower overall cost (level of evidence, A).
* In persons who are not penicillin-allergic, penicillin is the treatment of choice for GABHS pharyngitis (level of evidence, A).
* Chronic carriers of pharyngeal GABHS typically do not require treatment (level of evidence, C).
"Differences in guidelines are best explained by whether emphasis is placed on avoiding inappropriate antibiotic use or on relieving acute GABHS pharyngitis symptoms," the review authors conclude. "Several U.S. guidelines recommend confirmatory throat culture for negative RADT in children and adolescents."
Dr. Choby is an assistant editor of The Core Content Review of Family Medicine.
Am Fam Physician. 2009;79:383-390.
Management of Streptococcal Pharyngitis Reviewed CME/CE
News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd
Disclosures
Release Date: March 10, 2009; Valid for credit through March 10, 2010
Credits Available
Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians;
Nurses - 0.25 ANCC contact hours (0.25 contact hours are in the area of pharmacology)
To participate in this internet activity: (1) review the target audience, learning objectives, and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation; (4) view/print certificate View details.
Learning Objectives
Upon completion of this activity, participants will be able to:
1. Describe the prevalence, presentation, and diagnosis of group A beta-hemolytic streptococcus pharyngitis.
2. Describe treatment and follow up guidelines for acute, chronic, and recurrent group A beta-hemolytic streptococcus pharyngitis
Authors and Disclosures
Laurie Barclay, MD
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
Désirée Lie, MD, MSEd
Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.
Laurie Scudder, MS, NP
Disclosure: Laurie Scudder, MS, NP, has disclosed no relevant financial information.
Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.
March 10, 2009 — Best practices to diagnose and treat streptococcal pharyngitis in the primary care setting are reviewed in an article published in the March 1 issue of American Family Physician.
"Pharyngitis is diagnosed in 11 million patients in U.S. emergency departments and ambulatory settings annually," writes Beth A. Choby, MD, from University of Tennessee College of Medicine in Chattanooga. "Group A beta-hemolytic streptococcus (GABHS), the most common bacterial etiology, accounts for 15 to 30 percent of cases of acute pharyngitis in children and 5 to 20 percent in adults....The infection is transmitted via respiratory secretions, and the incubation period is 24 to 72 hours."
In addition to sore throat, signs and symptoms frequently associated with streptococcal pharyngitis include fever with temperature greater than 100.4°F (38°C), tonsillar exudates, and cervical adenopathy. Viral pharyngitis is more likely than streptococcal pharyngitis to be associated with cough, coryza, and diarrhea.
The gold standard for streptococcal pharyngitis is throat culture. However, there have been significant improvements in sensitivity and specificity of rapid antigen detection testing (RADT). To facilitate management, the modified Centor score can help clinicians determine which patients should need no testing, throat culture/RADT, or empiric treatment with antibiotics.
The Centor clinical decision rule allowing clinicians to determine appropriate management of patients with sore throat assigns 1 point for each of the following: absence of cough, swollen and tender anterior cervical nodes, elevated temperature of more than 100.4°F (38°C), tonsillar exudates or swelling, and ages 3 to 14 years. One point is subtracted for age 45 years and older.
For a score of 0 to 1, the risk for GABHS pharyngitis is 1% to 2.5% (score ≤ 0) or 5% to 10% (score 1), and no further testing or antibiotics are indicated, although throat culture or RADT may be performed for a score of 1. Other factors should be considered, such as recent family contact with documented streptococcal infection, which would lower the threshold for testing and/or treatment.
For a score of 2 or 3, the risk for GABHS pharyngitis is 11% to 18% (score 2) up to 28% to 35% (score 3), and throat culture or RADT should be performed and antibiotics given if culture results are positive.
For a score of 4 or more, the risk for GABHS pharyngitis is 51% to 53%, and empiric treatment with antibiotics should be considered.
"Although GABHS pharyngitis is common, the ideal approach to management remains a matter of debate," the review authors write. "U.S. guidelines differ in whether they recommend using clinical prediction models versus diagnostic testing. Several international guidelines recommend not testing for or treating GABHS pharyngitis at all."
Complications of GABHS pharyngitis may be either suppurative or nonsuppurative. The suppurative complications may include bacteremia, cervical lymphadenitis, endocarditis, mastoiditis, meningitis, otitis media, peritonsillar or retropharyngeal abscess, and/or pneumonia. Nonsuppurative complications may include poststreptococcal glomerulonephritis or rheumatic fever.
The treatment of choice for streptococcal pharyngitis is penicillin (10 days of oral treatment or 1 injection of intramuscular benzathine penicillin) because of cost, narrow spectrum of activity, and efficacy. However, amoxicillin tastes better and is equally effective. In patients with penicillin allergy, reasonable options are erythromycin and first-generation cephalosporins.
There have been reports of increased GABHS treatment failure with penicillin. Therefore, some guidelines recommend use of cephalosporins in all nonallergic patients, and not just in persons with penicillin allergy, because of improved eradication of GABHS and greater efficacy against chronic carriage of GABHS.
Despite appropriate antibiotic treatment, chronic GABHS colonization is common. There is generally no need to treat chronic carriers because they are thought to be at low risk of transmitting disease or developing invasive GABHS infections.
Persons or situations in which antibiotic treatment of chronic GABHS colonization may be appropriate include recurrent GABHS infection within a family; personal history of or close contact with a person with acute rheumatic fever or acute poststreptococcal glomerulonephritis; close contact with a person with group A streptococcal infection; community outbreak of acute rheumatic fever, poststreptococcal glomerulonephritis, or invasive group A streptococcal infection; healthcare workers or patients in hospitals, chronic care facilities, or nursing homes; families who cannot be reassured without antibiotic treatment; and children who are at risk for tonsillectomy for repeated GABHS pharyngitis.
It is still unclear whether tonsillectomy or adenoidectomy reduces the incidence of GABHS pharyngitis, but the potential benefits are thought to be too small to outweigh the associated costs and surgical risks.
Specific clinical recommendations for practice, and their accompanying level of evidence rating, are as follows:
* Use of clinical decision rules to diagnose GABHS pharyngitis is associated with better quality of care, less unnecessary treatment, and lower overall cost (level of evidence, A).
* In persons who are not penicillin-allergic, penicillin is the treatment of choice for GABHS pharyngitis (level of evidence, A).
* Chronic carriers of pharyngeal GABHS typically do not require treatment (level of evidence, C).
"Differences in guidelines are best explained by whether emphasis is placed on avoiding inappropriate antibiotic use or on relieving acute GABHS pharyngitis symptoms," the review authors conclude. "Several U.S. guidelines recommend confirmatory throat culture for negative RADT in children and adolescents."
Dr. Choby is an assistant editor of The Core Content Review of Family Medicine.
Am Fam Physician. 2009;79:383-390.
bloeddruk hypertension
Simplified hypertension management strategy proposed
27 March 2009
MedWire News: A simplified antihypertensive treatment algorithm involving an initial low-dose, fixed-dose combination is superior to guideline-based management of uncomplicated hypertension, Canadian researchers have found.
According to the findings, this algorithm is “implementable, changes physician-prescribing patterns, and results in better blood pressure control than conventional guideline-based care,” the team writes in the journal Hypertension.
Ross Feldman (Robarts Research Institute, London, Ontario) and colleagues note that poor patient adherence to multidrug regimens contribute to the well-documented treatment gap in patients with hypertension.
Furthermore, “therapeutic inertia,” whereby practitioners fail to escalate the intensity of therapy despite poorly controlled hypertension, is an issue. “We speculate that the increasingly complex treatment regimens currently advocated by experts, national guidelines, and the pharmaceutical industry might contribute to this undesirable behavior,” they write.
In light of these barriers, they developed the Simplified Treatment Intervention to Control Hypertension (STITCH) – a simple, step-care–based algorithm.
The study included 45 single-physician practices randomly assigned to treat patients according to STITCH care or to usual management of patients according to the Canadian Hypertension Education Program (CHEP) guidelines.
Data for a total of 2104 patients with uncontrolled hypertension treated at these practices were available for analysis, of whom 49% were already being treated at baseline.
Patients assigned to STITCH care were more likely to reach target blood pressure levels, with 64.7% achieving target levels at 6 months compared with 52.7% of those assigned to guideline care (p=0.026).
The STITCH group also had greater reductions in systolic and diastolic blood pressure levels, at means of 22.6 versus 17.5 mmHg (p=0.002) and 10.4 versus 8.2 mmHg (p=0.03), respectively.
The STITCH care patients were prescribed more individual drugs (2.3 vs 1.9 drugs, p<0.001), consistent with greater use of fixed-dose combinations in this group.
They also tended to have fewer standard doses prescribed than in the guideline care group (1.7 versus 2.0, p=0.06), but a greater proportion were uptitrated (82.6% vs 69.6%, p=0.007).
The authors comment that the six-fold increase in use of fixed-dose combination drugs by the STITCH-care physicians in comparison with guideline care practices shows that the implementation process changed physician behavior.
“Furthermore, STITCH-care physicians reported greater satisfaction with their management of hypertension, suggesting that STITCH care is a practicable strategy for use by community physicians,” they write.
MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009
Hypertension 2009; 95: 577–583
27 March 2009
MedWire News: A simplified antihypertensive treatment algorithm involving an initial low-dose, fixed-dose combination is superior to guideline-based management of uncomplicated hypertension, Canadian researchers have found.
According to the findings, this algorithm is “implementable, changes physician-prescribing patterns, and results in better blood pressure control than conventional guideline-based care,” the team writes in the journal Hypertension.
Ross Feldman (Robarts Research Institute, London, Ontario) and colleagues note that poor patient adherence to multidrug regimens contribute to the well-documented treatment gap in patients with hypertension.
Furthermore, “therapeutic inertia,” whereby practitioners fail to escalate the intensity of therapy despite poorly controlled hypertension, is an issue. “We speculate that the increasingly complex treatment regimens currently advocated by experts, national guidelines, and the pharmaceutical industry might contribute to this undesirable behavior,” they write.
In light of these barriers, they developed the Simplified Treatment Intervention to Control Hypertension (STITCH) – a simple, step-care–based algorithm.
The study included 45 single-physician practices randomly assigned to treat patients according to STITCH care or to usual management of patients according to the Canadian Hypertension Education Program (CHEP) guidelines.
Data for a total of 2104 patients with uncontrolled hypertension treated at these practices were available for analysis, of whom 49% were already being treated at baseline.
Patients assigned to STITCH care were more likely to reach target blood pressure levels, with 64.7% achieving target levels at 6 months compared with 52.7% of those assigned to guideline care (p=0.026).
The STITCH group also had greater reductions in systolic and diastolic blood pressure levels, at means of 22.6 versus 17.5 mmHg (p=0.002) and 10.4 versus 8.2 mmHg (p=0.03), respectively.
The STITCH care patients were prescribed more individual drugs (2.3 vs 1.9 drugs, p<0.001), consistent with greater use of fixed-dose combinations in this group.
They also tended to have fewer standard doses prescribed than in the guideline care group (1.7 versus 2.0, p=0.06), but a greater proportion were uptitrated (82.6% vs 69.6%, p=0.007).
The authors comment that the six-fold increase in use of fixed-dose combination drugs by the STITCH-care physicians in comparison with guideline care practices shows that the implementation process changed physician behavior.
“Furthermore, STITCH-care physicians reported greater satisfaction with their management of hypertension, suggesting that STITCH care is a practicable strategy for use by community physicians,” they write.
MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009
Hypertension 2009; 95: 577–583
Saturday, March 21, 2009
bloedverdunners, aspirine
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New Antiplatelet That May Not Up Bleeding: Phase 2 Results Published
from Heartwire — a professional news service of WebMD
Sue Hughes
Information from Industry
The Institute for Advances in Point-of-Care Testing
Keep up with emerging trends in glycemic control, anticoagulation management, and other areas of point-of-care testing, to help reduce costs, enhance the efficacy of healthcare management, and improve patient outcomes.
March 13, 2009 (Durham, North Carolina) — A phase 2 study of the novel antiplatelet drug SCH 530348 (Schering-Plough), suggesting it may be able to reduce ischemic events without increasing bleeding in patients undergoing elective PCI, has now been published in the March 14, 2009, issue of the Lancet [1].
The study was first presented, and reported by heartwire at the time, at the American College of Cardiology (ACC) meeting in 2007, where it was greeted with much excitement over the possibility of a drug that might be able to separate the benefits of platelet inhibition (reduced ischemic events) from the risks (increased bleeding).
Lead author Dr Richard Becker (Duke University, Durham, NC) told heartwire that the Lancet paper contains the same data that were presented at ACC 2007, along with "quite a lot of additional information."
"For example, at the ACC presentation, we focused on the group of patients who actually underwent PCI, which is the set of primary interest, but in the paper we also report on the whole population of patients, including those who received the bolus dose of the drug but who then did not end up undergoing PCI but were managed medically (381 patients) or underwent CABG (76 patients) and so would not have received maintenance doses." He described this as a real-world population that would receive the drug. He added that in the patients managed medically, the bolus dose of SCH 530348 was associated with a very low rate of bleeding and no TIMI major bleeding.
SCH 530348 blocks the protease-activated receptor 1 (PAR-1) on platelets to which thrombin binds, so the drug inhibits thrombin-induced platelet activation. Becker explained why this is thought to be able to separate the reduction in ischemia from the increased bleeding risk seen with other antiplatelet agents. "The theory is that hemostasis is predominantly platelet mediated, whereas thrombosis in the coronary artery is mediated by both platelets and thrombin generation. This drug appears to prevent the ischemic effect of thrombin generation by preventing thrombin from binding to platelets, whereas it still allows thrombin to cleave fibrinogen and form fibrin--the final step in coagulation--and it still allows platelets to aggregate for normal hemostasis. So we are attempting to uncouple the benefit/risk relationship seen with all previous antithrombotic drugs."
