Adding Clopidogrel to Aspirin Offers No Benefit in Preventing Heart Attacks or Strokes

A study posted on the Web site of the New England Journal of Medicine on Mar. 12, 2006 found that the blockbuster anti-clotting drug clopidogrel (PLAVIX), 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.

Clopidogrel was approved by the Food and Drug Administration (FDA) in November 1997 for use in patients who had recently suffered a heart attack or stroke to reduce the risk of a new heart attack or stroke. Clopidogrel has also been approved for a condition known as acute coronary syndrome, or ACS, in patients who may be treated either medically or with a stent (a metal device placed in a coronary vessel to keep it open) or bypass surgery to reduce the rate of heart attack, stroke, and cardiovascular death. ACS consists of unstable chest pain (angina) and changes in the electrocardiogram (EKG or ECG) that suggest a heart attack.

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.

In 2005, clopidogrel accounted for almost $2.5 billion in sales, ranking it as the seventh-best-selling drug in the U.S. for that year. The drug is co-marketed by Sanofi Aventis and Bristol Myers Squibb.

The study posted on the New England Journal of Medicine’s Web site is known as the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance, or the CHARISMA trial for short. The trial was funded by clopidogrel’s co-marketers.

CHARISMA used the scientific “gold standard” methodology. In this randomized controlled trial, 15,603 patients with cardiovascular disease or multiple risk factors for cardiovascular events were randomly assigned to receive 75 milligrams of clopidogrel per day in combination with low dose aspirin, taking from 75 milligrams to 162 milligrams per day. These patients were compared to a group receiving a placebo plus low dose aspirin. The patients were followed for a median of 28 months.  

The researchers compared the combined number of heart attacks, strokes, and deaths from cardiovascular causes in the two groups. This is referred to as the study’s primary endpoint.

In the 7,802 patients receiving clopidogrel with aspirin, 534 (6.8 percent) experienced a heart attack, stroke, or death from a cardiovascular cause compared to 573 (7.3 percent) of the 7,801 patients taking aspirin alone. This is a difference of 0.5 percent in favor of clopidogrel. This difference was too small to be statistically different, meaning that the difference was most likely due to chance rather than any difference in impact between the two groups.

A major safety concern with both clopidogrel and aspirin is the risk of bleeding, particularly gastrointestinal (GI) bleeding. Research published in the Jan. 20, 2005 New England Journal of Medicinefound “an astonishingly high rate of bleeding ulcers” in patients taking clopidogrel compared to patients taking plain aspirin plus the antiulcer/heartburn drug esomeprazole (NEXIUM). The results of this research appeared in the March 2005 Worst Pills, Best Pills News.

In the CHARISMA trial, a total of 346 (4.4%) of patients taking clopidogrel with aspirin experienced bleeding episodes described as fatal bleeding, moderate bleeding, severe bleeding, or bleeding into the brain (intracranial hemorrhage). This compares to 249 (3.2percent) of the patients taking only aspirin who experienced one of these bleeding episodes.  

This represent a 1.2 percent greater chance of bleeding in those patients receiving clopidogrel and aspirin than in the group taking aspirin alone.  

The CHARISMA researchers concluded:

...the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction [heart attack], stroke, or death from cardiovascular causes among patients with stable cardiovascular disease or multiple cardiovascular risk factors. Furthermore, the risk of moderate-to-severe bleeding was increased. Our findings do not support the use of dual antiplatelet therapy across the broad population tested.

The weight of the evidence indicates that there is a beneficial role for the short term use of clopidogrel and aspirin in acute situations, such as after the placement of a mesh tube to keep an artery open, called a stent. The CHARISMA trial answered the question about the value of the long term use of the two-drug combination.

The economic impact of the CHARISMA results could have a substantial impact on individual patients who must pay out-of-pocket for their drugs and for the healthcare system as a whole. A one month supply of clopidogrel at a large chain pharmacy retails for $134.99. Over a year this adds up to $1,619.88.

At the same pharmacy, a one month supply of 81 milligram generic low dose aspirin is $1.20. This is a cost of $14.40 per year. The savings over a year for not purchasing clopidogrel is $1,605.48.

In 2005, there were almost 19 million prescriptions dispensed for clopidogrel at a retail cost approaching $2.5 billion. Widespread acceptance and prescribing by physicians is not proof of a drug’s safety and effectiveness. This is a fact that has been known for almost 50 years. The success of clopidogrel in the marketplace is a testament to the advertising prowess of the pharmaceutical industry. If more prescribing decisions were based on scientific evidence, rather than advertising, the U.S. may be able to fund meaningful prescription drug benefit for all Americans similar to what is done in other developed countries.

What You Can Do

If you have had a previous heart attack or stroke or have blood vessel disease, you should be on aspirin treatment rather than clopidogrel with or without aspirin. You should only take clopidogrel if you cannot tolerate aspirin.