Revisiting Clopidogrel (PLAVIX) Plain Aspirin Still Preferred in Preventing Stroke, Heart Attack and Blood Clots

Editor’s Note: Due to requests from many readers we are updating an article on clopidogrel (PLAVIX), first published in Worst Pills, Best Pills News in November 1999. A new review of this subject has just been published in the Journal of the American Medical Association (see below).

In the August 1999 issue of the journal Stroke, researchers compared the benefits of clopidogrel (PLAVIX) to aspirin in reducing stroke, heart attack, and death from diseases of the blood vessels. Clopidogrel, manufactured by Bristol-Myers Squibb, was approved by the Food and Drug Administration (FDA) in 1997. It was among the top ten products released in 1998, with over $88 million in retail sales. Clopidogrel’s sales have since skyrocketed to almost $1.7 billion in 2003, thanks in part to an aggressive direct-to-consumer advertising campaign.

In contrast, aspirin is approved by the FDA in a dose of 50 to 325 milligrams once per day for the prevention of stroke and in a dose of 75 to 325 milligrams daily for the prevention of recurrent heart attacks.

Clopidogrel and aspirin are known as antiplatelet drugs because they inhibit the aggregation (clumping together) of platelets, the cells in the blood that are important in forming blood clots. These two drugs work in different ways to prevent platelet aggregation, and currently there is no evidence that one way is better than the other.

Clopidogrel is chemically similar to ticlopidine (TICLID), another antiplatelet drug. In the October 1998 Worst Pills, Best Pills News, we reported that ticlopidine’s labeling had been strengthened to warn about the possibility of bone marrow toxicity that can cause a potentially life-threatening blood disorder known as thrombotic thrombocytopenic purpura (TTP).

Clopidogrel Versus Aspirin

Clopidogrel and aspirin were directly compared in a large clinical trial published in 1996, known by the acronym CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events). This trial examined the efficacy of the two drugs in preventing a second heart attack or stroke and death from diseased blood vessels in 19,185 patients with either (1) a recent heart attack, (2) a recent stroke, or (3) significant blood vessel disease. The study participants were randomly assigned to take either 325 milligrams of plain aspirin or 75 milligrams of clopidogrel once daily. At the end of the three-year study the incidence of heart attack, stroke, and vascular deaths in the clopidogrel and aspirin groups were compared.

The comparison found 5.83 deaths per year in the aspirin group versus 5.32 deaths per year in those receiving clopidogrel. This difference was statistically significant (one peculiarity of statistics is that no matter how small a difference is found, it can become statistically significant if the study is large enough). This difference is equivalent to a risk of five additional deaths per 1,000 patients.

The major problems that have been discussed concerning the findings of the CAPRIE trial include the small magnitude and marginal statistical significance of the absolute difference between the two treatments. This leaves open questions about whether such a difference is clinically meaningful or, in fact, reproducible. Reproducibility of a study’s results is an important part of the scientific method and cuts down on the possibility that the first set of results was due to chance.

By far, the greatest benefit of clopidogrel occurred in the group with blood vessel disease. Over 75 percent of the advantage of clopidogrel over aspirin occurred in those patients with blood vessel disease.

The Safety Of Clopidogrel
And Aspirin

Aspirin has been consumed by millions of people over the last 100 years. Its adverse effects are widely recognized and include gastrointestinal (GI) discomfort; gastric erosions or ulcers; GI bleeding; other bleeding episodes including hemorrhagic stroke and allergic reactions; and an increase in symptomatic gout. GI disturbances are the most common of these adverse effects and depend on the dose of the drug and the duration of its use.

In the CAPRIE study, the same percentage (11.4 percent) of patients withdrew from treatment in the clopidogrel and aspirin groups because of adverse reactions. GI tract symptoms and generalized bleeding were the most frequently reported adverse effects for both drugs. However, there were slight differences in the occurrence of certain other adverse effects between the two groups. The overall incidences of rash and diarrhea were greater in the clopidogrel group than in the aspirin group. The overall incidence of GI discomfort, GI hemorrhage, peptic ulcer, and abnormal liver function were greater in the aspirin group than in the clopidogrel group. These adverse reactions are summarized above along with the percentage of patients that experienced each type of reaction.

As mentioned above, clopidogrel is a chemical relative of ticlopidine, a drug with known bone marrow toxicity. At the time we wrote our first review of clopidogrel, the bone marrow toxicity of ticlopidine had not been seen with clopidogrel. However, a study was published in the June 15, 2000 issue of The New England Journal of Medicine linking clopidogrel to TTP, the same bone marrow disorder seen with ticlopidine. TTP is characterized by a low number of platelets in the blood. Platelets are an important step in the body’s first-line defense against unwanted bleeding. Anemia, neurologic changes, progressive kidney failure and fever are also part of the constellation of symptoms seen in this disorder (see Worst Pills, Best Pills News June 2000).

The FDA required that the professional product label, or package insert, for clopidogrel be amended in April 2000 to warn of the possibility of TTP with the use of clopidogrel.

The FDA-approved labeling for clopidogrel also cautions that rates of major and minor bleeding were higher in patients treated with the drug plus aspirin, compared to placebo plus aspirin in a clinical trial.

The Cost Of Clopidogrel
And Aspirin

The out-of-pocket cost of a 100-day supply of clopidogrel 75 milligram tablets, or 100 tablets, in a Washington, DC area chain pharmacy was $361.99 in 1999. The cost is now $419.99. At the same pharmacy, a 100-day supply of aspirin, or 100 tablets, in a dosage of 325 milligrams, costs $2.33. The 81 milligram strength now costs $5.99. Put another way, clopidogrel will cost $4.19 a day versus aspirin at pennies a day. Over the course of a year, the many older adults without prescription drug coverage would have to pay approximately $1,500 a year for just this one drug.

The authors of the CAPRIE study concluded “When the efficacy, safety, cost, and convenience of aspirin and clopidogrel are compared, the balance of the evidence favors the use of aspirin in the prevention of recurrent thromboembolic [blood clots] events in stroke and myocardial infarction [heart attack] patients.”

The authors go on to say clopidogrel is an alternative to aspirin in patients who cannot take aspirin or whose treatment has failed with aspirin. We agree.

New Recommendations: Clopidogrel Or Aspirin?

Publishing in the October 20, 2004 Journal of the American Medical Association, Canadian researchers summarized the evidence regarding antiplatelet drugs. They for all practical purposes searched the world’s medical literature from 1960 through August 2004. The search included scientific statements, and guidelines from official professional organizations. Their conclusion:

“Current clinical trial evidence favors the use of aspirin or clopidogrel as first-line agents for the majority of patients with vascular disease.”

Vascular diseases include stroke, coronary artery disease, and blood vessel disease.

The researchers went on to say:

“Clopidogrel may be preferred in patients with aspirin intolerance.”

This is essentially our 1999 recommendation, which we reprint below.

What You Can Do

If you have had a previous heart attack, stroke, or have blood vessel disease you should be on aspirin treatment rather than clopidogrel unless you cannot tolerate aspirin, or aspirin treatment has failed.

If you are now taking ticlopidine and cannot take aspirin, talk to your doctor about clopidogrel.