Saturday, November 25, 2006
aspirin (groot artikel)
- Aspirin shown to block arterial inflammation
- Other anti-inflammatory and anticoagulation agents may not yield similar preventive benefit in reducing the risk of heart attack and stroke compared with aspirin
- Aspirin use lessens stroke severity
- Therapeutic benefit shown when combining aspirin with additional agents, such as anticoagulants and statins
- Nighttime use of aspirin yields greater reductions in blood pressure
- Aspirin still underused and potentially underprescribed
- Guidelines stipulate patients at risk of coronary artery disease without history of heart disease should be administered aspirin therapy
Described below, recent studies further confirm the therapeutic benefits of aspirin by highlighting its anti-inflammatory properties and by demonstrating its efficacy over other pharmacologic regimens.
Aspirin's Anti-inflammatory Role
For years, clinicians have attributed aspirin's circulatory benefits to its anticlotting properties. However, the latest data suggest that the drug's anti-inflammatory actions may also play a role. According to a study published in the June 4th issue of Circulation,[2] aspirin may be able to protect blood vessels from the deleterious effects of inflammation and infection, 2 factors thought to initiate and promote atherosclerosis. Researchers from University College (London, England) tested the effects of aspirin on 17 healthy volunteers who were given a typhoid vaccine to initiate a blood vessel inflammatory response. Twelve of the participants were randomized to receive either 1.2 g of oral aspirin or placebo 2 hours prior to the vaccination. The remaining 5 received a local infusion of aspirin after the vaccination.Before and after vaccination, researchers measured levels of interleukin-1 (IL-1), which, when elevated in the blood, indicates inflammation. In the placebo group, IL-1 peaked at 3 hours and remained elevated until 8 hours following vaccination. By contrast, the group that received aspirin prior to the vaccination showed no change in IL-1 response. Venous occlusion plethysmography was performed 16 hours prior to and 8 hours following the vaccination to assess endothelial function in the forearm vessels. Researchers found that the placebo group had a significant decrease in forearm blood flow 8 hours after the vaccination, which was indicative of an inflammatory response that temporarily stiffened the blood vessels. By contrast, those who received pretreatment aspirin maintained blood flow at prevaccination levels. In addition, aspirin seemed to exert anti-inflammatory effects only when administered prior to vaccination, as patients treated with an aspirin infusion following vaccination showed no improvement in endothelial function. The results confirm previous studies showing that mild systemic inflammation impairs endothelium-dependent blood vessel dilation. This study provides evidence that pretreatment with aspirin can provide an anti-inflammatory protective effect to the vasculature.
Are All Anti-inflammatory and Anticoagulation Agents Created Equal?
The correlation between inflammation and atherosclerosis may lead one to believe that other anti-inflammatory agents such as ibuprofen and acetaminophen may also have similar cardiovascular benefits. As the population ages and as the incidence and prevalence of arthritis and other painful conditions increases, a growing number of patients will be taking other pain-reliever medicines, including nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors. The cardiovascular effects of such drugs, however, remain uncertain.Researchers at Harvard Medical School (Boston, Massachusetts) concluded that, with the exception of naproxen, NSAIDs did not reduce heart attack risk (Table 1). Their study findings, published in the Archives of Internal Medicine,[3] were based on an analysis of 22,125 patients (4425 hospitalized for a heart attack and a control group of 17,700 without heart attack). Patients who had been prescribed an NSAID were no more or less likely to have a heart attack than those without a prescription. Upon examining individual NSAIDs, the researchers found that patients receiving naproxen were 16% to 20% less likely to suffer a heart attack, but that the cardiovascular benefits of naproxen did not exceed those of aspirin therapy.