Note of Caution--Too Early to Know for Sure
While there clearly is much enthusiasm over this new drug, some experts are being cautious about basing too much on a phase 2 trial. Dr Shamir Mehta (McMaster University, Hamilton, ON) summed such feeling up: "There is no question that the mechanism of action of the drug is novel and the initial results are promising. But remember, this is just a phase 2 study, and we need to wait for phase 3 trials before making definitive statements with regard to efficacy or safety. Often, drugs may initially appear to be favorable but fail to live up to expectations when studied in larger numbers of patients," he commented to heartwire.
A similar view was voiced by Dr Shaun Goodman (St Michael's Hospital, Toronto, ON). He commented to heartwire: "This agent does indeed look promising, and, compared with several other 'antithrombin' therapies we have available at present, its mechanism of action is novel. However, as with all drugs at this stage (phase 2, dose finding), it is too early to tell whether its potential will be realized, and the ongoing phase 3 studies will need to inform us further about both the efficacy 'signal' and safety. Clearly, this phase 2 study was not powered to definitively address either of these, but it is encouraging that the absolute number of major and minor bleeding events (albeit quite low in this population that included patients undergoing non-urgent PCI) was not different from that seen in the placebo group (including in the subset of patients went on to bypass surgery). Since the non-TIMI bleeding rates were consistently numerically higher (although not statistically significant) in the SCH 530348 groups compared with placebo, I suspect there will ultimately be some increased risk of bleeding when you add another antithrombin therapy to standard therapy (eg, aspirin with or without clopidogrel) in this patient population."
Neither Mehta nor Goodman is involved with trials of SCH 530348.
Platelet-Function Tests
Becker noted that the Lancet paper also reported detailed results on platelet-function testing showing that SCH 530348 achieved 90% inhibition of PAR-1 at the lowest maintenance dose (0.5 mg), and this increased to 100% at the two higher maintenance doses. "We decided to go with the highest (2.5-mg) maintenance dose for the phase 3 studies, because the safety results suggested this was still not associated with an increase in bleeding, and we wanted to make sure that the drug was not underdosed in high-risk patients. Our feeling was that if we can induce 100% inhibition of the receptor, we should do it, so this hypothesis can be tested properly."
Two phase 3 studies with the drug are now ongoing. These are TRA-CER in ACS patients, which is being coordinated at Duke and in which SCH 530348 is being given at the 40-mg bolus dose plus a 2.5-mg maintenance dose, and the TRA-2P-TIMI-50 study, which is testing just the 2.5-mg maintenance dose in secondary prevention in patients with prior MI, stroke, or peripheral vascular disease. These two studies are still recruiting, and results are not expected for several years.
Becker explained that he envisages that SCH 530348 would need to be given in addition to aspirin and clopidogrel in patients undergoing PCI and receiving a new stent, especially for the first few weeks, but in secondary-prevention patients aspirin plus SCH 530348 may be all that is needed, because there is less propensity for thrombosis in these patients.
Possible Other Indications
He also pointed out that PAR-1 also occurs on smooth-muscle cells and inflammatory cells, and it is possible that drugs that inhibit this receptor may have other benefits, such as stabilizing plaques and reducing in-stent restenosis. The phase 3 studies under way will include substudies to investigate these effects--by looking at what the drug is doing to other cell types as well as platelets. There are several other PAR-1 blockers in development, and they are being investigated in other areas as well as cardiology. One of these is oncology, because there is some evidence that PAR-1 may be involved in tumor growth and metastases.
The current phase 2 study randomized 1030 patients undergoing coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio. Those in the SCH 530348 group who subsequently underwent PCI were randomly assigned again to one of three maintenance doses (0.5 mg, 1.0 mg, or 2.5 mg per day) for 60 days. The patients assigned to a placebo loading dose remained on placebo during the maintenance phase. Study drug was given on top of all normal drugs (aspirin, clopidogrel, and heparin or bivalirudin). The primary end point was the incidence of clinically significant major or minor bleeding according to the TIMI scale.
Patients who underwent PCI were the primary evaluable cohort. In this group, there was no significant difference in bleeding rates between any of the SCH 530348 doses and placebo. The authors say: "Although the bleeding rates were low overall, we cannot exclude a small to moderate increase in bleeding with SCH 530348."
TIMI Major/Minor Bleeding in PCI Cohort
Placebo (n=151), n (%) SCH all (n=422), n (%) SCH 10 mg load (n=129), n (%) SCH 20 mg load (n=120), n (%) SCH 40 mg load (n=173), n (%) SCH 0.5 mg maintenance (n=136), n (%) SCH 1 mg maintenance (n=139), n (%) SCH 2.5 mg maintenance (n=138), n (%) p*
5 (3) 12 (3) 2 (2) 3 (3) 7 (4) 3 (2) 5 (4) 4 (3) 0.7713
*For difference between all placebo groups combined and all SCH 530348 groups combined
The trial was not powered to specifically test clinical efficacy, but results showed a trend toward fewer ischemic events in SCH-530348–treated patients. The authors add: "The biology around inhibition of thrombin-induced platelet activation provides a mechanistic basis for differences that might be of clinical relevance."
Death/Major Adverse Cardiac Events in PCI Cohort
Placebo (n=151), n (%) SCH all (n=422), n (%) SCH 10-mg load (n=129), n (%) SCH 20-mg load (n=120), n (%) SCH 40-mg load (n=173), n (%)
13 (9) 24 (6) 10 (8) 6 (5) 8 (5)
They conclude: "Our study provides preliminary evidence for the feasibility and safety of thrombin-receptor inhibition among patients with coronary artery disease undergoing PCI."
In an accompanying editorial [2], Drs Alessandro Colombo and Piera Merlini (Luigi Sacco Hospital and Niguarda Hospital, Milano, Italy) say that the current study suggests that SCH 530348 is safe, a conclusion strengthened by its being used with two other antiplatelet agents. They add: "This clinical report of a new antithrombotic drug developed on the basis of new knowledge about the coagulation cascade suggests that the drug works. Is the dream of an effective antithrombotic drug with a low bleeding risk becoming reality? Will this approach be effective in the acute setting (eg, primary percutaneous coronary intervention) and even in secondary prevention? Phase 3 trials will determine whether we are entering a new antithrombotic era."
Becker receives research funding from Schering-Plough. Other coauthors have received honoraria, research funding, and consulting fees from Schering-Plough or are employees of Schering-Plough. One author owns stock and stock options in Schering-Plough.
1. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomized, double-blind, placebo-controlled phase II study. Lancet 2009; 373:919–928.
2. Colombo A and Merlini P. The ischaemia/bleeding balance in PCI. Lancet 2009; 373:872-873.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
* Email ThisEmail This
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New Antiplatelet That May Not Up Bleeding: Phase 2 Results Published
from Heartwire — a professional news service of WebMD
Sue Hughes
Information from Industry
The Institute for Advances in Point-of-Care Testing
Keep up with emerging trends in glycemic control, anticoagulation management, and other areas of point-of-care testing, to help reduce costs, enhance the efficacy of healthcare management, and improve patient outcomes.
March 13, 2009 (Durham, North Carolina) — A phase 2 study of the novel antiplatelet drug SCH 530348 (Schering-Plough), suggesting it may be able to reduce ischemic events without increasing bleeding in patients undergoing elective PCI, has now been published in the March 14, 2009, issue of the Lancet [1].
The study was first presented, and reported by heartwire at the time, at the American College of Cardiology (ACC) meeting in 2007, where it was greeted with much excitement over the possibility of a drug that might be able to separate the benefits of platelet inhibition (reduced ischemic events) from the risks (increased bleeding).
Lead author Dr Richard Becker (Duke University, Durham, NC) told heartwire that the Lancet paper contains the same data that were presented at ACC 2007, along with "quite a lot of additional information."
"For example, at the ACC presentation, we focused on the group of patients who actually underwent PCI, which is the set of primary interest, but in the paper we also report on the whole population of patients, including those who received the bolus dose of the drug but who then did not end up undergoing PCI but were managed medically (381 patients) or underwent CABG (76 patients) and so would not have received maintenance doses." He described this as a real-world population that would receive the drug. He added that in the patients managed medically, the bolus dose of SCH 530348 was associated with a very low rate of bleeding and no TIMI major bleeding.
SCH 530348 blocks the protease-activated receptor 1 (PAR-1) on platelets to which thrombin binds, so the drug inhibits thrombin-induced platelet activation. Becker explained why this is thought to be able to separate the reduction in ischemia from the increased bleeding risk seen with other antiplatelet agents. "The theory is that hemostasis is predominantly platelet mediated, whereas thrombosis in the coronary artery is mediated by both platelets and thrombin generation. This drug appears to prevent the ischemic effect of thrombin generation by preventing thrombin from binding to platelets, whereas it still allows thrombin to cleave fibrinogen and form fibrin--the final step in coagulation--and it still allows platelets to aggregate for normal hemostasis. So we are attempting to uncouple the benefit/risk relationship seen with all previous antithrombotic drugs."
Note of Caution--Too Early to Know for Sure
While there clearly is much enthusiasm over this new drug, some experts are being cautious about basing too much on a phase 2 trial. Dr Shamir Mehta (McMaster University, Hamilton, ON) summed such feeling up: "There is no question that the mechanism of action of the drug is novel and the initial results are promising. But remember, this is just a phase 2 study, and we need to wait for phase 3 trials before making definitive statements with regard to efficacy or safety. Often, drugs may initially appear to be favorable but fail to live up to expectations when studied in larger numbers of patients," he commented to heartwire.
A similar view was voiced by Dr Shaun Goodman (St Michael's Hospital, Toronto, ON). He commented to heartwire: "This agent does indeed look promising, and, compared with several other 'antithrombin' therapies we have available at present, its mechanism of action is novel. However, as with all drugs at this stage (phase 2, dose finding), it is too early to tell whether its potential will be realized, and the ongoing phase 3 studies will need to inform us further about both the efficacy 'signal' and safety. Clearly, this phase 2 study was not powered to definitively address either of these, but it is encouraging that the absolute number of major and minor bleeding events (albeit quite low in this population that included patients undergoing non-urgent PCI) was not different from that seen in the placebo group (including in the subset of patients went on to bypass surgery). Since the non-TIMI bleeding rates were consistently numerically higher (although not statistically significant) in the SCH 530348 groups compared with placebo, I suspect there will ultimately be some increased risk of bleeding when you add another antithrombin therapy to standard therapy (eg, aspirin with or without clopidogrel) in this patient population."
Neither Mehta nor Goodman is involved with trials of SCH 530348.
Platelet-Function Tests
Becker noted that the Lancet paper also reported detailed results on platelet-function testing showing that SCH 530348 achieved 90% inhibition of PAR-1 at the lowest maintenance dose (0.5 mg), and this increased to 100% at the two higher maintenance doses. "We decided to go with the highest (2.5-mg) maintenance dose for the phase 3 studies, because the safety results suggested this was still not associated with an increase in bleeding, and we wanted to make sure that the drug was not underdosed in high-risk patients. Our feeling was that if we can induce 100% inhibition of the receptor, we should do it, so this hypothesis can be tested properly."
Two phase 3 studies with the drug are now ongoing. These are TRA-CER in ACS patients, which is being coordinated at Duke and in which SCH 530348 is being given at the 40-mg bolus dose plus a 2.5-mg maintenance dose, and the TRA-2P-TIMI-50 study, which is testing just the 2.5-mg maintenance dose in secondary prevention in patients with prior MI, stroke, or peripheral vascular disease. These two studies are still recruiting, and results are not expected for several years.
Becker explained that he envisages that SCH 530348 would need to be given in addition to aspirin and clopidogrel in patients undergoing PCI and receiving a new stent, especially for the first few weeks, but in secondary-prevention patients aspirin plus SCH 530348 may be all that is needed, because there is less propensity for thrombosis in these patients.
Possible Other Indications
He also pointed out that PAR-1 also occurs on smooth-muscle cells and inflammatory cells, and it is possible that drugs that inhibit this receptor may have other benefits, such as stabilizing plaques and reducing in-stent restenosis. The phase 3 studies under way will include substudies to investigate these effects--by looking at what the drug is doing to other cell types as well as platelets. There are several other PAR-1 blockers in development, and they are being investigated in other areas as well as cardiology. One of these is oncology, because there is some evidence that PAR-1 may be involved in tumor growth and metastases.
The current phase 2 study randomized 1030 patients undergoing coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio. Those in the SCH 530348 group who subsequently underwent PCI were randomly assigned again to one of three maintenance doses (0.5 mg, 1.0 mg, or 2.5 mg per day) for 60 days. The patients assigned to a placebo loading dose remained on placebo during the maintenance phase. Study drug was given on top of all normal drugs (aspirin, clopidogrel, and heparin or bivalirudin). The primary end point was the incidence of clinically significant major or minor bleeding according to the TIMI scale.
Patients who underwent PCI were the primary evaluable cohort. In this group, there was no significant difference in bleeding rates between any of the SCH 530348 doses and placebo. The authors say: "Although the bleeding rates were low overall, we cannot exclude a small to moderate increase in bleeding with SCH 530348."
TIMI Major/Minor Bleeding in PCI Cohort
Placebo (n=151), n (%) SCH all (n=422), n (%) SCH 10 mg load (n=129), n (%) SCH 20 mg load (n=120), n (%) SCH 40 mg load (n=173), n (%) SCH 0.5 mg maintenance (n=136), n (%) SCH 1 mg maintenance (n=139), n (%) SCH 2.5 mg maintenance (n=138), n (%) p*
5 (3) 12 (3) 2 (2) 3 (3) 7 (4) 3 (2) 5 (4) 4 (3) 0.7713
*For difference between all placebo groups combined and all SCH 530348 groups combined
The trial was not powered to specifically test clinical efficacy, but results showed a trend toward fewer ischemic events in SCH-530348–treated patients. The authors add: "The biology around inhibition of thrombin-induced platelet activation provides a mechanistic basis for differences that might be of clinical relevance."
Death/Major Adverse Cardiac Events in PCI Cohort
Placebo (n=151), n (%) SCH all (n=422), n (%) SCH 10-mg load (n=129), n (%) SCH 20-mg load (n=120), n (%) SCH 40-mg load (n=173), n (%)
13 (9) 24 (6) 10 (8) 6 (5) 8 (5)
They conclude: "Our study provides preliminary evidence for the feasibility and safety of thrombin-receptor inhibition among patients with coronary artery disease undergoing PCI."
