Thursday, December 23, 2010
dabigatran warfarin A F atrial fibrillation
Dabigatran or Warfarin for Atrial Fibrillation?
Chances are, warfarin has begun its ride into the sunset.
THE SETTING
Warfarin has a long history of success in the prevention of thromboembolism in patients with atrial fibrillation (AF) and the treatment of deep venous thrombosis and pulmonary embolism; the drug is also used to prevent both venous and arterial clots and to treat several other conditions (e.g., anticardiolipin antibody syndrome). However, warfarin requires frequent monitoring of the international normalized ratio (INR) and dose adjustment; even with meticulous care, warfarin recipients often have INRs outside of the narrow therapeutic window.
Indeed, many pharmaceutical companies have been hard at work on replacements for warfarin. Warfarin is an inhibitor of thrombin synthesis. Most of the drugs currently under evaluation for preventing venous and arterial thromboembolism are direct inhibitors of factor Xa or thrombin. Ximelagatran, the first antithrombin inhibitor to undergo large-scale clinical trials, showed efficacy similar to warfarin for the prevention of thromboembolism in patients with AF; however, increased levels of liver enzyme leakage prevented FDA approval of ximelagatran for use in the U.S.
THE STORY
Now, the FDA has approved dabigatran, a direct thrombin inhibitor with peak concentrations 1 to 2 hours after ingestion and a half-life of 12 to 14 hours, for prevention of thromboembolism in patients with AF. Dabigatran exhibits very little drug–drug or drug–food interaction and is excreted renally. FDA approval was based largely on findings from the RE-LY trial involving 18,113 patients with AF and a CHADS2 score (measuring risk for stroke) of 1 or more (JW Cardiol Sep 1 2009). In the RECOVER trial, researchers compared high-dose dabigatran with an adjusted dose of warfarin for the treatment of venous thromboembolism in 2539 patients; dabigatran demonstrated efficacy and bleeding risk similar to that of warfarin (JW Gen Med Dec 8 2009).
The major question about dabigatran has now shifted from efficacy and safety to cost. Not only insurers but also many in the medical community fear that the high price of this agent will drive up healthcare costs. Warfarin itself is inexpensive; however, its total cost also includes healthcare personnel time, laboratory expenses of frequent INR monitoring, and the costs of hospitalization for the consequences of both subtherapeutic and supertherapeutic INRs. In a recently published Markov decision model of cost-effectiveness, the cost of dabigatran compared with warfarin was approximately $50,000 per quality-adjusted life-year (JW Gen Med Dec 2 2010); the price of dabigatran has subsequently fallen.
THE DENOUEMENT
As a practicing cardiac electrophysiologist, I often find warfarin to be the bane of my care of patients with AF. The FDA's rejection of ximelagatran (which I considered promising) and fear of the high cost of a new agent made me initially somewhat pessimistic that an alternative to warfarin would ever be released. I am therefore quite pleased to have an available option with an improved safety profile, albeit at a higher economic cost. Furthermore, the cost of dabigatran will be driven down if rivaroxaban, a direct Xa inhibitor (Physician's First Watch Nov 16 2010) or other alternatives to dabigatran and warfarin prove effective and obtain FDA approval.
Other lingering concerns include the lack of tools for careful monitoring and rapid reversal of dabigatran's effects; thus, in the short term, dabigatran will be used primarily in patients who have problems with warfarin, such as those treated at institutions with low rates of INR control (JW Cardiol Aug 30 2010), or who are at high risk for bleeding or for poor compliance with warfarin treatment. But I can easily envision a future in which I transfer all of my warfarin patients to direct thrombin or Xa inhibitors and relegate warfarin to a fitting pharmaceutical graveyard.
Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009 Sep 17 ; 361:1139.
Wednesday, December 22, 2010
rivaroxabin warfarin
Summary and Comment
Rivaroxaban — An Alternative for Acute DVT
Fully oral treatment with rivaroxaban was as safe and effective as enoxaparin plus warfarin for deep venous thrombosis.
Rivaroxaban, an oral factor Xa inhibitor that is not yet FDA approved, is one of several new potential substitutes for warfarin. In this report, researchers present the results of two industry-sponsored trials that involved rivaroxaban.
In one study, 3449 patients with acute symptomatic proximal deep venous thrombosis (DVT) — but without clinically apparent pulmonary embolism — were randomized to receive either oral rivaroxaban or standard therapy (enoxaparin followed by warfarin); treatment duration was 3 to 12 months. The incidence of recurrent venous thromboembolism was slightly lower with rivaroxaban than with standard therapy (2.1% vs. 3.0%), and the incidence of bleeding was the same in both groups.
In another study, 1197 patients who had completed 6 to 12 months of treatment for acute venous thromboembolism were randomized to receive either oral rivaroxaban or placebo for 6 to 12 additional months. Recurrent venous thromboembolism occurred significantly less often with rivaroxaban than with placebo (1.3% vs. 7.1%); DVT accounted for most of the difference. Rivaroxaban recipients experienced fewer pulmonary embolic events than did placebo recipients (3 vs. 14) but suffered more major bleeding episodes (4 vs. 0).
Comment: Fully oral treatment with rivaroxaban is a safe and effective alternative to standard acute DVT therapy, and it simplifies treatment. Not surprisingly, extending treatment beyond 6 to 12 months prevents recurrent venous thromboembolism while posing a small but finite bleeding risk — as would be expected for any antithrombotic agent. This study establishes that rivaroxaban could be used for indefinite prophylaxis, but it doesn't identify patient subgroups for which benefits of indefinite therapy outweigh risks.