COX-2 inhibitors may complicate those at high risk for heart disease. Preclinical research[4] from the University of Pennsylvania (Philadelphia) indicated that COX-2 inhibitors were more likely to promote blood clotting and blood vessel constriction compared with NSAIDs. Whereas traditional NSAIDs block both COX-1 and -2 enzymes, COX-2 inhibitors inhibit the production of prostacyclin, a component known to prevent thrombus formation and promote vasodilation. Researchers postulate that, without the presence of prostacyclin, the vasoconstrictive effects associated with thromboxane A2 (a product of the COX-1 enzyme) will increase cardiovascular risk. When comparing the injury response in mice genetically engineered to lack both prostacyclin and thromboxane A2 vs those engineered to lack prostacyclin alone, platelet response was substantially more overactive in the latter group. This finding led investigators to conclude that an increased response to injury may also translate into higher cardiovascular risk, particularly in patients who are already at high risk of cardiac events. As a result of an earlier this study, which found that Vioxx (Merck, rofecoxib), a COX-2 inhibitor used for the treatment of arthritis, was associated with higher rates of heart attack and other cardiac events compared with patients on naproxen, Merck announced a label change for its arthritis drug, Vioxx to account for the drugs potential cardiovascular risks.
While they will not cause an initial occurrence of heart failure (HF), NSAIDs may increase the risk of recurrence in patients with 1 previous episode of HF, according to a Dutch study published in the Archives of Internal Medicine.[5] Researchers found that among 345 patients with previous HF, those who filled at least 1 NSAID prescription were nearly 10 times more likely than those who did not use NSAIDs to have a recurrence of HF.
According to researchers at the University of Pennsylvania (Philadelphia), combining ibuprofen with aspirin may interfere with the latter's antiplatelet properties. The study, published in The New England Journal of Medicine (NEJM),[6] examined the potential effects of combining aspirin with 4 other common pain medications: acetaminophen and 3 NSAIDs -- ibuprofen, rofecoxib (Vioxx), and diclofenac. While none of the other pain relievers showed a deleterious effect, when used in combination with aspirin therapy, ibuprofen was found to undermine the cardioprotective effects of aspirin.
Other recent findings suggest that patients with heart disease who are less sensitive to the effects of aspirin are at significantly higher risk of heart attack and death. A study published in the April 9th issue of Circulation[7] found that people with higher blood levels of thromboxane, a substance usually blocked by aspirin, were significantly more likely to have a heart attack or stroke. The data suggest that these patients are resistant to the effects of aspirin and should be treated with higher aspirin doses or another antiplatelet agent, such as clopidogrel, in combination with aspirin.
In general, these studies have demonstrated that NSAIDs and COX-2 inhibitors are relatively safe for the general population, but caution should be exercised when prescribing them for patients with existing heart disease or those at high cardiac risk. The substantial increase in availability of over-the-counter (OTC) pain-reliever drugs places a great burden on the healthcare industry to properly educate patients on potential adverse effects (both immediate and long-term) associated with combining any drugs, whether they be prescribed or otherwise. There is often a misconception on the part of the patient that OTC drugs are harmless, in part because of their easy accessibility. Acknowledging the potential interactions and limitations of such agents is pivotal to ensuring proper heart disease prevention and risk reduction.
Reducing Stroke Severity
Aspirin may also have a preventive benefit among patients at high risk of ischemic stroke, and recent research suggests that aspirin may help limit stroke severity. Trial of Org 10172 in Acute Stroke Treatment (TOAST), a 1200-patient study published in Stroke,[8] found that people who took aspirin within a week prior to suffering an ischemic stroke were more likely to have a milder stroke than those who had not taken aspirin within the same timeframe. Overall, about 50% of patients who used aspirin had mild strokes and about 10% had severe strokes. By contrast, 43% of nonaspirin users had mild strokes and about 15% had a severe stroke. Rates of death, however, did not differ between the 2 groups. Researchers believe that these results could be due in part to the antioxidant properties of aspirin, which may help prevent tissue damage during stroke.Further support for these findings is presented in a recent joint scientific statement from the American Stroke Association and the American Academy of Neurology, which reports that the administration of 160-325 mg of aspirin within as little as a 48-hour window before stroke onset significantly reduces the death rates and disability from stroke.[9] Derived from a systematic review of the literature that examined large, prospective studies, the statement aimed to define the roles of antiplatelet agents vs anticoagulants. Unlike aspirin, anticoagulants such as heparin were not shown to reduce risk of death when used within the same time period. Recommendations could not be made regarding the therapeutic benefits of other antiplatelet agents, such as clopidogrel and ticlopidine, due to insufficient data. The statement recommends that the use of subcutaneous heparin may be considered to prevent deep-vein thrombosis in some at-risk patients, but the dose of the drug should be minimized in order to prevent hemorrhage.