In an accompanying editorial [2], Drs Alessandro Colombo and Piera Merlini (Luigi Sacco Hospital and Niguarda Hospital, Milano, Italy) say that the current study suggests that SCH 530348 is safe, a conclusion strengthened by its being used with two other antiplatelet agents. They add: "This clinical report of a new antithrombotic drug developed on the basis of new knowledge about the coagulation cascade suggests that the drug works. Is the dream of an effective antithrombotic drug with a low bleeding risk becoming reality? Will this approach be effective in the acute setting (eg, primary percutaneous coronary intervention) and even in secondary prevention? Phase 3 trials will determine whether we are entering a new antithrombotic era."
Becker receives research funding from Schering-Plough. Other coauthors have received honoraria, research funding, and consulting fees from Schering-Plough or are employees of Schering-Plough. One author owns stock and stock options in Schering-Plough.
1. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomized, double-blind, placebo-controlled phase II study. Lancet 2009; 373:919–928.
2. Colombo A and Merlini P. The ischaemia/bleeding balance in PCI. Lancet 2009; 373:872-873.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
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Combination antihypertensive therapy beats doubling monotherapy dose
20 March 2009
MedWire News: Blood pressure (BP) reduction from combining drugs from different classes can be predicted on the basis of additive effects, and is approximately five times greater than doubling the dose of a single drug, a study indicates.
Effectiveness of low-dose drug combinations as initial treatment for BP reduction relies on the effects of the combined drugs being additive.
To examine the evidence for this, a team from the London Queen Mary’s School of Medicine and Dentistry, UK, led by David Wald, conducted a meta-analysis of 42 factorial trials involving 10,968 participants in which combinations of any two of thiazides, beta-blockers, ACE inhibitors (ACEIs), and calcium channel blockers (CCBs) were tested against each drug given alone and placebo.
With thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mmHg, and 14.6 mmHg combined with a drug from another class. The corresponding reductions were 9.3 mmHg and 18.9 mmHg with beta-blocker, 6.8 mmHg and 13.9 mmHg with ACEI, and 8.4 mmHg and 14.3 mmHg with CCB.
The expected blood pressure reduction from two drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from one drug were, respectively, for thiazides, beta-blockers, ACEIs, and CCBs: 1.04, 1.00, 1.16, and 0.89. The overall average was 1.01.
Comparison of results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of one drug had approximately one fifth of the equivalent incremental effect (0.22).
Writing in the American Medical Journal, the researchers conclude: “The results leave little doubt over the advantages of adopting low-dose combination blood pressure-lowering treatment as routine initial therapy for all, instead of a monotherapy and stepped-care approach.”
They also note: “Low-dose therapy has the advantage of reducing adverse effects that… are strongly dose related… Using more than two drugs in combination also would increase efficacy”.
MedWire is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009
Am J Med 2009; 122: 290–300
Text size
News quick search
Cardiovascular news provides daily news updates to help you stay informed.
Combination antihypertensive therapy beats doubling monotherapy dose
20 March 2009
MedWire News: Blood pressure (BP) reduction from combining drugs from different classes can be predicted on the basis of additive effects, and is approximately five times greater than doubling the dose of a single drug, a study indicates.
Effectiveness of low-dose drug combinations as initial treatment for BP reduction relies on the effects of the combined drugs being additive.
To examine the evidence for this, a team from the London Queen Mary’s School of Medicine and Dentistry, UK, led by David Wald, conducted a meta-analysis of 42 factorial trials involving 10,968 participants in which combinations of any two of thiazides, beta-blockers, ACE inhibitors (ACEIs), and calcium channel blockers (CCBs) were tested against each drug given alone and placebo.
With thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mmHg, and 14.6 mmHg combined with a drug from another class. The corresponding reductions were 9.3 mmHg and 18.9 mmHg with beta-blocker, 6.8 mmHg and 13.9 mmHg with ACEI, and 8.4 mmHg and 14.3 mmHg with CCB.
The expected blood pressure reduction from two drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from one drug were, respectively, for thiazides, beta-blockers, ACEIs, and CCBs: 1.04, 1.00, 1.16, and 0.89. The overall average was 1.01.
Comparison of results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of one drug had approximately one fifth of the equivalent incremental effect (0.22).
Writing in the American Medical Journal, the researchers conclude: “The results leave little doubt over the advantages of adopting low-dose combination blood pressure-lowering treatment as routine initial therapy for all, instead of a monotherapy and stepped-care approach.”
They also note: “Low-dose therapy has the advantage of reducing adverse effects that… are strongly dose related… Using more than two drugs in combination also would increase efficacy”.
MedWire is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009
Am J Med 2009; 122: 290–300
Friday, March 20, 2009
cholesterol statines
Free Full-Text Article
Summary and Comment
Treatment-Mediated Change in HDL Cholesterol Levels and CHD Risks
Lowering LDL levels yielded benefit; raising HDL levels did not.
High-density lipoprotein (HDL) cholesterol level is associated independently and inversely with coronary heart disease risk. Nevertheless, evidence that treatment-mediated increases in HDL cholesterol levels lower CHD risk is lacking. In this analysis of 108 randomized trials, involving nearly 300,000 patients, investigators assessed whether treatment-mediated changes in HDL cholesterol levels are associated with all-cause death, CHD-related death, and adverse CHD events (CHD-related death and nonfatal myocardial infarction).
All but five trials involved lipid-modifying drugs. After adjustment for changes in low-density lipoprotein (LDL) cholesterol levels related to treatment and drug class, no associations were noted between treatment-mediated changes in HDL cholesterol levels and all-cause death, CHD-related death, or adverse CHD events. However, after adjustments for changes in HDL cholesterol levels and drug class, treatment-mediated changes in LDL cholesterol levels were associated with significant outcomes: For a 10 mg/dL reduction in LDL cholesterol level, relative risks were lowered for all-cause death by 4.4%, for CHD-related death by 7.2%, and for adverse CHD events by 7.1%.
Comment: In this analysis, no association was found between treatment-mediated increases in HDL cholesterol level and CHD-related morbidity and mortality. However, the overall mean treatment-mediated HDL increase was small (4%) compared with the LDL reduction (16%). As a result, the authors acknowledge that detecting a benefit associated with HDL-raising therapy might have been hindered. Nevertheless, the results affirm that lowering LDL cholesterol levels should be the goal of lipid-modifying treatments.
— Paul S. Mueller, MD, MPH, FACP
Published in Journal Watch General Medicine March 19, 2009
Citation(s):
Briel M et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: Systematic review and meta-regression analysis. BMJ 2009 Feb 16; 338:b92. (http://dx.doi.org/10.1136/bmj.b92)
Original article (Subscription may be required)
Medline abstract (Free)
Summary and Comment
Treatment-Mediated Change in HDL Cholesterol Levels and CHD Risks
Lowering LDL levels yielded benefit; raising HDL levels did not.
High-density lipoprotein (HDL) cholesterol level is associated independently and inversely with coronary heart disease risk. Nevertheless, evidence that treatment-mediated increases in HDL cholesterol levels lower CHD risk is lacking. In this analysis of 108 randomized trials, involving nearly 300,000 patients, investigators assessed whether treatment-mediated changes in HDL cholesterol levels are associated with all-cause death, CHD-related death, and adverse CHD events (CHD-related death and nonfatal myocardial infarction).
All but five trials involved lipid-modifying drugs. After adjustment for changes in low-density lipoprotein (LDL) cholesterol levels related to treatment and drug class, no associations were noted between treatment-mediated changes in HDL cholesterol levels and all-cause death, CHD-related death, or adverse CHD events. However, after adjustments for changes in HDL cholesterol levels and drug class, treatment-mediated changes in LDL cholesterol levels were associated with significant outcomes: For a 10 mg/dL reduction in LDL cholesterol level, relative risks were lowered for all-cause death by 4.4%, for CHD-related death by 7.2%, and for adverse CHD events by 7.1%.
Comment: In this analysis, no association was found between treatment-mediated increases in HDL cholesterol level and CHD-related morbidity and mortality. However, the overall mean treatment-mediated HDL increase was small (4%) compared with the LDL reduction (16%). As a result, the authors acknowledge that detecting a benefit associated with HDL-raising therapy might have been hindered. Nevertheless, the results affirm that lowering LDL cholesterol levels should be the goal of lipid-modifying treatments.
— Paul S. Mueller, MD, MPH, FACP
Published in Journal Watch General Medicine March 19, 2009
Citation(s):
Briel M et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: Systematic review and meta-regression analysis. BMJ 2009 Feb 16; 338:b92. (http://dx.doi.org/10.1136/bmj.b92)
Original article (Subscription may be required)
Medline abstract (Free)
Thursday, March 19, 2009
PPI
SUMMARY AND COMMENT
Pantoprazole vs. Ranitidine for Prevention of Peptic Ulcer Rebleeding
March 6, 2009 | David J. Bjorkman, MD, MSPH (HSA), SM (Epid.) | Gastroenterology
Rebleeding outcomes were similar with either medication.
Reviewing: van Rensburg C et al. Aliment Pharmacol Ther 2009 Mar 1; 29:497
Pantoprazole vs. Ranitidine for Prevention of Peptic Ulcer Rebleeding
March 6, 2009 | David J. Bjorkman, MD, MSPH (HSA), SM (Epid.) | Gastroenterology
Rebleeding outcomes were similar with either medication.
Reviewing: van Rensburg C et al. Aliment Pharmacol Ther 2009 Mar 1; 29:497
race difference
Original Article
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Volume 360:1179-1190 March 19, 2009 Number 12
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Racial Differences in Incident Heart Failure among Young Adults
Kirsten Bibbins-Domingo, Ph.D., M.D., Mark J. Pletcher, M.D., M.P.H., Feng Lin, M.S., Eric Vittinghoff, Ph.D., Julius M. Gardin, M.D., Alexander Arynchyn, M.D., Cora E. Lewis, M.D., O. Dale Williams, Ph.D., and Stephen B. Hulley, M.D., M.P.H.
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Background The antecedents and epidemiology of heart failure in young adults are poorly understood.
Methods We prospectively assessed the incidence of heart failure over a 20-year period among 5115 blacks and whites of both sexes who were 18 to 30 years of age at baseline. Using Cox models, we examined predictors of hospitalization or death from heart failure.
Results Over the course of 20 years, heart failure developed in 27 participants (mean [±SD] age at onset, 39±6 years), all but 1 of whom were black. The cumulative incidence of heart failure before the age of 50 years was 1.1% (95% confidence interval [CI], 0.6 to 1.7) in black women, 0.9% (95% CI, 0.5 to 1.4) in black men, 0.08% (95% CI, 0.0 to 0.5) in white women, and 0% (95% CI, 0 to 0.4) in white men (P=0.001 for the comparison of black participants and white participants). Among blacks, independent predictors at 18 to 30 years of age of heart failure occurring 15 years, on average, later included higher diastolic blood pressure (hazard ratio per 10.0 mm Hg, 2.1; 95% CI, 1.4 to 3.1), higher body-mass index (the weight in kilograms divided by the square of the height in meters) (hazard ratio per 5.7 units, 1.4; 95% CI, 1.0 to 1.9), lower high-density lipoprotein cholesterol (hazard ratio per 13.3 mg per deciliter [0.34 mmol per liter], 0.6; 95% CI, 0.4 to 1.0), and kidney disease (hazard ratio, 19.8; 95% CI, 4.5 to 87.2). Three quarters of those in whom heart failure subsequently developed had hypertension by the time they were 40 years of age. Depressed systolic function, as assessed on a study echocardiogram when the participants were 23 to 35 years of age, was independently associated with the development of heart failure 10 years, on average, later (hazard ratio for abnormal systolic function, 36.9; 95% CI, 6.9 to 198.3; hazard ratio for borderline systolic function, 3.5; 95% CI, 1.2 to 10.2). Myocardial infarction, drug use, and alcohol use were not associated with the risk of heart failure.
Conclusions Incident heart failure before 50 years of age is substantially more common among blacks than among whites. Hypertension, obesity, and systolic dysfunction that are present before a person is 35 years of age are important antecedents that may be targets for the prevention of heart failure. (ClinicalTrials.gov number, NCT00005130 [ClinicalTrials.gov] .)
Source Information
From the Departments of Medicine (K.B.-D., M.J.P.) and Epidemiology and Biostatistics (K.B.-D., M.J.P., F.L., E.V., S.B.H.) and the Division of General Internal Medicine and the UCSF Center for Vulnerable Populations, San Francisco General Hospital (K.B.-D.), University of California, San Francisco, San Francisco; the Department of Medicine, Hackensack University Medical Center, Hackensack, NJ (J.M.G.); and the Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham (A.A., C.E.L., O.D.W.).
Full Text of this Article
This article has been cited by other articles:
* (2009). Does Race Affect Risk for Early Heart Failure?. Journal Watch Cardiology 2009: 2-2 [Full Text]
PreviousPrevious
Volume 360:1179-1190 March 19, 2009 Number 12
NextNext
Racial Differences in Incident Heart Failure among Young Adults
Kirsten Bibbins-Domingo, Ph.D., M.D., Mark J. Pletcher, M.D., M.P.H., Feng Lin, M.S., Eric Vittinghoff, Ph.D., Julius M. Gardin, M.D., Alexander Arynchyn, M.D., Cora E. Lewis, M.D., O. Dale Williams, Ph.D., and Stephen B. Hulley, M.D., M.P.H.
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Background The antecedents and epidemiology of heart failure in young adults are poorly understood.
Methods We prospectively assessed the incidence of heart failure over a 20-year period among 5115 blacks and whites of both sexes who were 18 to 30 years of age at baseline. Using Cox models, we examined predictors of hospitalization or death from heart failure.