Published in Journal Watch General Medicine December 21, 2010
Sunday, December 19, 2010
aspirine
Can Aspirin-Phosphatidylcholine Reduce Aspirin-Induced Ulcers?
Use of a novel formulation of aspirin resulted in fewer ulcers or erosions.
Aspirin use is associated with an increase in complicated gastroduodenal ulcers from both topical and systemic effects. Topical effects include erosions and ulcerations that occur shortly after ingestion of aspirin. To test a novel approach to reducing topical aspirin-induced gastroduodenal damage, investigators conducted an industry-supported, multicenter, randomized, phase II trial of a drug-delivery system that covalently links aspirin to the lipophilic molecule phosphatidylcholine (PC), thus facilitating transit of the resultant aspirin-PC compound across the gastrointestinal (GI) mucosal layer.
A total of 204 healthy individuals (age range, 50–75) with age-related increased risk for nonsteroidal anti-inflammatory drug (NSAID)-induced gastroduodenal damage were included in the study. All participants underwent baseline endoscopy, received low-dose (325 mg/day) aspirin or aspirin-PC for 7 days, and then underwent a second endoscopy.
Fewer participants in the aspirin-PC group than in the aspirin group developed an ulcer (5.1% vs. 17.6%; P=0.0069) or developed either an ulcer or 
6 erosions (the primary endpoint; 22.2% vs. 42.2%; P=0.0027). The authors concluded that using phospholipids to circumvent local mechanisms of mucosal damage from aspirin might provide an additional way to reduce the incidence of ulceration in high-risk individuals.
Comment: The immediate gastric mucosal local effects of aspirin (or other NSAIDs that are weak acids) have been well established. However, these effects have not been correlated with long-term risks for systemic prostaglandin inhibition. Whether reductions in immediate local damage from aspirin result in better long-term outcomes for patients at high risk for GI events remains to be determined.
— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)
Published in Journal Watch Gastroenterology December 10, 2010
Saturday, December 18, 2010
statins
Free Full-Text Article
Summary and Comment
Statins Sharply Lower Cardiovascular Risk Regardless of Baseline LDL Cholesterol
Results of a meta-analysis suggest that guidelines should be reevaluated.
Previous studies and meta-analyses have suggested that vascular risk decreases linearly with reduction in LDL cholesterol (LDL-C) by statins (e.g., 20% reduction in vascular events per 40-mg/dL reduction in LDL-C). A new meta-analysis includes patient-level data from 21 placebo-controlled trials (almost 130,000 patients), and from 5 trials comparing high-dose to low-dose statin therapy (almost 40,000 patients), with average follow-up of 5 years.
In the placebo-controlled trials, statin recipients had a 41-mg/dL greater decline in LDL-C and a significant 22% reduction in first major vascular events (2.8% vs. 3.6% annually). In the high-dose versus low-dose trials, high-dose patients had a 20-mg/dL greater decline in LDL-C and a significant 15% reduction in first major vascular events (4.5% vs. 5.3% annually). Relative risk reductions of about 20% per 40-mg/dL decline in LDL-C were seen in both placebo-controlled and high- versus low-dose trials for all prespecified patient subgroups, and at all baseline LDL-C levels (including <80>
The largest study to date of high-dose versus low-dose statin therapy was published simultaneously with — and included in — the meta-analysis. In this manufacturer-funded U.K. trial, >12,000 patients with a history of myocardial infarction were randomized to simvastatin (80 mg or 20 mg daily) and followed for a mean of 6.7 years. The high-dose group had a 14-mg/dL greater average decline in LDL-C and 6% fewer major vascular events than did the low-dose group — a result consistent with the meta-analysis.
Comment: LDL cholesterol reduction with statins seems to predictably and safely lower cardiovascular risk regardless of baseline LDL level, suggesting that current target-based treatment guidelines should be reevaluated. Editorialists note that absolute risk reduction will be small in patients at low cardiovascular risk and urge that priority be given to identifying high-risk patients who will benefit most from statin therapy.
Published in Journal Watch General Medicine December 16, 2010
suicide veterans
Significant Mortality Ratios
The standardized mortality ratios (SMRs) showed that the risk of dying by suicide in the 18- to 34-year age range was 3 times higher for the veterans-only group vs nonveterans group (3.05; 95% confidence interval [CI], 2.31 – 3.96).
The SMRs were also significantly higher for the veterans only between the age of 35 and 44 years at 1.78 (95% CI, 1.37 – 2.29) and for those between 45 and 64 years old at 1.58 (95% CI, 1.27 – 1.95) compared with the nonveterans.
When using the broader definition of current and past military service, the women in the 18- to 34-year range had an SMR of 1.76 (95% CI, 1.32 – 2.27) and those in the 35- to 44-year range had an SMR of 1.30 (95% CI, 1.00 – 1.66) compared with the nonveterans.
"Very few women aged 45 to 64 were currently active in military service" at the time of their deaths," explain the investigators. So there was no SMR estimated that included that subpopulation.
"Overall, the broader definition brought the rate down a little bit, but it was still significantly higher than among nonveteran women," said Dr. Kaplan. "No matter how you define it, the numbers are still substantial."
Study limitations cited include "presumed undercounting of suicides [and] absence of data on military sexual trauma or combat exposure," the researchers write.
Dr. Kaplan noted that many past studies on suicide among the veteran population have focused almost exclusively on men.
"When we think about suicide we often think about suicide completion among men and suicide attempts among women. But I think this study shows that there is definitely a heightened risk among women with military experience," he said.
