Drug Profile

Clopidogrel (PLAVIX) is a member of the thienopyridine family, which are commonly referred to as "antiplatelet agents." Other members of this drug family include prasugrel (EFFIENT) and ticlopidine. These drugs work by inhibiting platelets and, thus, blood clot formation.

Clopidogrel is a widely used drug that has been approved by the Food and Drug Administration (FDA) to reduce the risk of a new heart attack, stroke or cardiovascular death in the following patient groups:

• Patients who have a condition known as acute coronary syndrome and who are to be treated with medicines, a stent (a tube-shaped metal mesh device placed in a coronary artery vessel to keep it open) or coronary artery bypass surgery. Acute coronary syndrome consists of unstable angina (worsening chest pain due to inadequate blood flow to the heart) or changes on an electrocardiogram (EKG) that suggest a heart attack is occurring. In such patients, clopidogrel should be administered with aspirin.
• Patients who have definitive changes on an EKG indicating that an acute heart attack is occurring and who are to be treated with medicines. In such patients, clopidogrel should be administered with aspirin.
• Patients who have a history of a recent heart attack or stroke or have established peripheral vascular disease (for example, evidence of narrowed or blocked arteries in the legs or neck).[1]

Studies say...

Cardiovascular events

Researchers have struggled to show that clopidogrel is better than aspirin, the oldest and most frequently used antiplatelet drug, in preventing certain cardiovascular incidents, such as heart attacks and strokes, and they have been largely unsuccessful.

A single clinical trial was the basis for FDA approval of clopidogrel for preventing a second heart attack or stroke. In this trial, clopidogrel was directly compared with aspirin.[2] The difference between clopidogrel and aspirin was very small but statistically significant in favor of clopidogrel. A critique of the trial concluded by saying that the result “leaves open questions about whether such a difference is clinically meaningful, or in fact, reproducible.”[3]

The trial did not show clopidogrel to be superior to aspirin in preventing a second heart attack or stroke. The fact that clopidogrel is no better than aspirin for this use did not stop its manufacturer from advertising it as a better drug overall. This resulted in the FDA warning Bristol-Myers Squibb/Sanofi in April 2001 about its false and misleading promotion of clopidogrel as being superior to aspirin.[4]

In the August 1999 issue of the journal Stroke, researchers compared the benefits of clopidogrel with those of aspirin in reducing stroke, heart attack and death from diseases of the blood vessels, concluding that these two drugs work in different ways to prevent platelet aggregation. Currently, there is no evidence that one of these ways is better than the other. (See article from January 2005.)

Also, a New England Journal of Medicine (NEJM) 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%. 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% more patients taking clopidogrel had a major bleeding episode compared with the aspirin-treated patients, but there was no statistical difference between those taking clopidogrel or aspirin in regards to episodes of life-threatening bleeding.[6]

A further analysis of the aforementioned trial found that in patients with acute coronary syndrome who were taking aspirin, adding clopidogrel was beneficial, compared with placebo, in reducing major cardiovascular events.[7] However, it has been noted that beyond 30 days there was no significant advantage to treatment with clopidogrel over placebo in regards to cardiovascular death or nonfatal heart attack. The long-term role of clopidogrel remains unclear.[8]

In 2013, The Lancet published an article on patients undergoing percutaneous coronary interventions taking oral anticoagulant therapy (blood thinners). The study examined adding clopidogrel alone or clopidogrel and aspirin to oral anticoagulant therapy. The results of the study indicated that patients receiving clopidogrel without aspirin had a lower risk of bleeding complications and no increased risk of thrombotic events in comparison with those who used both clopidogrel and aspirin.[9]

In July 2018 the New England Journal of Medicine published an article asserting that patients taking a combination of clopidogrel and aspirin after a minor stroke had a 25% lower risk of a subsequent major adverse cardiovascular event (ischemic stroke, heart attack or cardiovascular-related death) but a more than twofold higher risk of major bleeding than patients taking aspirin alone.[10]

Effect decreased when combined with omeprazole (PRILOSEC) and other proton pump inhibitors (PPIs)

A study published in 2008 investigating the effect of the heartburn drug omeprazole (PRILOSEC, PRILOSEC OTC, ZEGERID, ZEGERID OTC), a PPI, on the action of clopidogrel plus aspirin therapy found that omeprazole significantly decreased the effect of clopidogrel, meaning that it could be less effective in preventing strokes and heart attacks. Physicians should be aware of this association, since this drug combination is widely prescribed.[11] Patients also should be made aware of this drug interaction since omeprazole is available over the counter without a prescription.

In 2009, the FDA also issued information that the concurrent use of clopidogrel and omeprazole resulted in a reduction in the effectiveness of clopidogrel. The FDA release also stated that staggering the administration times of the drugs did not reduce this harmful interaction.