Results Over the course of 20 years, heart failure developed in 27 participants (mean [±SD] age at onset, 39±6 years), all but 1 of whom were black. The cumulative incidence of heart failure before the age of 50 years was 1.1% (95% confidence interval [CI], 0.6 to 1.7) in black women, 0.9% (95% CI, 0.5 to 1.4) in black men, 0.08% (95% CI, 0.0 to 0.5) in white women, and 0% (95% CI, 0 to 0.4) in white men (P=0.001 for the comparison of black participants and white participants). Among blacks, independent predictors at 18 to 30 years of age of heart failure occurring 15 years, on average, later included higher diastolic blood pressure (hazard ratio per 10.0 mm Hg, 2.1; 95% CI, 1.4 to 3.1), higher body-mass index (the weight in kilograms divided by the square of the height in meters) (hazard ratio per 5.7 units, 1.4; 95% CI, 1.0 to 1.9), lower high-density lipoprotein cholesterol (hazard ratio per 13.3 mg per deciliter [0.34 mmol per liter], 0.6; 95% CI, 0.4 to 1.0), and kidney disease (hazard ratio, 19.8; 95% CI, 4.5 to 87.2). Three quarters of those in whom heart failure subsequently developed had hypertension by the time they were 40 years of age. Depressed systolic function, as assessed on a study echocardiogram when the participants were 23 to 35 years of age, was independently associated with the development of heart failure 10 years, on average, later (hazard ratio for abnormal systolic function, 36.9; 95% CI, 6.9 to 198.3; hazard ratio for borderline systolic function, 3.5; 95% CI, 1.2 to 10.2). Myocardial infarction, drug use, and alcohol use were not associated with the risk of heart failure.
Conclusions Incident heart failure before 50 years of age is substantially more common among blacks than among whites. Hypertension, obesity, and systolic dysfunction that are present before a person is 35 years of age are important antecedents that may be targets for the prevention of heart failure. (ClinicalTrials.gov number, NCT00005130 [ClinicalTrials.gov] .)
Source Information
From the Departments of Medicine (K.B.-D., M.J.P.) and Epidemiology and Biostatistics (K.B.-D., M.J.P., F.L., E.V., S.B.H.) and the Division of General Internal Medicine and the UCSF Center for Vulnerable Populations, San Francisco General Hospital (K.B.-D.), University of California, San Francisco, San Francisco; the Department of Medicine, Hackensack University Medical Center, Hackensack, NJ (J.M.G.); and the Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham (A.A., C.E.L., O.D.W.).
Full Text of this Article
This article has been cited by other articles:
* (2009). Does Race Affect Risk for Early Heart Failure?. Journal Watch Cardiology 2009: 2-2 [Full Text]
Original Article
PreviousPrevious
Volume 360:1179-1190 March 19, 2009 Number 12
NextNext
Racial Differences in Incident Heart Failure among Young Adults
Kirsten Bibbins-Domingo, Ph.D., M.D., Mark J. Pletcher, M.D., M.P.H., Feng Lin, M.S., Eric Vittinghoff, Ph.D., Julius M. Gardin, M.D., Alexander Arynchyn, M.D., Cora E. Lewis, M.D., O. Dale Williams, Ph.D., and Stephen B. Hulley, M.D., M.P.H.
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More Information
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ABSTRACT
Background The antecedents and epidemiology of heart failure in young adults are poorly understood.
Methods We prospectively assessed the incidence of heart failure over a 20-year period among 5115 blacks and whites of both sexes who were 18 to 30 years of age at baseline. Using Cox models, we examined predictors of hospitalization or death from heart failure.
Results Over the course of 20 years, heart failure developed in 27 participants (mean [±SD] age at onset, 39±6 years), all but 1 of whom were black. The cumulative incidence of heart failure before the age of 50 years was 1.1% (95% confidence interval [CI], 0.6 to 1.7) in black women, 0.9% (95% CI, 0.5 to 1.4) in black men, 0.08% (95% CI, 0.0 to 0.5) in white women, and 0% (95% CI, 0 to 0.4) in white men (P=0.001 for the comparison of black participants and white participants). Among blacks, independent predictors at 18 to 30 years of age of heart failure occurring 15 years, on average, later included higher diastolic blood pressure (hazard ratio per 10.0 mm Hg, 2.1; 95% CI, 1.4 to 3.1), higher body-mass index (the weight in kilograms divided by the square of the height in meters) (hazard ratio per 5.7 units, 1.4; 95% CI, 1.0 to 1.9), lower high-density lipoprotein cholesterol (hazard ratio per 13.3 mg per deciliter [0.34 mmol per liter], 0.6; 95% CI, 0.4 to 1.0), and kidney disease (hazard ratio, 19.8; 95% CI, 4.5 to 87.2). Three quarters of those in whom heart failure subsequently developed had hypertension by the time they were 40 years of age. Depressed systolic function, as assessed on a study echocardiogram when the participants were 23 to 35 years of age, was independently associated with the development of heart failure 10 years, on average, later (hazard ratio for abnormal systolic function, 36.9; 95% CI, 6.9 to 198.3; hazard ratio for borderline systolic function, 3.5; 95% CI, 1.2 to 10.2). Myocardial infarction, drug use, and alcohol use were not associated with the risk of heart failure.
Conclusions Incident heart failure before 50 years of age is substantially more common among blacks than among whites. Hypertension, obesity, and systolic dysfunction that are present before a person is 35 years of age are important antecedents that may be targets for the prevention of heart failure. (ClinicalTrials.gov number, NCT00005130 [ClinicalTrials.gov] .)
Source Information
From the Departments of Medicine (K.B.-D., M.J.P.) and Epidemiology and Biostatistics (K.B.-D., M.J.P., F.L., E.V., S.B.H.) and the Division of General Internal Medicine and the UCSF Center for Vulnerable Populations, San Francisco General Hospital (K.B.-D.), University of California, San Francisco, San Francisco; the Department of Medicine, Hackensack University Medical Center, Hackensack, NJ (J.M.G.); and the Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham (A.A., C.E.L., O.D.W.).
Full Text of this Article
This article has been cited by other articles:
* (2009). Does Race Affect Risk for Early Heart Failure?. Journal Watch Cardiology 2009: 2-2 [Full Text]
PreviousPrevious
Volume 360:1179-1190 March 19, 2009 Number 12
NextNext
Racial Differences in Incident Heart Failure among Young Adults
Kirsten Bibbins-Domingo, Ph.D., M.D., Mark J. Pletcher, M.D., M.P.H., Feng Lin, M.S., Eric Vittinghoff, Ph.D., Julius M. Gardin, M.D., Alexander Arynchyn, M.D., Cora E. Lewis, M.D., O. Dale Williams, Ph.D., and Stephen B. Hulley, M.D., M.P.H.
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This Article
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- Purchase this article
Commentary
- Perspective
by Peterson, E.
Tools and Services
- Add to Personal Archive
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More Information
- PubMed Citation
ABSTRACT
Background The antecedents and epidemiology of heart failure in young adults are poorly understood.
Methods We prospectively assessed the incidence of heart failure over a 20-year period among 5115 blacks and whites of both sexes who were 18 to 30 years of age at baseline. Using Cox models, we examined predictors of hospitalization or death from heart failure.
Results Over the course of 20 years, heart failure developed in 27 participants (mean [±SD] age at onset, 39±6 years), all but 1 of whom were black. The cumulative incidence of heart failure before the age of 50 years was 1.1% (95% confidence interval [CI], 0.6 to 1.7) in black women, 0.9% (95% CI, 0.5 to 1.4) in black men, 0.08% (95% CI, 0.0 to 0.5) in white women, and 0% (95% CI, 0 to 0.4) in white men (P=0.001 for the comparison of black participants and white participants). Among blacks, independent predictors at 18 to 30 years of age of heart failure occurring 15 years, on average, later included higher diastolic blood pressure (hazard ratio per 10.0 mm Hg, 2.1; 95% CI, 1.4 to 3.1), higher body-mass index (the weight in kilograms divided by the square of the height in meters) (hazard ratio per 5.7 units, 1.4; 95% CI, 1.0 to 1.9), lower high-density lipoprotein cholesterol (hazard ratio per 13.3 mg per deciliter [0.34 mmol per liter], 0.6; 95% CI, 0.4 to 1.0), and kidney disease (hazard ratio, 19.8; 95% CI, 4.5 to 87.2). Three quarters of those in whom heart failure subsequently developed had hypertension by the time they were 40 years of age. Depressed systolic function, as assessed on a study echocardiogram when the participants were 23 to 35 years of age, was independently associated with the development of heart failure 10 years, on average, later (hazard ratio for abnormal systolic function, 36.9; 95% CI, 6.9 to 198.3; hazard ratio for borderline systolic function, 3.5; 95% CI, 1.2 to 10.2). Myocardial infarction, drug use, and alcohol use were not associated with the risk of heart failure.
Conclusions Incident heart failure before 50 years of age is substantially more common among blacks than among whites. Hypertension, obesity, and systolic dysfunction that are present before a person is 35 years of age are important antecedents that may be targets for the prevention of heart failure. (ClinicalTrials.gov number, NCT00005130 [ClinicalTrials.gov] .)
Source Information
From the Departments of Medicine (K.B.-D., M.J.P.) and Epidemiology and Biostatistics (K.B.-D., M.J.P., F.L., E.V., S.B.H.) and the Division of General Internal Medicine and the UCSF Center for Vulnerable Populations, San Francisco General Hospital (K.B.-D.), University of California, San Francisco, San Francisco; the Department of Medicine, Hackensack University Medical Center, Hackensack, NJ (J.M.G.); and the Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham (A.A., C.E.L., O.D.W.).
Full Text of this Article
This article has been cited by other articles:
* (2009). Does Race Affect Risk for Early Heart Failure?. Journal Watch Cardiology 2009: 2-2 [Full Text]
race difference
SUMMARY AND COMMENT
Does Race Affect Risk for Early Heart Failure?
March 18, 2009 | Harlan M. Krumholz, MD, SM
Findings from the CARDIA study reveal a much higher incidence of heart failure in young blacks than in young whites.
Reviewing: Bibbins-Domingo K et al. N Engl J Med 2009 Mar 19; 360:1179
Peterson E and Yancy CW. N Engl J Med 2009 Mar 19; 360:1172
Does Race Affect Risk for Early Heart Failure?
March 18, 2009 | Harlan M. Krumholz, MD, SM
Findings from the CARDIA study reveal a much higher incidence of heart failure in young blacks than in young whites.
Reviewing: Bibbins-Domingo K et al. N Engl J Med 2009 Mar 19; 360:1179
Peterson E and Yancy CW. N Engl J Med 2009 Mar 19; 360:1172
Wednesday, March 18, 2009
statines triglycerides
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Ask the Experts about Triglycerides in Cardiovascular Disease
What Are the Effects of Statins on Triglycerides and What Are the Results of Major Outcomes Studies?
Michael Miller, MD, FACC, FAHA
Medscape Family Medicine. 2009; ©2009 Medscape
Posted 03/12/2009
Question
What are the effects of statins on triglycerides and what are the results of major outcomes studies?
Response from Michael Miller, MD, FACC, FAHA
Associate Professor of Medicine, Epidemiology, and Preventive Medicine; Director, Center for Preventive Cardiology, Division of Cardiology, University of Maryland Medical Center, Baltimore, Maryland
Although the most prominent effects attributable to statin therapy are its potent low-density lipoprotein cholesterol (LDL-C) lowering properties, it is also well established that statins significantly reduce non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides (TG), and biomarkers of inflammation, most notably C-reactive protein (CRP). Overall, statins reduce TG levels in the range of 10% to 20% ( Table ), although it has been acknowledged that the higher the baseline TG level, the greater the TG-lowering effect. For example, baseline TG levels exceeding 250 mg/dL have been associated with reductions in the range of 22% to 45%, whereas more modest reductions have been observed with lower baseline levels.[1] This can be best identified in randomized, placebo-controlled trials ( Table ). In these outcome studies, the TG cutpoint for study exclusion has generally been 350 mg/dL to 400 mg/dL because higher levels have been viewed as a basis for pharmacologic (eg, nonstatin) treatment. Therefore, it is not surprising that, with few exceptions, the baseline TG in clinical outcome trials that evaluate statin therapy is customarily in the 100 to 200 mg/dL range, with a corresponding TG-lowering effect between 10% and 20%.[2-11] Although no relationship was observed between major coronary heart disease (CHD) events and on-treatment TG in one clinical trial of patients with CHD and high LDL-C,[12] another trial in patients with acute coronary syndrome demonstrated that lower on-treatment TG correlated with reduced CHD events.[13] Therefore, ongoing and future clinical trials will provide additional insight into the relationship between statin (monotherapy and/or combination) therapy, TG lowering, and CHD risk.
This activity is supported by an independent educational grant from GlaxoSmithKline.
Submit a Question on Effects of Statins on Triglycerides
Table. Effect of Statins vs Placebo on Triglyceride Levels in 10 Primary and Secondary Placebo-Controlled Outcome Trials
Trial Statin dose (mg) Baseline TG* TG-Lowering Effect Ref
4s Simvastatin 10-40 132 (mean) 10%† [2]
WOSCOPS Pravastatin 40 162 (mean) 12%†‡ [3]
CARE Pravastatin 40 156 (mean) 14%‡ [4]
LIPID Pravastatin 40 142 (median) 11%‡ [5]
PROSPER Pravastatin 40 133 (mean) 13%‡ [6]
AFCAPS Lovastatin 20-40 158§ (median) 13%‡ [7]
ASCOT Atorvastatin 10 150 (mean) 14%‡ [8]
CARDS Atorvastatin 10 173 (mean) 19%‡ [9]
HPS Simvastatin 40 186§ (mean) 14%║ [10]
JUPITER Rosuvastatin 20 118 (median) 17%‡ [11]
AFCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT = Anglo Scandinavian Cardiac Outcome Trial; CARDS = Collaborative AtoRvastatin Diabetes Study; CARE = Cholesterol and Recurrent Events Study; HPS = Heart Protection Study; JUPITER = Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LIPID = Long-Term Intervention with Pravastatin in Ischemic Disease; PROSPER = Prospective Study of Pravastatin in the Elderly at Risk; TG = triglyceride; 4s = Scandinavian Simvastatin Survival Study; WOSCOPS = West of Scotland Coronary Prevention Study
* Baseline represents the mean or median TG level of the treatment group at the start of each study, except where noted.