Aspirin appears to be an effective preventive agent in nearly all patients at risk for ischemic stroke, with the notable exception of patients with atrial fibrillation (AF), which is known to greatly increase the risk of embolic stroke. In AF patients, the anticoagulant warfarin has been demonstrated to be significantly more effective at preventing stroke than aspirin, although warfarin carries a higher risk for bleeding. In the November 15th issue of NEJM,[10] researchers presented data comparing the preventive benefits of aspirin and warfarin in patients with AF who had already experienced a stroke. More than 2200 stroke patients were randomized to receive either aspirin or warfarin and were then followed for 2 years. Mortality rates were similar in the 2 groups, as were bleeding and other side effects, indicating that aspirin therapy may be an effective (and less costly) preventive option in this patient group.
A report published in the July issue of NEJM[11] confirmed the cost-effective benefits of using aspirin therapy over clopidogrel (Plavix). In a cost comparison that evaluated the drug cost and the patient-years of life saved for patients receiving either drug alone or in combination with one another, one 75-mg tablet of clopidogrel was found to cost $3.22, 80 times the cost of one 325-mg tablet of aspirin. Researchers believe the most cost-effective way to use the 2 drugs is to prescribe aspirin to the 94.3% of coronary heart disease patients who can tolerate it and offer clopidogrel to the remaining 5.7% who cannot take aspirin because of allergy or other causes. An editorial published in the same issue of NEJM[12] criticized the study, suggesting that it was unfair to assume that the costs of a new treatment with equivalent or superior therapeutic benefits would have to parallel the costs of an existing and established therapy.
Benefits of Aspirin Combination Therapy
Some have proposed that when aspirin is used in combination with other anticoagulant agents, its benefits may be magnified, particularly in the setting of acute coronary syndrome (ACS). The Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2), published in the July 13th issue of The Lancet,[13] randomized 999 ACS patients with acute myocardial infarction (MI) or unstable angina to 1 of 3 arms: low-dose aspirin, high-dose oral anticoagulation (phenprocoumon or acenocoumarol), or a low-dose aspirin plus mild-intensity anticoagulation. With respect to the trial's composite clinical end point (MI, stroke, or death), patients treated with high-intensity anticoagulation or mild-intensity anticoagulation and low-dose aspirin therapy had a significantly reduced risk when compared with low-dose aspirin therapy (5% vs 5% vs 9%, respectively). However, secondary end points of major and minor bleeding were as high or higher in patients on high-intensity or on combination therapy compared with aspirin therapy alone. Researchers attribute the findings to the clinical efficacy of controlling the activation of the coagulation cascade that occurs in ACS.Closely following the publication of the ASPECT-2 trial, investigators from the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APRICOT)-2 study[14] confirmed the angiographic and clinical benefits of combined anticoagulant therapy (aspirin + moderate dose of coumarin [n = 123]) vs aspirin alone (n = 128) in patients who had suffered an MI. Patients on combination therapy also received heparin until moderate anticoagulation was achieved, translating into an additional 66 additional hours of heparin therapy. Aspirin-only patients did not receive any additional heparin. Three-month follow-up revealed that fewer reocclusions had occurred in the combination group (15% vs 28%), and problem-free survival was significantly higher than in the group receiving aspirin therapy alone (86% vs 66%, respectively).