According to the FDA, "Other drugs that are expected to have a similar effect and should be avoided in combination with clopidogrel include: cimetidine [TAGAMET, TAGAMET HB], fluconazole [DIFLUCAN], ketoconazole [NIZORAL], voriconazole [VFEND], etravirine [INTELENCE], felbamate [FELBATOL], fluoxetine [PROZAC, PROZAC WEEKLY, SARAFEM, SELFEMRA, SYMBYAX], fluvoxamine [LUVOX, LUVOX CR], and ticlopidine [available in generic version only]."[12]

Genetic factors

Published medical literature shows that clopidogrel is less effective in some patients than in others. This is likely due to the effects of genetic factors or certain other drugs (such as PPIs) that influence how the body metabolizes clopidogrel. Clopidogrel first must be converted in the liver to an active metabolite that inhibits platelets. Some people inherit genes that cause their livers to convert clopidogrel to its active form more slowly. For such patients, the drug is less effective.

In 2010, the drug label for clopidogrel was updated to include a black-box warning indicating that patients treated with clopidogrel who are poor metabolizers of the drug because of their genetic makeup have higher rates of adverse cardiovascular events after acute coronary syndrome or coronary artery stent placement than those who are normal metabolizers of the drug.[13]

Adverse effects

Blood disorder — Thrombocytopenic purpura (TTP)

Clopidogrel has been linked to a life-threatening blood disorder called thrombotic thrombocytopenic purpura (TTP). Ticlopidine, the first available thienopyridine, also has been linked to TTP.[14] TTP was identified in 11 patients in a two-year period from March 1998 to March 2000 from an active surveillance program that involved blood banks around the U.S.[15] From the end of 1997 to the fourth quarter of 2001, the FDA received 16 reports of TTP linked to clopidogrel. It is not known if these 16 reports included the 11 cases mentioned above.

Bleeding ulcers and other GI bleeding

Research published in the Jan. 20, 2005, issue of NEJM found “an astonishingly high rate of bleeding ulcers” in patients taking clopidogrel (PLAVIX) compared with patients taking plain aspirin plus the anti-ulcer/heartburn drug esomeprazole (NEXIUM). No safety advantage was found for clopidogrel over aspirin plus esomeprazole in ulcer bleeding. (See complete article from March 2005.)

Combining clopidogrel with nonsteroidal anti-inflammatory drugs, including aspirin, also increases the risk of gastrointestinal bleeding.

When you fill a prescription for clopidogrel, the dispensing pharmacist should provide the FDA-approved Medication Guide for this drug. The guide provides important safety information regarding use of the drug.

Regulatory actions surrounding clopidogrel

2005: In response to an action letter request by the FDA, the manufacturer of clopidogrel revised the precaution section of the product label to include the following statement: “In patients with recent TIA [transient ischemic attack] or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding.”[16]

2010: The FDA issued an advisory that a black-box warning had been added to the product information for clopidogrel regarding patients who are poor metabolizers of the drug.

2013: The Medicines and Healthcare products Regulatory Agency (a government agency in the U.K. similar to the FDA) announced that it had received reports of acquired hemophilia (a rare bleeding disorder) in patients taking clopidogrel. It is important for health care professionals to use caution in identifying bleeding in these patients, either due to acquired hemophilia or due to the already established risk of bleeding with clopidogrel therapy.[17]

In December 2013, the FDA added a similar warning of acquired hemophilia with clopidogrel therapy in its postmarketing reports.[18]

2014: In November, the FDA announced that it was reviewing data from the Dual Antiplatelet Therapy study showing that there was an increased risk of death in patients taking clopidogrel or prasugrel plus aspirin for 30 months after stent placement compared with patients taking such dual antiplatelet therapy for only 12 months.[19]

Health Canada (an agency similar to the FDA in Canada) also announced that it was reviewing data from this clinical trial.[20]

2015: Health Canada issued a warning that dangerously low blood sugar levels can occur when the diabetes drug repaglinide (PRANDIN) and clopidogrel are taken together. Health Canada stated that this drug combination should not be used under any circumstances.[21]

2017: In 2016, Public Citizen petitioned the FDA to require that the product labeling for clopidogrel be revised to warn against taking it together with the diabetes drug repaglinide (PRANDIN) because of a drug interaction that could cause dangerously low blood sugar levels. In 2017, the FDA approved changes to the product labeling for both clopidogrel and repaglinide indicating that this drug combination should be avoided.[22]

Petition to the FDA

In August 2013, Public Citizen petitioned the FDA to add a black-box warning to the label for clopidogrel stating that taking the drug for more than a year after having a drug-eluting coronary artery stent (DES) implanted can lead to major bleeding.[23]

Clopidogrel is given routinely to patients after a DES is implanted, usually after a heart attack, to reduce the risk of such events recurring. But it should be given for no more than 12 months after implantation. Public Citizen’s petition cited evidence from randomized controlled trials and other studies indicating that taking clopidogrel for longer than one year after the implantation of a DES offers no further benefit in terms of reduced risk of death from cardiac causes, heart attack or other thrombotic events than does taking it for a year or less. It does, however, increase the likelihood of major bleeding, which may be fatal. The requested warnings apply only to people using the drug in conjunction with a DES.

The FDA denied our petition in December 2018.