Clopidogrel Can Be Effective in Reducing Cardiac Risk


Drug shown to reduce the risk of cardiovascular events in both men and women

16 nov 2009-- The antiplatelet drug clopidogrel is likely effective in reducing the risk of cardiovascular events in both men and women, according to a study in the Nov. 17 issue of the Journal of the American College of Cardiology.

Jeffrey S. Berger, M.D., of the New York University School of Medicine in New York City, and colleagues performed a meta-analysis of five randomized clinical trials involving 79,613 patients (30 percent women) that examined the safety and efficacy of clopidogrel at reducing cardiovascular events.

The researchers found that clopidogrel significantly reduced the risk of cardiovascular events by 14 percent (odds ratio, 0.86), with similar efficacy in men and women. Clopidogrel significantly reduced the risk of myocardial infarction in both women and men (odds ratios, 0.81 and 0.83, respectively). In men, clopidogrel also reduced the risk of stroke (odds ratio, 0.83) and total death (odds ratio, 0.91), while in women the effects were not statistically significant. In addition, clopidogrel increased the risk of major bleeding in both men and women (odds ratios, 1.22 and 1.43, respectively).

"The cumulative evidence continues to show that women with coronary artery disease differ from men in many important ways, including the response to antiplatelet therapy," the author of an accompanying editorial writes. "The good news is that clopidogrel is an exception."

Several authors of the article and editorial reported financial and consulting relationships with pharmaceutical companies.

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ESC: Effects of Combining PPIs and Thienopyridines Examined

Coadministration of PPI with clopidogrel or prasugrel may not increase heart risks

03 sept 2009-- In patients receiving clopidogrel or prasugrel, use of proton-pump inhibitors (PPIs) is not associated with an increased risk of cardiovascular events, according to a study published online Sept. 1 in The Lancet and presented at the European Society of Cardiology Congress 2009, held from Aug. 29 to Sept. 2 in Barcelona, Spain.

Michelle L. O'Donoghue, M.D., of Brigham and Women's Hospital in Boston, and colleagues analyzed two trials: the PRINCIPLE-TIMI 44 trial, in which 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel or high-dose clopidogrel; and the TRITON-TIMI 38 trial, in which 13,608 patients with an acute coronary syndrome were randomly assigned to prasugrel or clopidogrel.

In the first trial, the researchers found that PPI use was associated with significantly lower inhibition of platelet aggregation after clopidogrel loading, but a more modest inhibition of platelet aggregation after prasugrel loading. In the second trial, they observed no association between PPI use and the primary end point -- a composite of cardiovascular death, myocardial infarction, or stroke -- for patients treated with clopidogrel or prasugrel (adjusted hazard ratios, 0.94 and 1.00, respectively).

"Although only a randomized trial of PPI use can definitively establish the clinical implications of combining a PPI with a thienopyridine, our findings do not support the need to avoid concomitant use of PPIs for gastric protection in patients receiving thienopyridine therapy who are at increased risk for gastrointestinal bleeding," the authors conclude.

Daiichi Sankyo and Eli Lilly sponsored the two trials; several co-authors reported financial relationships with the companies.

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Anti-clot drug combinations boost

CHICAGO, 04 june 2009-- Heart patients are often given two or three different drugs to prevent life-threatening blood clots but these combinations can double, triple or even quadruple the risk of stomach or intestinal bleeding, U.S. researchers said on Tuesday.

Clot-preventing drugs such as aspirin, warfarin or Coumadin and clopidogrel or Plavix sold by Bristol-Myers Squibb and Sanofi-Aventis are increasingly being given to heart patients in combinations.

"They are often prescribed to prevent that second event -- that heart attack or stroke," Dr. Neena Abraham of Baylor College of Medicine in Houston, Texas, told reporters at the Digestive Disease Week meeting in Chicago.

"However, each of these drugs independently is associated with a high risk of clinically significant upper gastrointestinal events, which are defined as ulcers of the stomach or intestines, bleeding or perforations," she said.

"These drugs are commonly prescribed in combination; however, the magnitude of the risk of using these drugs on the gastrointestinal tract remains relatively unknown."

To study this, Abraham and colleagues used national pharmacy data and medical records from the Veterans Affairs Department to identify people aged 60 to 99 who had been given four combinations of clot-preventing drugs.