† Compared with baseline
‡ Compared with placebo
§ For all randomized patients
║ Estimated using value for all randomized patients for baseline.
References
1. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol. 1998;81:66B-69B. Abstract
2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389. Abstract
3. Shepherd J, Cobbe S, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307. Abstract
4. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001-1009. Abstract
5. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357. Abstract
6. Shepherd J, Blauw G, Murphy M, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623-1630. Abstract
7. Downs J, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622. Abstract
8. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158. Abstract
9. Colhoun H, Betteridge D, Durrington P, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696. Abstract
10. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. Abstract
11. Ridker PM, Danielson E, Fonseca FA, et al.; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207. Abstract
12. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97:1453-1460. Abstract
13. Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E; PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724-730. Abstract
Michael Miller, MD, FACC, FAHA, Associate Professor of Medicine, Epidemiology, and Preventive Medicine; Director, Center for Preventive Cardiology, Division of Cardiology, University of Maryland Medical Center, Baltimore, Maryland
Disclosure: Michael Miller, MD, FACC, FAHA, has disclosed that he has received grants for clinical research from Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Merck & Co., Inc./Schering-Plough Corporation, Pfizer Inc., and Roche Laboratories Inc. Dr. Miller has also disclosed that he has served as an advisor or consultant to GlaxoSmithKline and Roche Laboratories.
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Ask the Experts about Triglycerides in Cardiovascular Disease
What Are the Effects of Statins on Triglycerides and What Are the Results of Major Outcomes Studies?
Michael Miller, MD, FACC, FAHA
Medscape Family Medicine. 2009; ©2009 Medscape
Posted 03/12/2009
Question
What are the effects of statins on triglycerides and what are the results of major outcomes studies?
Response from Michael Miller, MD, FACC, FAHA
Associate Professor of Medicine, Epidemiology, and Preventive Medicine; Director, Center for Preventive Cardiology, Division of Cardiology, University of Maryland Medical Center, Baltimore, Maryland
Although the most prominent effects attributable to statin therapy are its potent low-density lipoprotein cholesterol (LDL-C) lowering properties, it is also well established that statins significantly reduce non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides (TG), and biomarkers of inflammation, most notably C-reactive protein (CRP). Overall, statins reduce TG levels in the range of 10% to 20% ( Table ), although it has been acknowledged that the higher the baseline TG level, the greater the TG-lowering effect. For example, baseline TG levels exceeding 250 mg/dL have been associated with reductions in the range of 22% to 45%, whereas more modest reductions have been observed with lower baseline levels.[1] This can be best identified in randomized, placebo-controlled trials ( Table ). In these outcome studies, the TG cutpoint for study exclusion has generally been 350 mg/dL to 400 mg/dL because higher levels have been viewed as a basis for pharmacologic (eg, nonstatin) treatment. Therefore, it is not surprising that, with few exceptions, the baseline TG in clinical outcome trials that evaluate statin therapy is customarily in the 100 to 200 mg/dL range, with a corresponding TG-lowering effect between 10% and 20%.[2-11] Although no relationship was observed between major coronary heart disease (CHD) events and on-treatment TG in one clinical trial of patients with CHD and high LDL-C,[12] another trial in patients with acute coronary syndrome demonstrated that lower on-treatment TG correlated with reduced CHD events.[13] Therefore, ongoing and future clinical trials will provide additional insight into the relationship between statin (monotherapy and/or combination) therapy, TG lowering, and CHD risk.
This activity is supported by an independent educational grant from GlaxoSmithKline.
Submit a Question on Effects of Statins on Triglycerides
Table. Effect of Statins vs Placebo on Triglyceride Levels in 10 Primary and Secondary Placebo-Controlled Outcome Trials
Trial Statin dose (mg) Baseline TG* TG-Lowering Effect Ref
4s Simvastatin 10-40 132 (mean) 10%† [2]
WOSCOPS Pravastatin 40 162 (mean) 12%†‡ [3]
CARE Pravastatin 40 156 (mean) 14%‡ [4]
LIPID Pravastatin 40 142 (median) 11%‡ [5]
PROSPER Pravastatin 40 133 (mean) 13%‡ [6]
AFCAPS Lovastatin 20-40 158§ (median) 13%‡ [7]
ASCOT Atorvastatin 10 150 (mean) 14%‡ [8]
CARDS Atorvastatin 10 173 (mean) 19%‡ [9]
HPS Simvastatin 40 186§ (mean) 14%║ [10]
JUPITER Rosuvastatin 20 118 (median) 17%‡ [11]
AFCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT = Anglo Scandinavian Cardiac Outcome Trial; CARDS = Collaborative AtoRvastatin Diabetes Study; CARE = Cholesterol and Recurrent Events Study; HPS = Heart Protection Study; JUPITER = Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LIPID = Long-Term Intervention with Pravastatin in Ischemic Disease; PROSPER = Prospective Study of Pravastatin in the Elderly at Risk; TG = triglyceride; 4s = Scandinavian Simvastatin Survival Study; WOSCOPS = West of Scotland Coronary Prevention Study
* Baseline represents the mean or median TG level of the treatment group at the start of each study, except where noted.
† Compared with baseline
‡ Compared with placebo
§ For all randomized patients
║ Estimated using value for all randomized patients for baseline.
References
1. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol. 1998;81:66B-69B. Abstract
2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389. Abstract
3. Shepherd J, Cobbe S, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307. Abstract
4. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001-1009. Abstract
5. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357. Abstract
6. Shepherd J, Blauw G, Murphy M, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623-1630. Abstract
7. Downs J, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622. Abstract
8. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158. Abstract
9. Colhoun H, Betteridge D, Durrington P, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696. Abstract
10. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. Abstract
11. Ridker PM, Danielson E, Fonseca FA, et al.; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207. Abstract
12. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97:1453-1460. Abstract
13. Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E; PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724-730. Abstract
Michael Miller, MD, FACC, FAHA, Associate Professor of Medicine, Epidemiology, and Preventive Medicine; Director, Center for Preventive Cardiology, Division of Cardiology, University of Maryland Medical Center, Baltimore, Maryland
Disclosure: Michael Miller, MD, FACC, FAHA, has disclosed that he has received grants for clinical research from Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Merck & Co., Inc./Schering-Plough Corporation, Pfizer Inc., and Roche Laboratories Inc. Dr. Miller has also disclosed that he has served as an advisor or consultant to GlaxoSmithKline and Roche Laboratories.
statines
Ask the Experts about Pharmacotherapy
How Low Is Too Low for Suppressing the Lipid Profile With Statins?
Jodi H. Walker, BS, PharmD, BCPS
Medscape Pharmacists. 2009; ©2009 Medscape
Posted 03/06/2009
Question
Target levels of LDL cholesterol keep going down, but should we use higher doses of statins to achieve those goals?
Response from Jodi H. Walker, BS, PharmD, BCPS
Adjunct Faculty, Albany College of Pharmacy, Albany, New York; Clinical Pharmacy Specialist, VA Medical Center, Bath, New York
Although hyperlipidemia is a modifiable cardiovascular disease (CVD) risk factor, about 40 million American adults are at high risk due to total cholesterol levels of 240 mg/dL or higher.[1,2] The most recent guidelines, issued by the Third National Cholesterol Educational Program Adult Treatment Panel (NCEP ATP III), identified low-density lipoprotein cholesterol (LDL-C) as the prime target for lipid intervention to prevent CVD, with optimal LDL-C levels being below 100 mg/dL.[3] An optional goal of 70 mg/dL was proposed for those at very high risk for atherosclerosis.[4]
Hydroxymethylglutaryl- coenzyme A (HMG-CoA) reductase inhibitors, otherwise known as "statins," have been found to be the most effective means for lowering LDL-C. Recent studies have shown a clear reduction in clinical events in patients treated with high doses of statins to lower the LDL-C well below the target goals.
A recent study, called The Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22), evaluated the safety and efficacy of intensive statin therapy (atorvastatin 80 mg daily) on LDL-C levels in patients after acute coronary syndrome.[5] Results were divided by 4-month LDL-C values into groups: > 100, > 80 to 100, > 60 to 80, > 40 to 60, and < 40 mg/dL. Among 1825 patients, the < 40 mg/dL and 40-60 mg/dL groups had fewer major cardiac events. Compared with patients whose LDL-C goal was 80-100 mg/dL, lower LDL-C levels did not cause increased adverse effects. Patients with lower LDL-C had fewer cardiac events but no significant difference in overall mortality.
The Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial evaluated the effect of LDL-C levels 80 mg/dL or below in patients with a history of known heart disease treated with intensive atorvastatin therapy. Overall cardiac events were reduced by 17% in the study patients compared with usual care. Risk for nonfatal myocardial infarction was reduced by 47%.[6] This study, along with PROVE IT - TIMI 2, demonstrated the superior benefit of LDL-C lowering below current guidelines in high-risk patients.
Statin doses should be no higher than needed to prevent or minimize adverse effects. The debate, however, continues over what is the "magic" LDL-C number, and how low is too low? The goal line seems to keep moving, yet it remains controversial as to when the benefits stop. Some of the benefits of statin use may also be due to anti-inflammatory properties. Greater reductions in C-reactive protein, a marker associated with inflammation, and LDL-C values due to intensive statin treatment may be related to a slower progression of atherosclerosis compared with moderate statin therapy in patients with coronary artery disease.[7]
Although lower LDL-C reduces cardiovascular risk, the risks for liver enzyme elevations and muscle damage must be taken into consideration based on the dose of the statin used. It is well documented that higher statin doses can promote higher rates of elevated liver enzymes. However, no significant relationship between elevated liver enzymes or rhabdomyolysis and the degree of LDL-C reduction exists. Lower LDL-C may be associated with an increased risk of cancer, which may offset the cardiovascular benefits of low LDL-C.[8]
Overall, statins are very safe and the benefits are significant both in elderly and younger patients.[9] A recent study found that statin use was not associated with an increase in malignancy, liver enzymes, or rhabdomyolysis. In addition, LDL-C levels as low as 40 mg/dL appeared safe and improved survival.[4]
The safety implication rests in how the LDL-C level is lowered. Although there is no limit to how low the LDL-C should be, thought should be given to the possibility of using multiple drugs at moderate doses instead of maximizing the statin dosage and risking side effects. Combination therapy can often achieve the goal LDL-C.
Submit a Question on Pharmacotherapy
How Low Is Too Low for Suppressing the Lipid Profile With Statins?
Jodi H. Walker, BS, PharmD, BCPS
Medscape Pharmacists. 2009; ©2009 Medscape
Posted 03/06/2009
Question
Target levels of LDL cholesterol keep going down, but should we use higher doses of statins to achieve those goals?
Response from Jodi H. Walker, BS, PharmD, BCPS
Adjunct Faculty, Albany College of Pharmacy, Albany, New York; Clinical Pharmacy Specialist, VA Medical Center, Bath, New York
Although hyperlipidemia is a modifiable cardiovascular disease (CVD) risk factor, about 40 million American adults are at high risk due to total cholesterol levels of 240 mg/dL or higher.[1,2] The most recent guidelines, issued by the Third National Cholesterol Educational Program Adult Treatment Panel (NCEP ATP III), identified low-density lipoprotein cholesterol (LDL-C) as the prime target for lipid intervention to prevent CVD, with optimal LDL-C levels being below 100 mg/dL.[3] An optional goal of 70 mg/dL was proposed for those at very high risk for atherosclerosis.[4]
Hydroxymethylglutaryl- coenzyme A (HMG-CoA) reductase inhibitors, otherwise known as "statins," have been found to be the most effective means for lowering LDL-C. Recent studies have shown a clear reduction in clinical events in patients treated with high doses of statins to lower the LDL-C well below the target goals.
A recent study, called The Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22), evaluated the safety and efficacy of intensive statin therapy (atorvastatin 80 mg daily) on LDL-C levels in patients after acute coronary syndrome.[5] Results were divided by 4-month LDL-C values into groups: > 100, > 80 to 100, > 60 to 80, > 40 to 60, and < 40 mg/dL. Among 1825 patients, the < 40 mg/dL and 40-60 mg/dL groups had fewer major cardiac events. Compared with patients whose LDL-C goal was 80-100 mg/dL, lower LDL-C levels did not cause increased adverse effects. Patients with lower LDL-C had fewer cardiac events but no significant difference in overall mortality.
The Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial evaluated the effect of LDL-C levels 80 mg/dL or below in patients with a history of known heart disease treated with intensive atorvastatin therapy. Overall cardiac events were reduced by 17% in the study patients compared with usual care. Risk for nonfatal myocardial infarction was reduced by 47%.[6] This study, along with PROVE IT - TIMI 2, demonstrated the superior benefit of LDL-C lowering below current guidelines in high-risk patients.
Statin doses should be no higher than needed to prevent or minimize adverse effects. The debate, however, continues over what is the "magic" LDL-C number, and how low is too low? The goal line seems to keep moving, yet it remains controversial as to when the benefits stop. Some of the benefits of statin use may also be due to anti-inflammatory properties. Greater reductions in C-reactive protein, a marker associated with inflammation, and LDL-C values due to intensive statin treatment may be related to a slower progression of atherosclerosis compared with moderate statin therapy in patients with coronary artery disease.[7]
Although lower LDL-C reduces cardiovascular risk, the risks for liver enzyme elevations and muscle damage must be taken into consideration based on the dose of the statin used. It is well documented that higher statin doses can promote higher rates of elevated liver enzymes. However, no significant relationship between elevated liver enzymes or rhabdomyolysis and the degree of LDL-C reduction exists. Lower LDL-C may be associated with an increased risk of cancer, which may offset the cardiovascular benefits of low LDL-C.[8]
Overall, statins are very safe and the benefits are significant both in elderly and younger patients.[9] A recent study found that statin use was not associated with an increase in malignancy, liver enzymes, or rhabdomyolysis. In addition, LDL-C levels as low as 40 mg/dL appeared safe and improved survival.[4]
The safety implication rests in how the LDL-C level is lowered. Although there is no limit to how low the LDL-C should be, thought should be given to the possibility of using multiple drugs at moderate doses instead of maximizing the statin dosage and risking side effects. Combination therapy can often achieve the goal LDL-C.
