Peter B. Berger, M.D., Henry R. Black, M.D., William E. Boden, M.D.,

Patrice Cacoub, M.D., Eric A. Cohen, M.D., Mark A. Creager, M.D.,

J. Donald Easton, M.D., Marcus D. Flather, M.D., Steven M. Haffner, M.D.,

Christian W. Hamm, M.D., Graeme J. Hankey, M.D., S. Claiborne Johnston, M.D.,

Koon-Hou Mak, M.D., Jean-Louis Mas, M.D., Gilles Montalescot, M.D., Ph.D.,

Thomas A. Pearson, M.D., P. Gabriel Steg, M.D., Steven R. Steinhubl, M.D.,

Michael A. Weber, M.D., Danielle M. Brennan, M.S., Liz Fabry-Ribaudo, M.S.N., R.N.,

Joan Booth, R.N., and Eric J. Topol, M.D., for the CHARISMA Investigators*

ABSTRACT

Background:

Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied

in a broad population of patients at high risk for atherothrombotic events {blood clot of a coronary artery that supplies oxygen to the heart muscle}.

Method:

We randomly assigned 15,603 patients with either clinically evident cardiovascular

disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose

aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them

for a median of 28 months. The primary efficacy end point was a composite of

myocardial infarction, stroke, or death from cardiovascular causes.

Results:

The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin

and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence

interval, 0.83 to 1.05; P = 0.22). The respective rate of the principal secondary efficacy

end point, which included hospitalizations for ischemic events, was 16.7 percent and

17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P = 0.04),

and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95

percent confidence interval, 0.97 to 1.61 percent; P = 0.09). The rate of the primary end

point among patients with multiple risk factors was 6.6 percent with clopidogrel and

5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to

1.59; P = 0.20) and the rate of death from cardiovascular causes also was higher with

clopidogrel (3.9 percent vs. 2.2 percent, P = 0.01). In the subgroup with clinically evident

atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with

placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P = 0.046).

Conclusions:

In this trial, there was a suggestion of benefit with clopidogrel treatment in patients

with symptomatic atherothrombosis and a suggestion of harm in patients with multiple

risk factors. Overall, clopidogrel plus aspirin was not significantly more effective

than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from

cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.)

COMMENT BY JK:

Very likely the results would be much better if the aspirin given with the placebo was the standard dose of 325 mg.  I have strongly recommended this higher does because of the ability to very significantly reduce cancer risk and increase cancer survival, which is dose related.    The method by which aspirin accomplishes this is through the body’s mechanism of apoptosis (the destruction of abnormal cells) which it enhances. 

The difference between the two groups is a 0.5% lower incidence during the period of the study (28 months) of major atherothrombotic event. This translates into 1 less atherothrombotic event for every 200 taking the combination therapy.  Moreover in another study there was an increased major bleeding event (requiring a transfusion of 2 or more pints of blood) 1% of those on Plavix compared to aspirin alone.  SIDE EFFECTS AND COST MAKE IT CLEAR THAT ASPIRIN ALONE IS THE PREFERRED TREATMENT. 

The marketing  department of Bristol-Myers Squibb runs with what every positive crumb they can find, such as that in one study Plavix was slightly superior for aspirin for the first 30 day, but not thereafter,

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WORSTPILL.ORG at http://www.worstpills.org/member/drugprofile.cfm?m_id=217

Safety Warnings For This Drug: [top]

BOXED WARNING {FDA required on drug package}

• Warn about reduced effectiveness in patients who are poor metabolizers of PLAVIX. Poor metabolizers do not effectively convert PLAVIX to its active form in the body.
• Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function.
• Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for PLAVIX in patients identified as poor metabolizers.¹

Also, a New England Journal of Medicine study published on April 20, 2006, found that clopidogrel, when given in combination with aspirin, was overall no more effective than aspirin alone in reducing the rate of heart attacks, strokes, or deaths from cardiovascular causes.⁵

In a study examining the management of acute coronary syndromes, clopidogrel was found to be marginally better than aspirin by only 2.1 percent. However, there were statistically significantly more patients with major bleeding episodes (defined as needing a transfusion of at least two units of blood) in those taking clopidogrel. In this study, 1 percent more patients taking clopidogrel had a major bleeding episode compared to the aspirin-treated patients, but there was no statistical difference between those taking clopidogrel or aspirin in regard to episodes of life-threatening bleeding.⁶

In 2009 the FDA issued information concerning the use of clopidogrel and omeprazole. According to the FDA release, the concurrent use of clopidogrel and omeprazole resulted in a reduction in the effectiveness of clopidogrel. The FDA release also stated that separating the administration time of the dose of each drug did not reduce the harmful interaction of this therapy.

According to the FDA, “Other drugs that are expected to have a similar effect and should be avoided in combination with clopidogrel include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.” ¹⁰

Bleeding ulcers

Research published in the January 20, 2005, New England Journal of Medicine found “an astonishingly high rate of bleeding ulcers” in patients taking clopidogrel (PLAVIX) compared to patients taking plain aspirin plus the antiulcer/heartburn drug esomeprazole (NEXIUM). No safety advantage was found for clopidogrel over aspirin plus esomeprazole in ulcer bleeding. (See complete article from March 2005.)

Plavix is widely advertised on television.  Plavix is the world’s second best selling drug.  In the U.S. it sells for more than $4/day.  In 2006 48 million Americans use it daily, resulting in sales of $6 billion--jk

Delaying Generic Competition — Corporate Payoffs and the Future of Plavix

Miriam Shuchman, M.D.

N Engl J Med 2006; 355:1297-1300September 28, 2006

http://www.nejm.org/doi/pdf/10.1056/NEJMp068193

This article has no abstract; the first 100 words appear below.

In August, pharmacies began selling a cheaper, generic version of the blockbuster antiplatelet agent Plavix (clopidogrel). This was good news for patients with cardiac disease or stroke who cannot afford to buy the medication at more than $4 a day. But to Bristol-Myers Squibb and Sanofi-Aventis, who produce and market the drug, it was a financial disaster. Plavix is the world's second-best-selling drug — 48 million Americans use it on a daily basis — and with sales of more than $6 billion last year, it accounts for about 30 percent of Bristol-Myers's total earnings. In an effort to keep the . . 

For JK’s library on aspirin http://healthfully.org/aspirin/index.html

Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for any medical advice, diagnosis, and treatment.