When asked to speculate as to why these rates were so high, he responded that the data were pulled from the years 2004 to 2007, which was at "the height of the war in Iraq."
He noted that past research has suggested that 15% of women who served in Iraq had experienced sexual assault or harassment. Other possible contributing factors include long periods of separation from families, alcohol or other substance abuse, and some women having problems fitting into the male-dominated military culture.
"Some women actually adopt some of the traits that men show, such as emotional inexpressiveness or being stoic and being unwilling to seek mental healthcare even when necessary. Women veterans also often feel stigmatized when they use the VA facilities, although I must say the VA has become far more responsive to their needs," he said.
Dr. Kaplan also noted that many of the women in the study committed suicide with a firearm. "So as clinicians, we need to be thinking about the heightened risk associated with easy access to firearms and be more aggressive in terms of doing assessments, probing for gun availability among both female and male veterans."
Thursday, December 16, 2010
chocolade cholesterol vascular
SUMMARY AND COMMENT
Eating Chocolate Almost Every Day Keeps the Cardiologist Away
December 2, 2010 | Wendy S. Biggs, MD | Women's Health
Women who ate chocolate frequently were less likely to be hospitalized for or to die from atherosclerotic vascular disease.
Reviewing: Lewis JR et al. Arch Intern Med 2010 Nov 8; 170:1857
dabigatran warfarin AF atrial bibrillation
Dabigatran or Warfarin for Atrial Fibrillation?
Chances are, warfarin has begun its ride into the sunset.
THE SETTING
Warfarin has a long history of success in the prevention of thromboembolism in patients with atrial fibrillation (AF) and the treatment of deep venous thrombosis and pulmonary embolism; the drug is also used to prevent both venous and arterial clots and to treat several other conditions (e.g., anticardiolipin antibody syndrome). However, warfarin requires frequent monitoring of the international normalized ratio (INR) and dose adjustment; even with meticulous care, warfarin recipients often have INRs outside of the narrow therapeutic window.
Indeed, many pharmaceutical companies have been hard at work on replacements for warfarin. Warfarin is an inhibitor of thrombin synthesis. Most of the drugs currently under evaluation for preventing venous and arterial thromboembolism are direct inhibitors of factor Xa or thrombin. Ximelagatran, the first antithrombin inhibitor to undergo large-scale clinical trials, showed efficacy similar to warfarin for the prevention of thromboembolism in patients with AF; however, increased levels of liver enzyme leakage prevented FDA approval of ximelagatran for use in the U.S.
THE STORY
Now, the FDA has approved dabigatran, a direct thrombin inhibitor with peak concentrations 1 to 2 hours after ingestion and a half-life of 12 to 14 hours, for prevention of thromboembolism in patients with AF. Dabigatran exhibits very little drug–drug or drug–food interaction and is excreted renally. FDA approval was based largely on findings from the RE-LY trial involving 18,113 patients with AF and a CHADS2 score (measuring risk for stroke) of 1 or more (JW Cardiol Sep 1 2009). In the RECOVER trial, researchers compared high-dose dabigatran with an adjusted dose of warfarin for the treatment of venous thromboembolism in 2539 patients; dabigatran demonstrated efficacy and bleeding risk similar to that of warfarin (JW Gen Med Dec 8 2009).
The major question about dabigatran has now shifted from efficacy and safety to cost. Not only insurers but also many in the medical community fear that the high price of this agent will drive up healthcare costs. Warfarin itself is inexpensive; however, its total cost also includes healthcare personnel time, laboratory expenses of frequent INR monitoring, and the costs of hospitalization for the consequences of both subtherapeutic and supertherapeutic INRs. In a recently published Markov decision model of cost-effectiveness, the cost of dabigatran compared with warfarin was approximately $50,000 per quality-adjusted life-year (JW Gen Med Dec 2 2010); the price of dabigatran has subsequently fallen.
THE DENOUEMENT
As a practicing cardiac electrophysiologist, I often find warfarin to be the bane of my care of patients with AF. The FDA's rejection of ximelagatran (which I considered promising) and fear of the high cost of a new agent made me initially somewhat pessimistic that an alternative to warfarin would ever be released. I am therefore quite pleased to have an available option with an improved safety profile, albeit at a higher economic cost. Furthermore, the cost of dabigatran will be driven down if rivaroxaban, a direct Xa inhibitor (Physician's First Watch Nov 16 2010) or other alternatives to dabigatran and warfarin prove effective and obtain FDA approval.
Other lingering concerns include the lack of tools for careful monitoring and rapid reversal of dabigatran's effects; thus, in the short term, dabigatran will be used primarily in patients who have problems with warfarin, such as those treated at institutions with low rates of INR control (JW Cardiol Aug 30 2010), or who are at high risk for bleeding or for poor compliance with warfarin treatment. But I can easily envision a future in which I transfer all of my warfarin patients to direct thrombin or Xa inhibitors and relegate warfarin to a fitting pharmaceutical graveyard.
Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009 Sep 17 ; 361:1139.
Medline abstract (Free)
Schulman S et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009 Dec 10 ; 361:2342.
Medline abstract (Free)
Freeman JV et al. Cost-effectiveness of dabigatran compared with warfain for stroke prevention in atrial fibrillation. Ann Intern Med 2010 Nov 1 ; [e-pub ahead of print]. (http://www.annals.org/content/early/2010/11/01/0003-4819-154-1-201101040-00289.full)
Wallentin L et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: An analysis of the RE-LY trial. Lancet 2010 Sep 18 ; 376:975.