Although a US Food and Drug Administration advisory panel initially rejected Bristol-Myers Squibb's (BMS) proposed copackaging of its statin, pravastatin (Pravachol), with aspirin, the panel reversed its original decision in late July, voting in conditional support of the combination, which will be copackaged to contain 1 of 3 different doses of the statin with either 81 mg or 325 mg of aspirin. This recommendation comes a few weeks following the publication of the favorable Heart Protection Study (HPS),[15] which documented the therapeutic and preventive properties of statin therapy, even in nontraditional patients (see "HeartBytes: Does a Statin a Day Keep the Doctor Away?"). The combination may prove fruitful, particularly in light of recent findings confirming the benefit of aspirin therapy. BMS hopes to file for approval of a single combination tablet at a later date. The FDA is expected to make a final decision shortly.
Bedtime Use Best?
Research suggests that bedtime may be the best time for prophylactic aspirin use, especially for patients with high blood pressure. A study presented at the 17th Annual Scientific Meeting of the American Society of Hypertension, held in New York, NY, found that patients who took low-dose aspirin before going to bed had a significantly greater reduction in blood pressure than those who took aspirin at other times of the day. Other studies using aspirin to treat hypertension have shown inconsistent results, which may be due to the timing of aspirin administration, according to researchers. Patients in the study who took aspirin at night had an average 7-mm Hg decrease in their systolic blood pressure and 4.8-mm Hg decrease in their diastolic blood pressure. By contrast, those who took aspirin upon awakening showed no change in their blood pressure. The researchers speculate that when aspirin is taken at night, it reaches peak plasma levels at just about the same time that the activities of platelets and angiotensin, which have an impact on blood pressure, are at their highest levels.
Aspirin Underused and Underprescribed
Despite the well-published benefits of aspirin use for patients at high risk for cardiovascular disease, there are still many eligible patients who are not using aspirin therapy. According to the results of a Duke University Medical Center patient survey, published in the March 15th issue of the American Journal of Cardiology,[16] aspirin use increased substantially in the mid to late 1990s. Even though the percentage of patients reporting aspirin use rose from 59% in 1995 to 81% in 1999, these levels still fall short of what they should be. Perhaps most alarming, the survey found that people at high risk of coronary or neurovascular events, including those with HF, diabetes, or high blood pressure, were less likely to be taking aspirin than people without these risk factors. Patients in the survey who said they never took aspirin were 85% more likely to die during the 5-year study period than patients taking aspirin.
New Aspirin Guidelines
Recognizing the underutilization of aspirin therapy and the array of information regarding the candidates most likely to benefit, the US Preventive Services Task Force (USPSTF), a panel convened by the Agency for Healthcare Research and Quality, released new guidelines for the proper use of aspirin for preventive care in patients without a history of cardiovascular disease who are at increased risk of developing coronary heart disease (CHD). According to the guidelines, published in the January 15th issue of the Annals of Internal Medicine,[17] aspirin prevention therapy is best suited for people at high risk of developing CHD (those with a 5-year risk of >/= 3%), since the benefits of aspirin use in this patient population significantly outweigh the risks. The USPSTF studied 5 trials of aspirin in healthy people who had 1 or more risk factors for heart disease. Overall, regular aspirin use reduced the incidence of heart attack by 28% and reduced the risk of death from heart disease by 13%, but it also increased the risk of hemorrhagic stroke and major gastrointestinal (GI) bleeding (Table 2). When patients were stratified by risk category, the researchers calculated that aspirin use in patients with a moderately high risk of CHD events (5-year risk of 5%) would prevent 14 heart attacks and cause 1 hemorrhagic stroke and 3 major GI bleeds. In patients with a 1% risk, the number of bleeding events would equal or outweigh the benefits of the drug (Table 3). The task force recommends that patients at increased CHD risk discuss the potential benefits and risks of aspirin prevention protocols with their physician.
|
|
|
Mary Thompson is Editor-in-Chief, Medtech Insight, Tustin, California.
Medscape Cardiology 6(2), 2002. © 2002 Medscape
| |
In his article published in the August 29, 2006 issue of the Canadian Medical Association Journal, Dr. Jacob Karsh(1) claimed that both coxibs and traditional NSAIDs should not be prescribed in patients at higher cardiovascular (CV) risk.