Submit a Question on Pharmacotherapy
hart aspirine en clopidogrel
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IN THIS ARTICLE
* Abstract and Introduction
* Indications for Combination Therapy
* Benefits of Long-Term Use of Combination Therapy
* Bleeding Risks with Combination Therapy
* Conclusions
* Tables
* References
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From Journal of the American Board of Family Medicine
An Appraisal of Dual Antiplatelet Therapy with Clopidogrel and Aspirin for Prevention of Cardiovascular Events
Posted 03/10/2009
Chris Terpening, PhD, PharmD
Author Information
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Abstract and Introduction
Abstract
Combination antiplatelet therapy, typically with clopidogrel and aspirin, is commonly used for the prevention of cardiovascular events. When used for appropriate indications and duration, its benefits clearly outweigh its risks. However, it is not uncommon for the combination to be used outside of recommended indications or for longer than recommended durations. In these circumstances data are at best unclear and, at worst, indicative of harm. Furthermore, use for one of its indications—prevention of cardiac events after deployment of a coronary stent—is complicated by the type of stent used. This report reviews the evidence surrounding combination antiplatelet therapy with clopidogrel and aspirin, with an emphasis on identifying appropriate indications for and durations of therapy.
Introduction
Primary care physicians (PCPs) often find themselves in the situation in which a patient's cardiologist institutes therapy with clopidogrel in combination with low-dose aspirin, but then defers routine follow-up back to the PCP. This combination offers certain theoretical benefits. Platelet activation is a critical step in the formation of thrombotic clots. Aspirin inhibits the production of thromboxanes, which play a prominent role in platelet activation. Clopidogrel, a thienopyridine, acts by inhibiting adenosine receptors, which play a major role at a different step in platelet activation. Thus, their mechanisms are complementary and may decrease clot formation over either agent alone. Furthermore, resistance to the effects of each agent has been well reported,[1] but resistance to both agents in a given patient should be less frequent. Although this combination of antiplatelet agents has been demonstrated to offer clinical benefits under certain circumstances, it does raise problems as well. Most significantly, the reiterative platelet inhibition increases the likelihood of bleeding. Thus, it is incumbent on the PCP to understand the evidence behind the use of combination therapy and the point at which potential benefits may be offset by its risks. Only then can the PCP make an informed decision about when to return the patient to monotherapy with antiplatelets. Unfortunately, although the literature on this combination of agents is extensive, data regarding the benefits and risks of long-term use are often conflicting. Newer thienopyridines, such as prasugrel, seem to offer both greater benefit and greater risk and may confuse the situation further.[2] This article will outline what is known and make reasonable recommendations for the PCP.
Section 1 of 5
Next Page: Indications for Combination Therapy
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References
1. Gladding P, Webster M, Ormiston J, Olsen S, White H. Antiplatelet drug nonresponsiveness. Am Heart J 2008;155:591–9.
2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15.
3. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherosclerotic events. N Engl J Med 2006;354: 1706–17.
4. Fraker TD Jr, Fihn SD, Gibbons RJ. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 2007;116:2762–72.
5. Diener H-C, Bogousllovsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331–7.
6. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179–89.
7. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607–21.
8. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, writing on behalf of the 2004 Writing Committee. Circulation 2008;117: 296–329.
9. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502.
10. Bertrand ME, Rupprecht H-J, Urban P, Gershlick AH, CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624 –9.
11. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA 2002;288:2411–20.
12. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33.
13. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007;116:745–54.
14. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293):2126 –30.
15. Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007; 27:1500–10.
16. Lagerqvist B, James SK, Stenestrand U, et al. Longterm outcomes with drug-eluting stents versus baremetal stents in Sweden. N Engl J Med 2007;356: 1009–19.
17. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trial comparing sirolimus-eluting stents with baremetal stents. N Engl J Med 2007;356:1030 –9.
18. Grines CL, Bonow RO, Casey DE Jr, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115: 813–8.
19. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drugeluting stent implantation. JAMA 2007;297:159–68.
20. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369:667–78.
21. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral areterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:1982– 8.
22. Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006;333:726 –30.
23. Delaney JA, Opatrny L, Brophy JM, Suissa S. Drugdrug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 2007;177:347–51.
24. Verheugt FW, Clappers N. Incidence of severe bleeding with long-term clopidogrel-aspirin combination: comparison with chronic warfarin therapy [abstract]. Circulation 2007;116(suppl II):441.
25. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. J Am Board Fam Pract 2004;17:59–67.
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Chris Terpening, PhD, PharmD, from the Departments of Family Medicine and Clinical Pharmacy, West Virginia University, Charleston Division
J Am Board Fam Med. 2009;22(1):51-56. ©2009 American Board of Family Medicine
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IN THIS ARTICLE
* Abstract and Introduction
* Indications for Combination Therapy
* Benefits of Long-Term Use of Combination Therapy
* Bleeding Risks with Combination Therapy
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From Journal of the American Board of Family Medicine
An Appraisal of Dual Antiplatelet Therapy with Clopidogrel and Aspirin for Prevention of Cardiovascular Events
Posted 03/10/2009
Chris Terpening, PhD, PharmD
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Abstract and Introduction
Abstract
Combination antiplatelet therapy, typically with clopidogrel and aspirin, is commonly used for the prevention of cardiovascular events. When used for appropriate indications and duration, its benefits clearly outweigh its risks. However, it is not uncommon for the combination to be used outside of recommended indications or for longer than recommended durations. In these circumstances data are at best unclear and, at worst, indicative of harm. Furthermore, use for one of its indications—prevention of cardiac events after deployment of a coronary stent—is complicated by the type of stent used. This report reviews the evidence surrounding combination antiplatelet therapy with clopidogrel and aspirin, with an emphasis on identifying appropriate indications for and durations of therapy.
Introduction
Primary care physicians (PCPs) often find themselves in the situation in which a patient's cardiologist institutes therapy with clopidogrel in combination with low-dose aspirin, but then defers routine follow-up back to the PCP. This combination offers certain theoretical benefits. Platelet activation is a critical step in the formation of thrombotic clots. Aspirin inhibits the production of thromboxanes, which play a prominent role in platelet activation. Clopidogrel, a thienopyridine, acts by inhibiting adenosine receptors, which play a major role at a different step in platelet activation. Thus, their mechanisms are complementary and may decrease clot formation over either agent alone. Furthermore, resistance to the effects of each agent has been well reported,[1] but resistance to both agents in a given patient should be less frequent. Although this combination of antiplatelet agents has been demonstrated to offer clinical benefits under certain circumstances, it does raise problems as well. Most significantly, the reiterative platelet inhibition increases the likelihood of bleeding. Thus, it is incumbent on the PCP to understand the evidence behind the use of combination therapy and the point at which potential benefits may be offset by its risks. Only then can the PCP make an informed decision about when to return the patient to monotherapy with antiplatelets. Unfortunately, although the literature on this combination of agents is extensive, data regarding the benefits and risks of long-term use are often conflicting. Newer thienopyridines, such as prasugrel, seem to offer both greater benefit and greater risk and may confuse the situation further.[2] This article will outline what is known and make reasonable recommendations for the PCP.
Section 1 of 5
Next Page: Indications for Combination Therapy
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References
1. Gladding P, Webster M, Ormiston J, Olsen S, White H. Antiplatelet drug nonresponsiveness. Am Heart J 2008;155:591–9.
2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15.
3. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherosclerotic events. N Engl J Med 2006;354: 1706–17.
4. Fraker TD Jr, Fihn SD, Gibbons RJ. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 2007;116:2762–72.
5. Diener H-C, Bogousllovsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331–7.
6. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179–89.
7. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607–21.
8. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, writing on behalf of the 2004 Writing Committee. Circulation 2008;117: 296–329.
9. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502.
10. Bertrand ME, Rupprecht H-J, Urban P, Gershlick AH, CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624 –9.
11. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA 2002;288:2411–20.
12. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33.
13. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007;116:745–54.
14. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293):2126 –30.
15. Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007; 27:1500–10.
16. Lagerqvist B, James SK, Stenestrand U, et al. Longterm outcomes with drug-eluting stents versus baremetal stents in Sweden. N Engl J Med 2007;356: 1009–19.
17. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trial comparing sirolimus-eluting stents with baremetal stents. N Engl J Med 2007;356:1030 –9.
18. Grines CL, Bonow RO, Casey DE Jr, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115: 813–8.
19. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drugeluting stent implantation. JAMA 2007;297:159–68.
20. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369:667–78.
21. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral areterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:1982– 8.
22. Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006;333:726 –30.
23. Delaney JA, Opatrny L, Brophy JM, Suissa S. Drugdrug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 2007;177:347–51.
24. Verheugt FW, Clappers N. Incidence of severe bleeding with long-term clopidogrel-aspirin combination: comparison with chronic warfarin therapy [abstract]. Circulation 2007;116(suppl II):441.
25. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. J Am Board Fam Pract 2004;17:59–67.
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stroke, hersen infarct
Free Full-Text Article
Summary and Comment
Health-Related Behaviors and Stroke Risk
Stroke prevention involves not only treating risk factors, but also encouraging patients to embrace health-related behaviors.
Health-enhancing behaviors, such as exercising regularly and eating a diet rich in fruits and vegetables, can reduce risk for stroke. In this prospective, population-based study, U.K. investigators assessed the potential combined effect of four behaviors — not smoking, regular physical activity, moderate alcohol intake (1–14 drinks weekly), and high fruit and vegetable intake (based on high plasma vitamin C levels) — on risk for stroke in 20,000 men and women (age range, 40–79) without histories of stroke or myocardial infarction.
During an average follow-up of 11.5 years, 599 strokes occurred; 168 were fatal. Compared with people who engaged in all four health-related behaviors (and adjusted for numerous demographic and clinical variables), the relative risk for stroke was nonsignificantly higher for people who engaged in three behaviors (RR, 1.2) and significantly higher for those who engaged in two behaviors (RR, 1.6), one behavior (RR, 2.2), and none of the behaviors (RR, 2.3). Results were similar when stratified by age, sex, BMI, and social class.
Comment: Based on these results, the authors appropriately conclude that a combination of "relatively modest and achievable" health-related behaviors can substantially reduce risk for stroke in adults. Indeed, the study’s take-home message is that stroke prevention involves not only treating risk factors, but also encouraging patients to embrace health-related behaviors.
— Bruce Soloway, MD
Published in Journal Watch General Medicine March 17, 2009
Citation(s):
Myint PK et al. Combined effect of health behaviours and risk of first ever stroke in 20 040 men and women over 11 years’ follow-up in Norfolk cohort of European Prospective Investigation of Cancer (EPIC Norfolk): Prospective population study. BMJ 2009 Feb 19; 338:b349. (http://dx.doi.org/10.1136/bmj.b349)
Original article (Subscription may be required)
Medline abstract (Free)
Summary and Comment
Health-Related Behaviors and Stroke Risk
Stroke prevention involves not only treating risk factors, but also encouraging patients to embrace health-related behaviors.
Health-enhancing behaviors, such as exercising regularly and eating a diet rich in fruits and vegetables, can reduce risk for stroke. In this prospective, population-based study, U.K. investigators assessed the potential combined effect of four behaviors — not smoking, regular physical activity, moderate alcohol intake (1–14 drinks weekly), and high fruit and vegetable intake (based on high plasma vitamin C levels) — on risk for stroke in 20,000 men and women (age range, 40–79) without histories of stroke or myocardial infarction.
During an average follow-up of 11.5 years, 599 strokes occurred; 168 were fatal. Compared with people who engaged in all four health-related behaviors (and adjusted for numerous demographic and clinical variables), the relative risk for stroke was nonsignificantly higher for people who engaged in three behaviors (RR, 1.2) and significantly higher for those who engaged in two behaviors (RR, 1.6), one behavior (RR, 2.2), and none of the behaviors (RR, 2.3). Results were similar when stratified by age, sex, BMI, and social class.
Comment: Based on these results, the authors appropriately conclude that a combination of "relatively modest and achievable" health-related behaviors can substantially reduce risk for stroke in adults. Indeed, the study’s take-home message is that stroke prevention involves not only treating risk factors, but also encouraging patients to embrace health-related behaviors.
— Bruce Soloway, MD
Published in Journal Watch General Medicine March 17, 2009
Citation(s):
Myint PK et al. Combined effect of health behaviours and risk of first ever stroke in 20 040 men and women over 11 years’ follow-up in Norfolk cohort of European Prospective Investigation of Cancer (EPIC Norfolk): Prospective population study. BMJ 2009 Feb 19; 338:b349. (http://dx.doi.org/10.1136/bmj.b349)
Original article (Subscription may be required)
Medline abstract (Free)
Monday, March 16, 2009
statins
from Heartwire — a professional news service of WebMD
February 20, 2008 — A study published this week provides a little more evidence that the benefit of statins extends beyond their ability to lower low-density lipoprotein (LDL) cholesterol levels [1]. In a new meta-analysis, investigators showed that the use of statins was significantly associated with a decreased risk of incidence or recurrence of atrial fibrillation (AF) in patients in sinus rhythm with a history of previous AF, those undergoing cardiac surgery, or those prescribed the drugs after an acute coronary syndrome (ACS).
In a paper published in the February 18, 2008 issue of the Journal of the American College of Cardiology, a special issue focusing on AF, Dr Laurent Fauchier (Centre Hospitalier Universitaire Trousseau, Tours, France) and colleagues note that the "beneficial effect seemed more marked in the prevention of AF recurrence than in primary prevention of AF" but cautioned against making too much of this finding as there was only a trend of benefit in these patients.