Medline abstract (Free)
Published in Journal Watch Cardiology December 15, 2010
rivaroxaban AF atrial fibrillation
Rivaroxaban as Effective as Warfarin in Preventing Emboli and Stroke
Rivaroxaban may be an effective alternative to warfarin in prevention of stroke and emboli in patients with atrial fibrillation, according to the ROCKET AF trial, whose results were presented at the annual American Heart Association meeting on Monday.
Roughly 14,000 patients with atrial fibrillation not related to heart valve dysfunction were randomized to receive either warfarin or oral rivaroxaban (20 mg/day), an experimental drug that targets clotting factor Xa. Patients were treated for an average of 19 months.
In the per-protocol analysis, those taking rivaroxaban had fewer strokes and emboli than those taking warfarin (1.71 vs. 2.16 events per 100 patient-years); rates of major bleeding were similar between the groups. However, in the intention-to-treat analysis, rivaroxaban did not achieve statistical superiority over warfarin in the rate of strokes and blood clots; intracranial bleeding was more common with warfarin.
LINK(S):
AHA news release (Free)
Physician's First Watch coverage of earlier rivaroxaban trial (Free)
Published in Physician's First Watch November 16, 2010
Wednesday, December 15, 2010
dabigatran warfarin AF
SUMMARY AND COMMENT
Dabigatran for Patients with Atrial Fibrillation and Prior TIA or Stroke?
December 14, 2010 | Kirsten E. Fleischmann, MD, MPH
The drug compared favorably to warfarin in patients with previous transient ischemic attack or stroke.
Reviewing: Diener HC et al. Lancet Neurol 2010 Dec 9:1157
Lane DA and Lip GY. Lancet Neurol 2010 Dec 9:1140
Saturday, December 11, 2010
primary ovarian insufficiency POI depression
From Reuters Health Information
Primary Ovarian Insufficiency and Depression Linked
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NEW YORK (Reuters Health) November 29, 2010 — Women with spontaneous 46, xx primary ovarian insufficiency (POI) are at increased risk of depression, but the relationship between the conditions is unclear, researchers report in a November 3rd online paper in the Journal of Clinical Endocrinology & Metabolism.
However, "both women with POI and their care-givers need to know that POI is associated with an increased risk for depression," Dr. Peter J. Schmidt of the National Institute of Mental Health, Bethesda, Maryland, told Reuters Health by email.
Dr. Schmidt and colleagues note that some studies suggest that depression and its treatment may in fact prompt POI. To learn more, they studied 174 women with POI, evaluating them using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (4th edition).
These women had a significantly higher lifetime prevalence of major depression compared to 100 women with Turner's syndrome (54.5% versus 36.6%), and also compared to community-based samples of women.
In all, 95 of the POI patients reported at least one major depression episode, and 22 of the remainder (12.6%) reported at least one episode of minor depression.
In 68.4% women reporting major depression, its onset came before the POI diagnosis. There were similar findings in the minor depression group.
But depression occurred as often before the onset of menstrual cycle insufficiency -- a proxy for the early stages of ovarian insufficiency -- as afterward. Thus, the authors say, "depression is not likely to cause POI."
In fact, the team speculates that it's "possible that estrogen-based treatments could potentially be an effective therapeutic alternative to traditional antidepressants in depressed women with POI."
The researchers also point out the prevalence of POI (1%) is small compared with the lifetime rates of depression in women (20%). This suggests that ovarian insufficiency isn't the cause of depression in most women.
Nevertheless, the investigators conclude that "the high rates of depression accompanying the diagnosis of POI strongly suggest that attention to the possible presence of depression in these women should be part of the evaluation and management of all women who present with POI."
Dr Schmidt added that "a substantial number of depressive episodes clustered during the transition from normal menstrual cycle function to ovarian failure. We see the same pattern in older women who are transitioning to menopause."
"We need to identify the nature of the risk in this subgroup of young women and how we can intervene preemptively on an individual basis. Ultimately, understanding the connection between the menopause transition (both in POI and normally-timed) and depression may also tell us about the cause of depressions that occur in women at other times in their lives."
SOURCE: http://link.reuters.com/zed67q
J Clin Endocrinol Metab. Published online November 3, 2010.
omega-3 depression
Medscape Medical News from the:
This coverage is not sanctioned by, nor a part of, the American College of Neuropsychopharmacology.
From Medscape Medical News > Psychiatry
Not All Omega-3s Equal When It Comes to Antidepressant Effects
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....
December 8, 2010 (Miami Beach, Florida) — Not all omega-3 fatty acids are equal when it comes to their antidepressant effects, according to a meta-analysis presented at the American College of Neuropsychopharmacology 49th Annual Meeting.
In fact, only eicosapentaenoic acid (EPA) — and not docosahexaenoic acid (DHA) — is associated with mood improvement in patients with depression, concluded lead study author John M. Davis, MD, research professor at the University of Illinois in Chicago.
The meta-analysis of 15 randomized, double-blind, placebo-controlled studies clarifies which type of omega-3 fatty acid is effective for depression and why previous findings on the antidepressant effects of omega-3 fatty acids have been contradictory, said Dr. Davis at a press conference.
Omega-3 fatty acids are not synthesized by the body and therefore must be consumed in food (primarily fish and nuts) or supplements. In food, EPA and DHA are found together in a 1:1 ratio, but supplements can contain either fatty acid or a combination of both, he said.
The study concluded that an EPA-predominant formulation is necessary for the full therapeutic antidepressant action, whereas the DHA-predominant formulation has little antidepressant efficacy.