He also noted that in many painful conditions treatment with NSAIDs is not necessary or can be substituted for acetaminophen. In my opinion the rational choice for patients with CV and gastrointestinal(GI) risk factors is the use of aspirin combined with a proton-pump inhibitor.
There is good evidence that analgesic doses of aspirin (up to 1500mg) are associated with protection from CV events.(2,3) Furthermore, aspirin dose or its higher lifetime use is not significantly associated with hypertension(4) or renal toxicity.(5,6) Importantly, a recent meta- analysis of 24 randomised controlled trials found no evidence of dose- responsiveness for bleeds over a wide range of doses (50 to 1500 mg/day).(7) Indeed, aspirin in doses commonly used in practice, has an excellent safety profile.(8)
On the contrary, recent evidence suggest that both NSAIDs and acetaminophen can raise cardiovascular risk. (9) High acetaminophen use may also increase the risk of hypertension(4) and a decrease of renal function.(5) Interestingly, increased acetaminophen use has now been linked to increased prevalence of asthma and chronic obstructive pulmonary disease, and with lowered lung function.(10)
Surprisingly, a recent case-control study showed that paracetamol (>2 g per day) was associated with a greater risk of GI perforation or bleed(11) and one cohort study reported a dose-response relationship between paracetamol and dyspepsia.(12) It appears that regular use of acetaminophen is also associated with symptoms of severe diverticular disease, particularly bleeding.(13)
Lastly, compelling evidence suggests that aspirin and other NSAIDs are superior to acetaminophen for improving moderate-to-severe pain in patients with osteoarthritis(14,15,16) and rheumatoid arthritis.(17) Likewise, in acute pain states aspirin provides significant and more rapid analgesia than paracetamol.(18)
References
1. Karsh J. Anti-inflammatory drugs: what is safe? CMAJ 2006;175:449.
2. Antithrombotic Trialists' Collaboration. Collaborative meta- analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
3. Johnson ES, Lanes SF, Wentworth CE 3rd, Satterfield MH, Abebe BL, Dicker LW.A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med 1999;159:1248-53.
4. Forman JP, Stampfer MJ, Curhan GC. Non-narcotic analgesic dose and risk of incident hypertension in US women. Hypertension 2005;46:500-7.
5. Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ. Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med 2004;164:1519-24.
6. Dubach UC, Rosner B, Sturmer T. An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987) N Engl J Med 1991;324:155-60.
7. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-7.
8. Fries JF, Ramey DR, Singh G, Morfeld D, Bloch DA, Raynauld JP. A reevaluation of aspirin therapy in rheumatoid arthritis. Arch Intern Med 1993;153:2465-71.
9. Chan AT, Manson JE, Albert CM, Chae CU, Rexrode KM, Curhan GC, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006;113:1578-87.
10. McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA. The association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am J Respir Crit Care Med 2005;171:966-71.
11. Garcia Rodriguez LA, Hernandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570-6.
12. Rahme E, Pettitt D, LeLorier J. Determinants and sequelae associated with utilization of acetaminophen versus traditional nonsteroidal antiinflammatory drugs in an elderly population. Arthritis Rheum 2002;46:3046-54.
13. Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med 1998;7:255-60.
14. Lee C, Straus WL, Balshaw R, Barlas S, Vogel S, Schnitzer TJ. A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: a meta- analysis. Arthritis Rheum 2004;51:746-54.
15. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD004257.
16. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004;63:901-7.
17. Wienecke T, Gotzsche PC. Paracetamol versus nonsteroidal anti- inflammatory drugs for rheumatoid arthritis. Cochrane Database Syst Rev 2004;(1):CD003789.
18. Seymour RA, Hawkesford JE, Sykes J, Stillings M, Hill CM. An investigation into the comparative efficacy of soluble aspirin and solid paracetamol in postoperative pain after third molar surgery. Br Dent J 2003;194:153-7.
Michal R. Pijak, Assistant Professor and Consultant in Internal Medicine, Rheumatology and Clinical Immunology, Department of Internal Medicine, Slovak Medical University, Bratislava, Slovakia
: 1:28 AM << Home