Some got aspirin and an antiplatelet drug like Plavix that keeps blood platelets from forming clots. Others got an antiplatelet drug and an anticoagulant such as warfarin, which keeps the liver from making certain clotting factors. Some got aspirin and warfarin. And some got all three.

Of the more than 78,000 patients studied, 30.4 percent were prescribed some combination of anticlotting drugs, and 1,061 of these had bleeding events that needed immediate medical attention within the first year.

RISING RISK

"When we compared the risk of bleeding from these different combinations, what we see is a stepwise increase in risk," Abraham said.

The dual combination of an anticoagulant and antiplatelet drug, which proved to be least harmful, raised the risk of a serious bleeding problem within one year by 70 percent.

A combination of an aspirin and antiplatelet drug doubled the risk, while an aspirin-anticoagulant combination tripled the one-year bleeding risk.

And patients who got all three drugs had a four-fold increase in the risk of gastrointestinal bleeding within one year, Abraham said.

"These are significant gastrointestinal bleeding risks."

Abraham said triple therapy was most commonly given to younger patients in the study -- those aged 60 and 69 years of age -- and likely reflected recent changes in cardiac care.

She said the findings suggest the need for a careful balancing of the risks and benefits of these drugs.

Heart patients on triple therapy may want to ask their doctor about dropping down to a dual or single therapy.

"We know they are healthy for the heart at preventing strokes and heart attacks, but what physicians now need to consider is short-term potential risks of GI bleeding versus the potential long-term benefits of being on these protective drugs," she said.

Study shows benefits of anti-clotting medications reduced by common heartburn drugs

Proton pump inhibitors interfere with anti-clotting protection of clopidogrel

LAS VEGAS, 07 may 2009— The anti-clotting action of the medication clopidogrel (Plavix) can be compromised by common drugs for the treatment of heartburn and ulcers resulting in a roughly 50% increase in the combined risk of hospitalization for heart attack, stroke and other serious cardiovascular illnesses, according to a new study presented today at the Society for Cardiovascular Angiography and Interventions (SCAI) 32nd Annual Scientific Sessions. The study specifically focused on the effects of proton pump inhibitors (PPI) omeprazole (Prilosec), esomeprazole (Nexium), pantoprazole (Protonix), and lansoprazole (Prevacid), which together accounted for about 96% of PPI use in the study.

Patients who receive a drug-eluting stent benefit from taking anti-clotting medications, including thienopyradines (such as clopidogrel or ticlopidine) and aspirin, for at least one year following the procedure. Doctors often also prescribe PPIs to patients taking clopidogrel because of pre-existing stomach disease or to reduce the risk of common side effects such as nausea and gastroesophageal reflux (heartburn). Before clopidogrel can exert its anti-clotting effects, it must be converted from its inactive, pro-drug form to an active drug by enzymes in the liver. PPIs—the sixth most commonly prescribed drug class in the U.S.—can interfere with those liver enzymes, according to the study.

"Given the large number of patients who undergo coronary stent procedures each year, and the recommended and wide use of clopidogrel following this procedure, our findings have implications for many thousands of patients across the United States," said Eric J. Stanek, PharmD, senior director of research, personalized medicine research and development, Medco Health Solutions, Franklin Lakes, NJ, and the study's principal investigator. "Clopidogrel should continue to be taken as prescribed, and the need for PPI therapy should be carefully evaluated to ensure that it is prescribed only when clearly indicated."

For the study, researchers analyzed integrated data on pharmacy and medical claims from more than 10 million patients, including 16,690 patients taking clopidogrel for a full year following coronary stenting. Of these, 41% also took a PPI, on average, for more than nine months of the year. Over that 12-month period when patients took clopidogrel, investigators evaluated the risk of hospitalization for major adverse cardiovascular events (MACE), which they defined as a combination of heart attack, unstable angina, stroke or temporary stroke-like symptoms, repeat coronary procedures, or cardiovascular death.

The overall MACE risk was 51% higher among patients taking any PPI. The findings were equally concerning when the effects of individual PPIs were analyzed. Omeprazole correlated with a 39% increased risk of MACE, esomeprazole to a 57% increased risk, pantoprazole to a 61% increased risk and lansoprazole to a 39% increased risk. All of the associations were highly statistically significant. Overall, the incidence of hospitalization for upper gastrointestinal bleeding was only 1.1% among patients taking a PPI and 0.07% among those not taking a PPI.