The meta-analysis included six studies with approximately 3500 patients in sinus rhythm. Three studies investigated the use of statins in patients with a history of paroxysmal AF or persistent AF undergoing electrical cardioversion, while the others investigated the use of statins in primary prevention of AF in patients undergoing cardiac surgery or following ACS. The follow-up in the six trials ranged from three to 26 weeks, and in five of the six studies, atorvastatin was the statin prescribed.
Treatment with a statin reduced the incidence and recurrence of AF 61% compared with placebo. While there were trends toward significance in primary- and secondary-prevention subset analyses, none of these reductions were statistically significant. The overall results were similar when investigators excluded the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, which was published only in abstract form. They note that the protective benefit of statins did not appear to be related to dose, as individual odds ratios were similar in the studies that used atorvastatin 40 mg and 80 mg to studies that used lower doses.
Effect of statins on the occurrence of AF
End point Odds ratio (95% CI)
All AF 0.39 (0.18 - 0.85)
Primary prevention of AF
(postoperative or new-onset AF) 0.60 (0.27 - 1.37)
AF recurrence 0.33 (0.10 - 1.03)
While the mechanisms of benefit are still unknown, Fauchier and colleagues note that statins reduce inflammation and that inflammation is involved in the "development, recurrence, and persistence of AF." They also note that some evidence suggests an association between AF and enhanced renin angiotensin system (RAS) activity. Other studies have also suggested a link between dyslipidemia and the RAS, and with statins reducing cholesterol levels, the drugs might downregulate the RAS and possibly explain the antiarrhythmic effects observed.
Still, large-scale, prospective, randomized clinical trials are needed to establish whether statins bring a similar benefit to those not part of the patient population in this meta-analysis and to explore whether the drugs might be an appropriate therapeutic option in all subgroups of patients for the management of AF, conclude the authors.
The study authors have disclosed no relevant financial relationships.
Source
1. Fauchier L, Pierre B, de Labriolle A, et al. Antiarrhythmic effect of statin therapy and atrial fibrillation. J Am Coll Cardiol. 2008;51:828-835.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Clinical Context
AF is the most common arrhythmia, and patients undergoing coronary artery bypass graft (CABG) surgery are especially at risk for AF. A prospective, observational study by Mathew and colleagues, which appeared in the April 14, 2004, issue of the Journal of the American Medical Association, examined the incidence and risk factors for AF among 4657 patients undergoing CABG surgery. They found that 32.3% of study participants developed AF, and significant risk factors for AF included advanced age, a history of AF, chronic obstructive pulmonary disease, valvular surgery, and withdrawal of a beta-blocker or an angiotensin-converting enzyme (ACE) inhibitor after surgery. However, postoperative treatment with beta-blockers, ACE inhibitors, potassium supplementation, or nonsteroidal anti-inflammatory drugs reduced the risk for incident AF.
Some studies have suggested that statins might also reduce the risk for incident AF among high-risk individuals. The current meta-analysis addresses this issue.
February 20, 2008 — A study published this week provides a little more evidence that the benefit of statins extends beyond their ability to lower low-density lipoprotein (LDL) cholesterol levels [1]. In a new meta-analysis, investigators showed that the use of statins was significantly associated with a decreased risk of incidence or recurrence of atrial fibrillation (AF) in patients in sinus rhythm with a history of previous AF, those undergoing cardiac surgery, or those prescribed the drugs after an acute coronary syndrome (ACS).
In a paper published in the February 18, 2008 issue of the Journal of the American College of Cardiology, a special issue focusing on AF, Dr Laurent Fauchier (Centre Hospitalier Universitaire Trousseau, Tours, France) and colleagues note that the "beneficial effect seemed more marked in the prevention of AF recurrence than in primary prevention of AF" but cautioned against making too much of this finding as there was only a trend of benefit in these patients.
The meta-analysis included six studies with approximately 3500 patients in sinus rhythm. Three studies investigated the use of statins in patients with a history of paroxysmal AF or persistent AF undergoing electrical cardioversion, while the others investigated the use of statins in primary prevention of AF in patients undergoing cardiac surgery or following ACS. The follow-up in the six trials ranged from three to 26 weeks, and in five of the six studies, atorvastatin was the statin prescribed.
Treatment with a statin reduced the incidence and recurrence of AF 61% compared with placebo. While there were trends toward significance in primary- and secondary-prevention subset analyses, none of these reductions were statistically significant. The overall results were similar when investigators excluded the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, which was published only in abstract form. They note that the protective benefit of statins did not appear to be related to dose, as individual odds ratios were similar in the studies that used atorvastatin 40 mg and 80 mg to studies that used lower doses.
Effect of statins on the occurrence of AF
End point Odds ratio (95% CI)
All AF 0.39 (0.18 - 0.85)
Primary prevention of AF
(postoperative or new-onset AF) 0.60 (0.27 - 1.37)
AF recurrence 0.33 (0.10 - 1.03)
While the mechanisms of benefit are still unknown, Fauchier and colleagues note that statins reduce inflammation and that inflammation is involved in the "development, recurrence, and persistence of AF." They also note that some evidence suggests an association between AF and enhanced renin angiotensin system (RAS) activity. Other studies have also suggested a link between dyslipidemia and the RAS, and with statins reducing cholesterol levels, the drugs might downregulate the RAS and possibly explain the antiarrhythmic effects observed.
Still, large-scale, prospective, randomized clinical trials are needed to establish whether statins bring a similar benefit to those not part of the patient population in this meta-analysis and to explore whether the drugs might be an appropriate therapeutic option in all subgroups of patients for the management of AF, conclude the authors.
The study authors have disclosed no relevant financial relationships.
Source
1. Fauchier L, Pierre B, de Labriolle A, et al. Antiarrhythmic effect of statin therapy and atrial fibrillation. J Am Coll Cardiol. 2008;51:828-835.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Clinical Context
AF is the most common arrhythmia, and patients undergoing coronary artery bypass graft (CABG) surgery are especially at risk for AF. A prospective, observational study by Mathew and colleagues, which appeared in the April 14, 2004, issue of the Journal of the American Medical Association, examined the incidence and risk factors for AF among 4657 patients undergoing CABG surgery. They found that 32.3% of study participants developed AF, and significant risk factors for AF included advanced age, a history of AF, chronic obstructive pulmonary disease, valvular surgery, and withdrawal of a beta-blocker or an angiotensin-converting enzyme (ACE) inhibitor after surgery. However, postoperative treatment with beta-blockers, ACE inhibitors, potassium supplementation, or nonsteroidal anti-inflammatory drugs reduced the risk for incident AF.
Some studies have suggested that statins might also reduce the risk for incident AF among high-risk individuals. The current meta-analysis addresses this issue.
hart aspirine clopidogrel
This study shows that warfarin, aspirin and clopidogrel therapy following coronary stenting results in a significantly increased bleeding risk compared with dual antiplatelet therapy. Whether any modification of this traditional triple therapy would result in similar efficacy, but improved safety, needs further studies.
Previous studies of anticoagulation and concomitant antiplatelet therapy. Orford et al.[7] performed a retrospective study of 65 patients requiring triple therapy. They found a 9.2% incidence of bleeding events, with 3.1% major bleeding episodes. Treatment consisted mainly of stopping either warfarin or antiplatelet therapy. Rubboli et al.[8] performed an international survey of the various antithrombotic regimens following stent implantation in patients requiring chronic anticoagulation therapy. They found a wide spectrum of different regimens ranging from the triple therapy to dual antiplatelet therapy to any permutations in-between, including the addition of one antiplatelet agent to coumadin or replacement of warfarin with low-molecular weight heparin. This study did not report on clinical consequences, such as the bleeding or stent thrombosis rates. The randomized trials to evaluate the optimal post-stent regimen[1-4] consistently reported that the dual antiplatelet therapy resulted in reduced stent thrombosis and adverse cardiac events, as well as reduced bleeding risk compared with warfarin and aspirin therapy. Studies of anticoagulation and concomitant antiplatelet therapy in patients with prosthetic heart valves[9] suggest that antiplatelet therapy does increase the bleeding risk, with a lower dosage of aspirin resulting in less bleeding while providing benefit regarding systemic embolism or mortality. Buresly et al.[10] studied elderly (> 65 years) Canadian patients, who were admitted to Québec hospitals with acute myocardial infarction and whose prescription medications, including aspirin, warfarin and either ticlopidine or clopidogrel, were available from another database. They found the overall risk of bleeding to be 'small' in this population, although the addition of warfarin or thienopyridine to aspirin significantly increased the bleeding risk compared with aspirin alone.
Previous studies of anticoagulation and concomitant antiplatelet therapy. Orford et al.[7] performed a retrospective study of 65 patients requiring triple therapy. They found a 9.2% incidence of bleeding events, with 3.1% major bleeding episodes. Treatment consisted mainly of stopping either warfarin or antiplatelet therapy. Rubboli et al.[8] performed an international survey of the various antithrombotic regimens following stent implantation in patients requiring chronic anticoagulation therapy. They found a wide spectrum of different regimens ranging from the triple therapy to dual antiplatelet therapy to any permutations in-between, including the addition of one antiplatelet agent to coumadin or replacement of warfarin with low-molecular weight heparin. This study did not report on clinical consequences, such as the bleeding or stent thrombosis rates. The randomized trials to evaluate the optimal post-stent regimen[1-4] consistently reported that the dual antiplatelet therapy resulted in reduced stent thrombosis and adverse cardiac events, as well as reduced bleeding risk compared with warfarin and aspirin therapy. Studies of anticoagulation and concomitant antiplatelet therapy in patients with prosthetic heart valves[9] suggest that antiplatelet therapy does increase the bleeding risk, with a lower dosage of aspirin resulting in less bleeding while providing benefit regarding systemic embolism or mortality. Buresly et al.[10] studied elderly (> 65 years) Canadian patients, who were admitted to Québec hospitals with acute myocardial infarction and whose prescription medications, including aspirin, warfarin and either ticlopidine or clopidogrel, were available from another database. They found the overall risk of bleeding to be 'small' in this population, although the addition of warfarin or thienopyridine to aspirin significantly increased the bleeding risk compared with aspirin alone.
Sunday, March 15, 2009
hart charisma study
Original Article NEJM
PreviousPrevious
Volume 354:1706-1717 April 20, 2006 Number 16
NextNext
Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events
Deepak L. Bhatt, M.D., Keith A.A. Fox, M.B., Ch.B., Werner Hacke, M.D., Peter B. Berger, M.D., enzovoort
ABSTRACT
Background Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events.
Methods We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes.
Results The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046).
Conclusions In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817 [ClinicalTrials.gov] .)
PreviousPrevious
Volume 354:1706-1717 April 20, 2006 Number 16
NextNext
Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events
Deepak L. Bhatt, M.D., Keith A.A. Fox, M.B., Ch.B., Werner Hacke, M.D., Peter B. Berger, M.D., enzovoort
ABSTRACT
Background Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events.
Methods We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes.
Results The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046).
Conclusions In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817 [ClinicalTrials.gov] .)
hart plavix-aspirine
March 13, 2006
related story (March 19, 2006):
"Blame The Messenger": Reporting on Plavix and Aspirin
Plavix and Aspirin -- Stent Patients, Don't Stop Taking Your Meds
So you've just had a stent put in and your cardiologist has prescribed aspirin and Plavix (clopidogrel) for a year. And you're watching KARE11-TV in Minneapolis and see a news story, titled "Plavix and Aspirin a Dangerous Combination". This combination doubles the risk of death, says the reporter.
You might try calling your cardiologist to find out why you were given such a dangerous drug combination, but most likely the line is busy because all his/her other patients are calling about the same thing. (We're getting questions as well in our Forum topic on the subject.)
No doubt today doctors across the country are fielding questions from patients -- and the genesis for these reports is the CHARISMA study, presented yesterday at the annual meeting of the American College of Cardiology -- or rather the relatively misleading headlines about that study (some of the articles themselves are a bit clearer, but editors tend to go for attention-grabbing headlines; I call them dreadlines.)
So, first off and most important: if you have a stent, a recent angioplasty, heart attack, been diagnosed with acute coronary syndrome, etc. don't stop taking your Plavix/aspirin combo without discussing it with your doctor!
What has been left out of the scores of news articles I've read this morning is that nothing in this study changes the current indications for patients with Acute Coronary Syndrome, recent heart attack or coronary intervention with balloon or stent. And more importantly, if you have had a stent placed, stopping Plavix and aspirin could be very dangerous!
The combination of Plavix and aspirin has been shown in many studies to be a definite benefit to patients with confirmed vascular disease and premature withdrawal of Plavix, especially for patients with drug-eluting stents, can increase the incidence of stent thrombosis (blood clotting inside the stent). This has been the subject of other studies and a topic I have discussed before.
So the bottom line: the misleading media reports about this study are confusing and could be dangerous to heart patients.
For more on what the study really showed, read on.
CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance) was a study funded by sanofi-aventis and Bristol-Myers Squibb Company, the people who make Plavix. The study was designed to determine if clopidogrel (Plavix) and aspirin together were of benefit as a preventative therapy. The company obviously hoped that the results would be positive -- there's a lot of money to be made if the drug was shown to prevent coronary events. They were disappointed, to say the least.
The patient population was made up of two groups: symptomatic patients with established atherothrombotic disease (80%) and asymptomatic patients -- those with multiple risk factors (high blood pressure, etc.) for atherothrombotic events (20%) but who had not yet experienced the symptoms of vascular disease. The results did show a little benefit (about 1%) in the symptomatic patients, but not enough to warrant prescribing the combination therapy.
The surprise to researchers was that the asymptomatic group (those without actual disease) showed a higher rate of death from cardiovascular causes, from 2.2% in the aspirin only to 3.9% in the combination of aspirin plus Plavix. It is this subset of patients that has generated the headlines. One of the primary investigators for the CHARISMA study, Dr. Deepak Bhatt of the Cleveland Clinic, stated that the results mean that "dual antiplatelet therapy should not be used in patients without a history of established vascular disease. "
So the CHARISMA study is very important. It cautions against prescribing Plavix (clopidogrel) as a preventative therapy, especially when simple aspirin works as well or better. But for patients who already have more advanced disease, to the point where angioplasty has been performed, the dual antiplatelet combination of aspirin and Plavix is a life-saver.
related story (March 19, 2006):
"Blame The Messenger": Reporting on Plavix and Aspirin
Plavix and Aspirin -- Stent Patients, Don't Stop Taking Your Meds
So you've just had a stent put in and your cardiologist has prescribed aspirin and Plavix (clopidogrel) for a year. And you're watching KARE11-TV in Minneapolis and see a news story, titled "Plavix and Aspirin a Dangerous Combination". This combination doubles the risk of death, says the reporter.