Modern diets may predispose individuals to omega-3 deficiency because changes in farming have resulted in a dietary increase in omega-6 fatty acids, which compete with omega-3 fatty acids in the body, said Dr. Davis.
Although deficiency in omega-3 may predispose individuals to depression and supplementation may have antidepressant benefits, "omega-3 fatty acids are generally not euphoriants in that they do not help people whose mood is normal," he said.
A previous study by Dr. Davis and his colleagues looked at EPA intake among 8000 pregnant women participating in the Avon Longitudinal Study of Parents and Children and found that low intake was associated with high levels of depression (Epidemiology. 2009;20:598-603).
Specifically, compared with women consuming more than 1.5 g of omega-3 from seafood per week, those consuming none were more likely to have high levels of depressive symptoms at 32 weeks' gestation (adjusted odds ratio, 1.54).
François Lespérance, MD, a professor of psychiatry at the Centre Hospitalier de l'Université de Montréal in Quebec, Canada, was the lead investigator on a recently published randomized controlled trial that found a benefit of omega-3 supplementation vs placebo in patients with major depressive disorder (J Clin Psychiatry. June 15, 2010 [Epub ahead of print]).
Reached for comment on Dr. Davis's study Dr. Lespérance said, "This meta-analysis provides additional evidence to what is already known through a limited number of studies in this field. It is therefore a useful summary of several clinical trials that most people may not know in detail."
Dr. Davis has disclosed no relevant financial relationships. Dr. Lespérance received an unrestricted grant from Isodis Natura, a distributor of omega-3 supplements, to conduct his randomized controlled trial but had nothing else to declare.
American College of Neuropsychopharmacology (ACNP) 49th Annual Meeting. Presented December 9, 2010.
mindfulness depression
From Medscape Medical News > Psychiatry
Mindfulness CBT as Effective as Antidepressants in Preventing Depression Relapse
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| |
December 9, 2010 — Mindfulness-based cognitive therapy (MBCT) is as effective in preventing relapse in patients with recurrent major depressive disorder (MDD) as maintenance antidepressant monotherapy, the current standard of care, new research suggests.
In this study, 84 patients with MDD were randomized after achieving remission to receive continued antidepressant use, MBCT, or placebo. For the patients deemed "unstable remitters" with periodic symptom flurries, the relapse rates during 18 months of follow-up did not differ between the MBCT and antidepressant groups (28% vs 27%) but was significantly higher in the placebo group (71%).
"We were very pleased to find that [MBCT] could hold its own against active pharmacotherapy," lead study author Zindel V. Segal, PhD, head of the Cognitive Behavior Therapy Clinic in the Clinical Research Department at the Center for Addiction and Mental Health (CAMH) in Toronto, Ontario, Canada, and professor of psychiatry at the University of Toronto, told Medscape Medical News.
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| Dr. Zindel V. Segal |
He noted that "this makes it an important option" for a number of different subpopulations who become depressed, such as pregnant women. "Coming off medication can trigger a relapse. But now people can come off their medication knowing that there is an option that is nonpharmacological and protects them to the same degree," said Dr. Segal.
The investigators write that the findings also highlight "the importance of maintaining at least 1 long-term active treatment" in unstable remitters.
"I think the take-home message is that clinicians need to consider sequential treatment of mood disorders, where one treatment approach such as an antidepressant can be used in the acute phase to get people well and then people can be switched to another approach that's maybe psychological in nature to help them stay well," said Dr. Segal.
"This would give patients a larger envelope of care so they can deal with acute symptoms and also engage in lifestyle and behaviors that will increase wellness over the long term."
The study was published in the December issue of Archives of General Psychiatry.
40% Discontinuation
"Relapse and recurrence after recovery from [MDD] are common and debilitating outcomes that carry enormous personal, familial, and societal costs," write the researchers.
They note that although maintenance with antidepressant monotherapy is the current standard of care for prevention of relapse, up to 40% of MDD patients don't take their medication.
"Data from the community suggest that many depressed patients discontinue antidepressant medication far too soon, either because of an unwillingness to take medicine for years or side effects that have become unbearable, such as sexual side effects. So the importance of having alternatives to continued antidepressant use is a priority," said Dr. Zindel.
MBCT is a nonpharmacological, group-based intervention that teaches patients how to monitor for possible relapse triggers, changing automatic reactions associated with depression into opportunities for useful reflection. They also practice "health-enhancing behaviors" such as meditation or yoga.
"It's learning how to pay attention to present moment experiences and to ground oneself in an awareness of what is going on with both emotions and body," Dr. Zindel explained.
"People often aren't aware that emotional triggers can start a downward spiral of depression," he added. "In [MBCT], people learn how to regulate their emotions more effectively by paying attention and to work with their feelings in ways that don't involve pushing issues aside. Instead, it gives them more options for dealing with emotions in an adaptive way, making relapse less likely."
For this study, 160 patients between the ages of 18 and 65 years with recurrent MDD were enrolled at outpatient clinics at CAMH and at St. Joseph's Healthcare in Hamilton, Ontario, Canada.
Of these, 84 (63% female; mean age, 44 years; mean number of previous MDD episodes, 4.7) met remission criteria after 8 months of antidepressant monotherapy. Remission was defined for this study as a score of 7 or less on the Hamilton Rating Scale for Depression (HRSD).
Although 51% of these patients were classified as unstable remitters, defined as individuals who had intermittently higher scores on the HRSD, their average scores were low enough to qualify for remission. The other 49% were classified as stable remitters because their HRSD scores were consistently low.