Additional research is needed to determine whether newer, less widely used PPIs such as rabeprazole (Aciphex) and dexlansoprazole (Kapidex) are also associated with increased cardiovascular risk in patients taking clopidogrel. Researchers are also interested in examining how genetic variations in the liver enzymes that activate clopidogrel might alter the impact of PPIs on clopidogrel effectiveness, the potential influence of the timing of PPI administration, the effect of alternate dosing of clopidogrel, and the comparative effectiveness of other anti-clotting medications.

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This study was supported independently by Medco Health Solutions, Inc, and conducted in collaboration with investigators from the Indiana University School of Medicine.

Using PPIs with Clopidogrel Associated with Adverse Outcomes After ACS

04 mar 2009--After acute coronary syndrome, use of a proton pump inhibitor (PPI) alongside clopidogrel is associated with more frequent rehospitalization or mortality compared with clopidogrel alone, according to an observational study in JAMA.

Veterans Affairs researchers examined outcomes in some 8200 patients prescribed clopidogrel at discharge after ACS. Nearly two thirds of the patients also received a PPI either at discharge or during a median 1.5-year follow-up. The primary endpoint, a combination of rehospitalization for ACS or death from any cause, occurred more often among those taking clopidogrel with a PPI than among those taking clopidogrel alone.

The authors note that previous studies have shown that PPIs attenuate clopidogrel's antiplatelet effects.

In Journal Watch Cardiology, JoAnne Foody concludes: "Although [the current] results bear the limitations of all observational studies ... clinicians should consider this potential interaction when they weigh the pros and cons of prescribing a PPI with clopidogrel for ACS patients."

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Proton pump inhibitors increase risk of heart attacks for patients on common cardiac drug

29 jan 2009--Patients taking the common cardiac drug clopidogrel following a heart attack are at a significantly higher risk of a recurrence if they are also taking widely used acid-lowering medications called proton pump inhibitors, a new study published online in CMAJ has found (http://www.cmaj.ca/cgi/rapidpdf/cmaj.082001).

The study, conducted over 6 years in thousands of heart attack patients aged 66 years and older, found a significantly increased risk of readmission for heart attacks if patients were taking one of several proton pump inhibitors, including omeprazole, lansoprazole, or rabeprazole. The investigators found no such association with the proton pump inhibitor pantoprazole or with other acid-lowering medications called H2 receptor antagonists.

Previous research indicates that proton pump inhibitors other than pantoprazole can block the liver's ability to convert clopidogrel to its active form,a critical step required for clopidogrel's anti-platelet effect.

These findings could have significant public health implications. Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs in the world, with more than 12.4 million prescriptions in Canada alone in 2004. Clopidogrel is the second-highest selling drug in the world, with annual sales totalling $7.3 billion.

Recent guidelines from the American Heart Association, the American College of Gastroenterology, and the American College of Cardiology recommend proton pump inhibitor therapy for many patients following a heart attack to prevent bleeding from the stomach, including all patients aged 60 years or older receiving ASA. Because clopidogrel and ASA are often prescribed together following a heart attack, it is probable that millions of patients worldwide will take a proton pump inhibitor with clopidogrel.

"Depending on the exposure to these drugs following a heart attack, we estimate that 5% to 15% of early readmissions for myocardial infarction among patients taking clopidogrel could be the result of this drug interaction," writes Dr. David Juurlink, Head of the Division of Clinical Pharmacology and Toxicology at Sunnybrook Health Sciences Centre and lead author of the study, which was conducted at the Institute for Clinical Evaluative Sciences (ICES). "These findings highlight a widely unappreciated, extremely common and completely avoidable drug interaction in a population of patient at very high risk of reinfarction."

"Our findings suggest that indiscriminate treatment with a proton pump inhibitor could result in thousands of additional cases of recurrent myocardial infarction each year, all of which could be avoided simply by selectively prescribing pantoprazole in patients receiving clopidogrel who require treatment with a proton pump inhibitor," write the authors.

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The article will appear in the March 31, 2009 print version of the journal.

Visit www.cmaj.ca for medical knowledge that matters.