You might try calling your cardiologist to find out why you were given such a dangerous drug combination, but most likely the line is busy because all his/her other patients are calling about the same thing. (We're getting questions as well in our Forum topic on the subject.)
No doubt today doctors across the country are fielding questions from patients -- and the genesis for these reports is the CHARISMA study, presented yesterday at the annual meeting of the American College of Cardiology -- or rather the relatively misleading headlines about that study (some of the articles themselves are a bit clearer, but editors tend to go for attention-grabbing headlines; I call them dreadlines.)
So, first off and most important: if you have a stent, a recent angioplasty, heart attack, been diagnosed with acute coronary syndrome, etc. don't stop taking your Plavix/aspirin combo without discussing it with your doctor!
What has been left out of the scores of news articles I've read this morning is that nothing in this study changes the current indications for patients with Acute Coronary Syndrome, recent heart attack or coronary intervention with balloon or stent. And more importantly, if you have had a stent placed, stopping Plavix and aspirin could be very dangerous!
The combination of Plavix and aspirin has been shown in many studies to be a definite benefit to patients with confirmed vascular disease and premature withdrawal of Plavix, especially for patients with drug-eluting stents, can increase the incidence of stent thrombosis (blood clotting inside the stent). This has been the subject of other studies and a topic I have discussed before.
So the bottom line: the misleading media reports about this study are confusing and could be dangerous to heart patients.
For more on what the study really showed, read on.
CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance) was a study funded by sanofi-aventis and Bristol-Myers Squibb Company, the people who make Plavix. The study was designed to determine if clopidogrel (Plavix) and aspirin together were of benefit as a preventative therapy. The company obviously hoped that the results would be positive -- there's a lot of money to be made if the drug was shown to prevent coronary events. They were disappointed, to say the least.
The patient population was made up of two groups: symptomatic patients with established atherothrombotic disease (80%) and asymptomatic patients -- those with multiple risk factors (high blood pressure, etc.) for atherothrombotic events (20%) but who had not yet experienced the symptoms of vascular disease. The results did show a little benefit (about 1%) in the symptomatic patients, but not enough to warrant prescribing the combination therapy.
The surprise to researchers was that the asymptomatic group (those without actual disease) showed a higher rate of death from cardiovascular causes, from 2.2% in the aspirin only to 3.9% in the combination of aspirin plus Plavix. It is this subset of patients that has generated the headlines. One of the primary investigators for the CHARISMA study, Dr. Deepak Bhatt of the Cleveland Clinic, stated that the results mean that "dual antiplatelet therapy should not be used in patients without a history of established vascular disease. "
So the CHARISMA study is very important. It cautions against prescribing Plavix (clopidogrel) as a preventative therapy, especially when simple aspirin works as well or better. But for patients who already have more advanced disease, to the point where angioplasty has been performed, the dual antiplatelet combination of aspirin and Plavix is a life-saver.
Saturday, March 14, 2009
statins and pneumonia
www.medscape.com
To Print: Click your browser's PRINT button.
NOTE: To view the article with Web enhancements, go to:
http://www.medscape.com/viewarticle/588593
Prior Statin Use Is Associated With Improved Outcomes in Community-Acquired Pneumonia. An F1000 Hidden Jewel.
Charles Feldman; Erica Shaddock
F1000 Medicine. 2009; ©2009 Medicine Reports Ltd.
Posted 03/04/2009
Chalmers JD, Singanayagam A, Murray MP, Hill AT
Am J Med 2008 Nov 121(11):1002-1007.e1
Commentary from Charles Feldman with Erica Shaddock
Evidence for the pleiotrophic benefits of statins continues to mount. This recent paper published by Chalmers et al. adds to the growing evidence that the use of statins belongs to all physicians, not just cardiologists, and now it is the turn of the pulmonologist/intensivist to reap the benefits.
Community-acquired pneumonia (CAP) continues to be a leading cause of mortality and morbidity in both the developed and developing world. There has been improvement in outcomes since the introduction of antibiotics in the 1940s; however, 10-20% of patients hospitalised for CAP still require admission to the ICU, with a mortality of 20-50% in these patients.[1,2] With emerging antimicrobial resistance and few new antibiotics in development, any adjunctive treatment that shows benefit could have a significant role to play in the management of this common condition. Chalmers et al. have provided us with a prospective observational study of patients admitted with CAP. The primary outcome was 30-day mortality, with secondary outcomes including the need for mechanical ventilation, inotropic support, development of empyema/parapneumonic effusions and C-reactive protein levels on day 4. Using multivariate logistic regression, patients with prior statin use had lower 30-day mortality (adjusted odds ratio (AOR) 0.46, 95% CI: 0.25-0.85, p=0.01) and developed complicated pneumonia less frequently (AOR 0.44, 95% CI: 0.25-0.76, p=0.0060). Prior statin use was not associated with reduction in requirements for inotropic support or invasive ventilation. Also of interest is that those patients who had previously been prescribed statins had more severe pneumonia, as indicated by a higher Pneumonia Severity Index (PSI) score (PSI 4 compared with PSI 3). This makes the improved outcome seen in those patients with prior statin use even more relevant. It was also found that patients in the statin group had C-reactive protein levels on admission that were lower (median 119mg/L, IQR 46-215) than those of patients prescribed other cardiovascular drugs (176mg/L, IQR 67-290) or no cardiovascular drugs (182mg/L, IQR 66-326), p<0.0001. Statin use was also found to be independently protective against a C-reactive protein that failed to decrease by 50% or more at day 4 (AOR 0.52, 95% CI: 0.30-0.89, p=0.02). The authors were aware of the potential of benefit being due to "healthy user effect" and, therefore, also correlated the outcome for patients taking other cardiovascular drugs (aspirin, beta blockers, ACE inhibitors, and angiotensin II antagonists) that may also have had these benefits, to allow for comparison. Prior use of these drugs was not associated with statistically significant benefit, and, furthermore, prior beta-blocker use was associated with independent higher 30-day mortality and an increased risk for invasive ventilation or inotropic support. This is not the first study to have investigated the effect of prior statin use on pneumonia outcomes. There have been three retrospective studies which showed improved outcome in patients taking statins.[3-5] Another recently published study showed further statin benefit in a large population-based cohort study of 29,900 adults hospitalised with pneumonia in Northern Denmark. Mortality among statin users was shown to be 10.3% versus 15.7% after 30 days and 16.8% versus 22.4% after 90 days, with corresponding adjusted 30- and 90-day mortality rate ratios of 0.69 (95% CI: 0.58-0.82) and 0.75 (0.65-0.86).[6] These positive studies need to be counterbalanced by at least one negative population-based prospective cohort study which showed no reduced mortality or need for admission to the ICU in patients with pneumonia.[7] The exact mechanism of these benefits, should they be real, have not been fully identified, but there is evidence that statins reduce cytokine levels together with other inflammatory markers in cardiac patients,[8] and it is postulated that the improved outcome is due to the anti-inflammatory and immunomodulatory effects of the statins. A number of questions still remain that hopefully will be addressed by ongoing studies, including a consideration of how statins would perform when prescribed for the first time as part of the initial management, together with antibiotics, in patients with CAP.
Faculty of 1000 Medicine Evaluations, Dissents and Author responses for: [Chalmers JD, Singanayagam A, Murray MP, Hill AT. Prior statin use is associated with improved outcomes in community-acquired pneumonia. Am J Med 2008 Nov 121(11):1002-1007.e1]. 2009 Feb 10 www.f1000medicine.com/article/id/1147935/evaluation
References
1. Fine et al. JAMA 1996, 275:134-41.
2. Kaplan et al. Am J Respir Crit Care Med 2002, 165:766-72.
3. Schlienger et al. Pharmacotherapy 2007, 27:325-32.
4. Mortensen et al. Eur Respir J 2008, 31:611-7.
5. Mortensen et al. Respiratory Research 2005, 6:82.
6. Thomsen et al. Arch Intern Med 2008, 168:2081-7.
7. Majumdar et al. BMJ 2006, 333:999.
8. Strandberg et al. Lancet 1999, 353:118-9.
The following article was selected and commented on by these Faculty Members of Faculty of 1000 Medicine:
Charles Feldman with Erica Shaddock, University of the Witwatersrand, South Africa
Competing Interests: No potential interests relevant to this article were reported.
To Print: Click your browser's PRINT button.
NOTE: To view the article with Web enhancements, go to:
http://www.medscape.com/viewarticle/588593
Prior Statin Use Is Associated With Improved Outcomes in Community-Acquired Pneumonia. An F1000 Hidden Jewel.
Charles Feldman; Erica Shaddock
F1000 Medicine. 2009; ©2009 Medicine Reports Ltd.
Posted 03/04/2009
Chalmers JD, Singanayagam A, Murray MP, Hill AT
Am J Med 2008 Nov 121(11):1002-1007.e1
Commentary from Charles Feldman with Erica Shaddock
Evidence for the pleiotrophic benefits of statins continues to mount. This recent paper published by Chalmers et al. adds to the growing evidence that the use of statins belongs to all physicians, not just cardiologists, and now it is the turn of the pulmonologist/intensivist to reap the benefits.
Community-acquired pneumonia (CAP) continues to be a leading cause of mortality and morbidity in both the developed and developing world. There has been improvement in outcomes since the introduction of antibiotics in the 1940s; however, 10-20% of patients hospitalised for CAP still require admission to the ICU, with a mortality of 20-50% in these patients.[1,2] With emerging antimicrobial resistance and few new antibiotics in development, any adjunctive treatment that shows benefit could have a significant role to play in the management of this common condition. Chalmers et al. have provided us with a prospective observational study of patients admitted with CAP. The primary outcome was 30-day mortality, with secondary outcomes including the need for mechanical ventilation, inotropic support, development of empyema/parapneumonic effusions and C-reactive protein levels on day 4. Using multivariate logistic regression, patients with prior statin use had lower 30-day mortality (adjusted odds ratio (AOR) 0.46, 95% CI: 0.25-0.85, p=0.01) and developed complicated pneumonia less frequently (AOR 0.44, 95% CI: 0.25-0.76, p=0.0060). Prior statin use was not associated with reduction in requirements for inotropic support or invasive ventilation. Also of interest is that those patients who had previously been prescribed statins had more severe pneumonia, as indicated by a higher Pneumonia Severity Index (PSI) score (PSI 4 compared with PSI 3). This makes the improved outcome seen in those patients with prior statin use even more relevant. It was also found that patients in the statin group had C-reactive protein levels on admission that were lower (median 119mg/L, IQR 46-215) than those of patients prescribed other cardiovascular drugs (176mg/L, IQR 67-290) or no cardiovascular drugs (182mg/L, IQR 66-326), p<0.0001. Statin use was also found to be independently protective against a C-reactive protein that failed to decrease by 50% or more at day 4 (AOR 0.52, 95% CI: 0.30-0.89, p=0.02). The authors were aware of the potential of benefit being due to "healthy user effect" and, therefore, also correlated the outcome for patients taking other cardiovascular drugs (aspirin, beta blockers, ACE inhibitors, and angiotensin II antagonists) that may also have had these benefits, to allow for comparison. Prior use of these drugs was not associated with statistically significant benefit, and, furthermore, prior beta-blocker use was associated with independent higher 30-day mortality and an increased risk for invasive ventilation or inotropic support. This is not the first study to have investigated the effect of prior statin use on pneumonia outcomes. There have been three retrospective studies which showed improved outcome in patients taking statins.[3-5] Another recently published study showed further statin benefit in a large population-based cohort study of 29,900 adults hospitalised with pneumonia in Northern Denmark. Mortality among statin users was shown to be 10.3% versus 15.7% after 30 days and 16.8% versus 22.4% after 90 days, with corresponding adjusted 30- and 90-day mortality rate ratios of 0.69 (95% CI: 0.58-0.82) and 0.75 (0.65-0.86).[6] These positive studies need to be counterbalanced by at least one negative population-based prospective cohort study which showed no reduced mortality or need for admission to the ICU in patients with pneumonia.[7] The exact mechanism of these benefits, should they be real, have not been fully identified, but there is evidence that statins reduce cytokine levels together with other inflammatory markers in cardiac patients,[8] and it is postulated that the improved outcome is due to the anti-inflammatory and immunomodulatory effects of the statins. A number of questions still remain that hopefully will be addressed by ongoing studies, including a consideration of how statins would perform when prescribed for the first time as part of the initial management, together with antibiotics, in patients with CAP.
Faculty of 1000 Medicine Evaluations, Dissents and Author responses for: [Chalmers JD, Singanayagam A, Murray MP, Hill AT. Prior statin use is associated with improved outcomes in community-acquired pneumonia. Am J Med 2008 Nov 121(11):1002-1007.e1]. 2009 Feb 10 www.f1000medicine.com/article/id/1147935/evaluation
References
1. Fine et al. JAMA 1996, 275:134-41.
2. Kaplan et al. Am J Respir Crit Care Med 2002, 165:766-72.
3. Schlienger et al. Pharmacotherapy 2007, 27:325-32.
4. Mortensen et al. Eur Respir J 2008, 31:611-7.
5. Mortensen et al. Respiratory Research 2005, 6:82.
6. Thomsen et al. Arch Intern Med 2008, 168:2081-7.
7. Majumdar et al. BMJ 2006, 333:999.
8. Strandberg et al. Lancet 1999, 353:118-9.
The following article was selected and commented on by these Faculty Members of Faculty of 1000 Medicine:
Charles Feldman with Erica Shaddock, University of the Witwatersrand, South Africa
Competing Interests: No potential interests relevant to this article were reported.