All remitted patients were then randomized to receive either continued use of antidepressant monotherapy (n = 28), tapered use of antidepressant for 4 weeks plus placebo with clinical management (n = 30), or tapered use of antidepressant plus 8 weekly group sessions of MBCT (n = 26).
In addition to their group sessions, the MBCT patients received daily homework assignments consisting of taped awareness exercises and developing an action plan for ways to respond to early warning signs of relapse/recurrence. They were also offered an optional monthly refresher class at the conclusion of the weekly sessions.
Psychiatric visits and clinical assessments were conducted for all patients at regular intervals throughout 18 months of follow-up. Relapse was defined as a return of MDD symptoms for at least 2 weeks.
Equal Relapse Protection
Results showed no significant between-group differences in relapse rates for all study patients: 38% for MBCT, 46% for antidepressant maintenance, and 60% for placebo (P = .66).
However, both MBCT and antidepressant maintenance significantly reduced the risk for subsequent relapse in unstable remitters compared with placebo (P = .01 and P = .03, respectively).
Compared with placebo, the hazard ratio for MBCT for the unstable remitters was 0.26 (95% confidence interval [CI], 0.09 – 0.79), whereas antidepressant therapy had a hazard ratio of 0.24 (95% CI, 0.07 – 0.89). There was no change in risk between the 2 active treatment groups.
For stable remitters, there was no significant difference in relapse rates between the 3 groups: 62% for MBCT, 59% for antidepressant maintenance, and 50% for placebo.
"For those unwilling or unable to tolerate maintenance antidepressant treatment, MBCT offers equal protection from relapse during an 18-month period," write the study authors.
"Sequential intervention may keep more patients in treatment and thereby reduce the high risk of recurrence that is characteristic of this disorder," Dr. Segal added.
He noted that "this is still a relatively novel approach" and is not available in many centers outside larger cities. "Given the effectiveness of this approach, I think our next challenge is to find out how to get more people either trained in this treatment or to provide ways of delivering it perhaps online so that patients can have greater access to it.
"Taking antidepressants may seem to be the easier treatment for patients, as we're asking them to devote 20 to 30 minutes of their day to practicing mindfulness. But in the long run I think this approach will pay real dividends," said Dr. Segal.
Exciting Alternative
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| Dr. Stuart J. Eisendrath |
"These are very exciting findings," Stuart J. Eisendrath, MD, professor of clinical psychiatry at the University of California–San Francisco (UCSF), director of the UCSF Depression Center, and director of clinical services at Langley Porter Psychiatric Hospitals and Clinics, told Medscape Medical News.
"[MDD] is a relapsing disorder, so finding ways of preventing that is crucial and finding alternatives to medication is very important," said Dr. Eisendrath, who was not involved with this study. "For a variety of reasons, some people don't like to take medications on an ongoing basis, so having an alternative intervention that could help individuals prevent relapse is exciting."
He added that this treatment approach "also enhances the individual's self-efficacy. It gives them a way that they can feel they have some control over their own likelihood of relapsing or not."
However, Dr. Eisendrath noted that he found the way the authors characterized remission in the patients "was interesting" in that any of the 3 interventions were equally effective for those with a stable remission, including placebo. "What was the nature of the support of the nonspecific effects of the various interventions? It would be interesting to see further studies that would tease that information out."
Still, overall, "I think the takeaway point is that if people have an unstable remission, it's crucial that they have a maintenance strategy to prevent relapse. And this study points out that [MBCT] is equally effective to maintenance antidepressants as 1 such strategy," he concluded.
The study was funded by a grant from the National Institute of Mental Health. The study authors and Dr. Eisendrath reported no relevant financial relationships. This study was presented in part at the 43rd Annual Meeting of the Association for Behavioral and Cognitive Therapies.
Arch Gen Psychiatry. 2010;67:1256-1264.
aspirin
Can Aspirin-Phosphatidylcholine Reduce Aspirin-Induced Ulcers?
Use of a novel formulation of aspirin resulted in fewer ulcers or erosions.
Aspirin use is associated with an increase in complicated gastroduodenal ulcers from both topical and systemic effects. Topical effects include erosions and ulcerations that occur shortly after ingestion of aspirin. To test a novel approach to reducing topical aspirin-induced gastroduodenal damage, investigators conducted an industry-supported, multicenter, randomized, phase II trial of a drug-delivery system that covalently links aspirin to the lipophilic molecule phosphatidylcholine (PC), thus facilitating transit of the resultant aspirin-PC compound across the gastrointestinal (GI) mucosal layer.
A total of 204 healthy individuals (age range, 50–75) with age-related increased risk for nonsteroidal anti-inflammatory drug (NSAID)-induced gastroduodenal damage were included in the study. All participants underwent baseline endoscopy, received low-dose (325 mg/day) aspirin or aspirin-PC for 7 days, and then underwent a second endoscopy.
Fewer participants in the aspirin-PC group than in the aspirin group developed an ulcer (5.1% vs. 17.6%; P=0.0069) or developed either an ulcer or 
6 erosions (the primary endpoint; 22.2% vs. 42.2%; P=0.0027). The authors concluded that using phospholipids to circumvent local mechanisms of mucosal damage from aspirin might provide an additional way to reduce the incidence of ulceration in high-risk individuals.
Comment: The immediate gastric mucosal local effects of aspirin (or other NSAIDs that are weak acids) have been well established. However, these effects have not been correlated with long-term risks for systemic prostaglandin inhibition. Whether reductions in immediate local damage from aspirin result in better long-term outcomes for patients at high risk for GI events remains to be determined.
— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)
Published in Journal Watch Gastroenterology December 10, 2010
Friday, December 03, 2010
thrombocytopenia Romiplostin
Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia
N Engl J Med 2010; 363:1889-1899November 11, 2010
Background
Romiplostim, a thrombopoietin mimetic, increases platelet counts in patients with immune thrombocytopenia, with few adverse effects.
Methods
In this open-label, 52-week study, we randomly assigned 234 adult patients with immune thrombocytopenia, who had not undergone splenectomy, to receive the standard of care (77 patients) or weekly subcutaneous injections of romiplostim (157 patients). Primary end points were incidences of treatment failure and splenectomy. Secondary end points included the rate of a platelet response (a platelet count >50×109 per liter at any scheduled visit), safety outcomes, and the quality of life.
Results
The rate of a platelet response in the romiplostim group was 2.3 times that in the standard-of-care group (95% confidence interval [CI], 2.0 to 2.6; P<0.001).>
Conclusions
Patients treated with romiplostim had a higher rate of a platelet response, lower incidence of treatment failure and splenectomy, less bleeding and fewer blood transfusions, and a higher quality of life than patients treated with the standard of care. (Funded by Amgen; ClinicalTrials.gov number, NCT00415532.)
Dr. Kuter reports receiving consulting fees from Amgen, GlaxoSmithKline, Ligand, Pfizer, Eisai, MGI Pharma, Shionogi, and Ono Pharmaceutical and research support from Amgen, GlaxoSmithKline, Eisai, and Shionogi; Dr. Boccia reports receiving speaker's fees, consulting fees, and research support from Amgen; speaker's fees from GlaxoSmithKline; and holding equity in Amgen and Johnson and Johnson; Dr. Pabinger reports receiving consulting fees from Amgen and GlaxoSmithKline and helping to develop speakers' bureau programs for Amgen; Dr. Selleslag reports receiving consulting fees and speaker's fees from Amgen; Dr. Rodeghiero reports receiving research support from and serving on the boards of Amgen, GlaxoSmithKline, and Shionogi, as well as receiving speaker's fees from Amgen and GlaxoSmithKline; Dr. Chong reports serving on the board, receiving honoraria, and receiving research support from Amgen, GlaxoSmithKline, and Commonwealth Serum Lab; and Drs. Wang and Berger report being employees of, and holding equity in, Amgen.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
romiplostin thrombocytopenia
Original Article
Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia
N Engl J Med 2010; 363:1889-1899November 11, 2010
Background
Romiplostim, a thrombopoietin mimetic, increases platelet counts in patients with immune thrombocytopenia, with few adverse effects.
Methods
In this open-label, 52-week study, we randomly assigned 234 adult patients with immune thrombocytopenia, who had not undergone splenectomy, to receive the standard of care (77 patients) or weekly subcutaneous injections of romiplostim (157 patients). Primary end points were incidences of treatment failure and splenectomy. Secondary end points included the rate of a platelet response (a platelet count >50×109 per liter at any scheduled visit), safety outcomes, and the quality of life.
Results
The rate of a platelet response in the romiplostim group was 2.3 times that in the standard-of-care group (95% confidence interval [CI], 2.0 to 2.6; P<0.001).>
Conclusions
Patients treated with romiplostim had a higher rate of a platelet response, lower incidence of treatment failure and splenectomy, less bleeding and fewer blood transfusions, and a higher quality of life than patients treated with the standard of care. (Funded by Amgen; ClinicalTrials.gov number, NCT00415532.)
Dr. Kuter reports receiving consulting fees from Amgen, GlaxoSmithKline, Ligand, Pfizer, Eisai, MGI Pharma, Shionogi, and Ono Pharmaceutical and research support from Amgen, GlaxoSmithKline, Eisai, and Shionogi; Dr. Boccia reports receiving speaker's fees, consulting fees, and research support from Amgen; speaker's fees from GlaxoSmithKline; and holding equity in Amgen and Johnson and Johnson; Dr. Pabinger reports receiving consulting fees from Amgen and GlaxoSmithKline and helping to develop speakers' bureau programs for Amgen; Dr. Selleslag reports receiving consulting fees and speaker's fees from Amgen; Dr. Rodeghiero reports receiving research support from and serving on the boards of Amgen, GlaxoSmithKline, and Shionogi, as well as receiving speaker's fees from Amgen and GlaxoSmithKline; Dr. Chong reports serving on the board, receiving honoraria, and receiving research support from Amgen, GlaxoSmithKline, and Commonwealth Serum Lab; and Drs. Wang and Berger report being employees of, and holding equity in, Amgen.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
dabigatran atrial fibrillation
Cost-Effectiveness of Dabigatran for Stroke Prevention
Dabigatran, at the right price, is an attractive option for many atrial fibrillation patients.
Dabigatran (Pradaxa), a direct thrombin inhibitor that recently received FDA approval (JW Gen Med Oct 28 2010), is at least as effective and safe as warfarin for preventing strokes in patients with atrial fibrillation. However, is dabigatran cost-effective? Using a simulated population of patients with atrial fibrillation and CHADS2 scores 
1, researchers developed a mathematical model to compare outcomes and costs for warfarin (targeted international normalized ratio [INR], 2–3) and for twice-daily 150-mg dabigatran. The model was based on annual rates of ischemic stroke of 1.20% for warfarin and 0.92% for dabigatran. Rates of hemorrhage in the model were 0.74% for warfarin and 0.30% for dabigatran. Cost for dabigatran was estimated at US$13 daily.