Routine Use of Clopidogrel to Prevent Failure of New Fistulas Not Supported by Data

November 8, 2007 (San Francisco) — Results of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Dialysis Access Consortium (DAC) trial of clopidogrel for prevention of early thrombosis of hemodialysis-related arteriovenous (AV) fistulas do not support the routine use of clopidogrel to prevent the early failure of new fistulas.
Results from this trial were presented by Harold Feldman, MD, and Laura Dember, MD, here at Renal Week 2007, the American Society of Nephrology Annual Meeting. Dr. Feldman is national study chair of the DAC and a professor of medicine at the University of Pennsylvania, Philadelphia. Dr. Dember is a principal investigator for the DAC, associate professor of medicine at Boston University, and medical director of the DaVita-Boston Dialysis Center, Massachusetts.
According to Dr. Feldman, vascular access complications are a major source of morbidity in North America and worldwide. An estimated 16% of all hospitalizations for patients with end-stage renal disease are the result of vascular access complications. The DAC study was a large, multicenter clinical trial of an intervention (clopidogrel) to improve vascular access outcomes.
The rationale and design of the trial were based on the beliefs that fistulas are the preferred access type, that fewer complications and lower costs are associated with dialysis through fistulas, and that individuals dialyzed through fistulas have lower associated mortality. Early failure is a major barrier to increasing fistula prevalence, and the failure of fistula success and maturation leads to the prolonged use of catheters, with their attendant morbidity, Dr. Feldman said.
The DAC trial was designed to enroll 1284 subjects that would provide 85% power to detect a 30% reduction in thrombosis in 6 weeks.
At 6 weeks, 12.2% of the subjects in the clopidogrel group had thrombosis vs 19.5% of subjects in the placebo group. However, for the secondary outcome, suitability for dialysis, suitability failed in 63% of the clopidogrel group and in 60% of the placebo group.
"We were struck by the very high rate of fistula suitability failure, and so we performed a variety of sensitivity analyses to assess the frequency of suitability failure. Even with the least restrictive definition of fistula suitability, nearly half of the fistulas failed," Dr. Dember said.
The study was terminated early because the intervention was clearly efficacious with regard to the primary outcome of patency. Unexpectedly, however, the benefit of clopidogrel on patency was not accompanied by an improvement in fistula suitability. "From a clinical standpoint, the findings of our trial do not support the routine use of clopidogrel to prevent the early failure of new fistulas," Dr. Dember said.
"From a mechanistic standpoint, our findings suggest that patency is necessary but not sufficient for fistula maturation, and that properties not affected by clopidogrel are likely to be important for fistula maturation," he continued.
"We believe that the focus of future efforts should be on elucidating mechanisms underlying maturation failure, on determining which patients have acceptably high likelihood of fistula maturation success, and on identifying interventions to enhance fistula maturation," Dr. Dember said.
"The rate of failure, meaningful failure in terms of the suitability of these access devices, is huge. Sixty percent fail," Dr. Feldman told Medscape Nephrology after the presentation. "That's one point. The second point is that this treatment, which has a lot of attractiveness and was demonstrated to be effective with one particular outcome, meaning the thrombosis outcome, turns out unexpectedly to not be a useful clinical intervention."
"And that's really important because it helps to inform people that they should not be complacent and just treat people with this agent, even though in the short term they may believe they are doing their patients a world of good. In fact, we even showed that in the short term you can quantitate the benefit, but the long-term effect is that it has no benefit at all. It's always important to be able to inform people about what they shouldn't do, especially when there is a lot of information out there that is maybe leading them to believe that this is an effective therapy," Dr. Feldman continued.
"This was an excellently designed trial, and it was carried out with scientific rigor," said Sharon Adler, MD, one of the moderators of the session. "And it basically underscores the fact that we have more work to do in trying to provide the best access we can to hemodialysis patients." Dr. Adler is a professor of medicine at the Harbor-University of California, Los Angeles, Medical Center.
Collaborating institutions included Boston University, Duke University, the Maine Medical Center, the University of Alabama in Birmingham, the University of Iowa, the University of Texas Southwestern Medical Center, Vanderbilt University Medical Center, Washington University in St.Louis, Wake Forest University, the Cleveland Clinic Foundation, and the NIDDK.
Dr. Dember has disclosed receiving research support from Neurochem, Inc, the NIDDK, and Proteon, Inc. She has also disclosed that she is a consultant for Proteon, Inc. The clopidogrel used in the study was donated by Bristol-Myers Squibb and Sanofi-Aventis.
Renal Week 2007. Presented November 4, 2007.