Projected lifetime patient costs were $143,000 for treatment with warfarin and $168,000 with dabigatran. Compared with warfarin, dabigatran had an incremental cost-effectiveness ratio of $45,000 per quality-adjusted life-year (QALY).
Comment: Many consider QALY costs of 
$50,000 to be cost-effective. In this computer model, dabigatran costs would remain under this ceiling, assuming that the authors' estimated price of $13 daily is realistic. As of December 2010, the price at several national pharmacy chains was substantial but lower than $13 daily (range, $232–$280 for a 1-month supply of sixty 150-mg tablets). I suspect that most atrial fibrillation patients would gladly switch to dabigatran if a considerable portion of the cost was covered by insurance.
Published in Journal Watch General Medicine December 2, 2010
dabigatran. atrial fibrillation
Thursday, December 02, 2010
dementia vitamine B12 homocysteine
Biologically Active Vitamin B12, Homocysteine, and Alzheimer Disease
Baseline serum levels of homocysteine correlated positively and holotranscobalamin levels correlated negatively with AD risk in a population-based, 7-year cohort study.
Studies of the associations among the components of the vitamin B12 cascade and dementia have had inconsistent results (Eur J Neurol 2009; 16:808, Am J Clin Nutr 2007; 85:511, and Neurology 2004; 62:1972). In this study, researchers examined three of the cascade components — homocysteine, holotranscobalamin (holoTC, the biologically active fraction of vitamin B12), and folate — and subsequent risk for Alzheimer disease (AD). Participants were 271 initially nondemented older adults (baseline age range, 65–79) selected from a larger cohort based on the availability of baseline serum samples of these components. After a mean follow-up of 7.4 years, participants underwent a multistep AD screening process.
In a multiple logistic regression model adjusted for known cerebrovascular risk factors (including history of stroke, blood pressure, body-mass index, and smoking) and AD risk factors (including age, education, APOE 
4, and Mini-Mental State Exam score), the odds ratios for AD were 1.16 per increase of 1 µmol/L of Hcy and 0.980 per increase of 1 pmol/L of holoTC. Of note, 95% confidence intervals for both calculations did not include 1. The authors report an attenuated link between Hcy and AD when adjusting for holoTC; however, the reported 95% confidence interval for this association included 1 (0.96–1.25). Folate levels were not associated with AD. The authors conclude that further study is needed, in light of the established associations of elevated Hcy with vascular disease and of vitamin B12 deficiency with neurological illness.
Comment: The authors acknowledge the obvious limitations of the study (e.g., the small sample size and one-time Hcy and holoTC measurements). A more universal challenge arises in determining the most sensitive marker of vitamin B12 deficiency (e.g., total serum vitamin B12, holoTC, or methylmalonic acid) and the true range of normal values. Nonetheless, these findings are provocative and suggest that simple supplementation with vitamin B12 in an aging population might be beneficial.
Published in Journal Watch Neurology November 9, 2010
Wednesday, December 01, 2010
cholesterol HDL anacetrabip
Anacetrapib for Lipid Management: Safety in Numbers
Promising results from an initial trial put cholesteryl ester transfer protein inhibition back on the map.
Anacetrapib is a new drug that raises HDL levels and reduces LDL levels by inhibiting the cholesteryl ester transfer protein (CETP). Another CETP inhibitor, torcetrapib, was withdrawn from development when it was found to increase rates of cardiovascular outcomes and death (JW Cardiol Nov 5 2007). Investigators have now conducted an international, manufacturer-funded, randomized, double-blind, placebo-controlled trial of anacetrapib in 1623 patients (mean age, 63) with or at high risk for coronary disease (55% and 45%, respectively).
By week 24, the mean LDL level had decreased significantly more in anacetrapib patients (from 81 mg/dL to 45 mg/dL) than in placebo patients (from 82 mg/dL to 77 mg/dL). The mean HDL level had increased significantly — and markedly — more with anacetrapib (from 41 mg/dL to 101 mg/dL) than with placebo (from 40 mg/dL to 46 mg/dL). Reductions in apolipoprotein B levels and increases in apolipoprotein A-I levels were greater in anacetrapib patents than in placebo patients — by 21.0% and 44.7%, respectively. All lipid changes persisted throughout the 76-week study period.
Study treatment was discontinued in 143 patients (142 on anacetrapib and 1 on placebo) whose LDL levels fell below 25 mg/dL. The rate of study-drug discontinuation for other reasons was similar in the two groups (14.6% and 17.4%, respectively). The rate of adverse events did not differ appreciably between the two groups. A prespecified, adjudicated safety endpoint (cardiovascular death, myocardial infarction, hospitalization for unstable angina, or stroke) occurred in 2.0% of anacetrapib patients and 2.6% of placebo patients, a nonsignificant difference. In all, 11 patients in the anacetrapib group and 8 in the placebo group died.
Comment: It is important to note that this study was designed to assess safety and changes in lipid levels, and that it was underpowered to assess the efficacy of anacetrapib for preventing clinical cardiovascular events. Nonetheless, anacetrapib demonstrated profound LDL-lowering and HDL-raising effects and appeared to have none of the adverse cardiovascular effects observed with torcetrapib. These results provide a strong rationale for the large clinical outcomes trial that will surely follow.
Published in Journal Watch Cardiology November 17, 2010
Citation(s):
Cannon CP et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010 Nov 16; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa1009744).
Reader Remarks:
Review and add to remarks on this article
- prognosis
JJ Mendoza, issste hospital, 18 Nov 2010 1:20 PM EST
Specialty: Cardiovascular Disease
do exist any large observational placebo control study with this drug related to improve cardiovascular morbimortality?
