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Important Information to Know About Clopidogrel

Worst Pills, Best Pills Newsletter article June, 2014

Clopidogrel (PLAVIX) is a widely used drug approved by the Food and Drug Administration (FDA) to reduce the risk of a new heart attack or stroke or cardiovascular death in patients with a history of a recent heart attack, stroke or established peripheral vascular disease (for example, evidence of narrowed or blocked arteries in the legs or neck). The drug has also been approved by the FDA for a condition known as acute coronary syndrome in patients who may be treated medically or with a...

Clopidogrel (PLAVIX) is a widely used drug approved by the Food and Drug Administration (FDA) to reduce the risk of a new heart attack or stroke or cardiovascular death in patients with a history of a recent heart attack, stroke or established peripheral vascular disease (for example, evidence of narrowed or blocked arteries in the legs or neck). The drug has also been approved by the FDA for a condition known as acute coronary syndrome in patients who may be treated 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. Acute coronary syndrome consists of unstable chest pain (angina) and changes in the electrocardiogram that suggest a heart attack.

Public Citizen’s Health Research Group has designated clopidogrel — which works by inhibiting platelets and, therefore, clot formation — as a Limited Use drug based on our experts’ belief that it offers limited benefit for certain people or conditions.

Studies of clopidogrel

Cardiovascular events

Researchers have struggled but have been largely unsuccessful in showing that clopidogrel is better than aspirin in preventing certain cardiovascular incidents such as heart attack and stroke.

A single clinical trial was the basis for the FDA approving clopidogrel for preventing a second heart attack or stroke. In this trial, clopidogrel was directly compared to aspirin.[1] The difference between clopidogrel and aspirin was very small but statistically significant, favoring 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.”[2]

The trial did not show clopidogrel to be superior to aspirin in preventing a second heart attack or stroke. That fact 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.[3]

In the August 1999 issue of the journal Stroke, researchers compared the benefits of clopidogrel to 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 (clumping), and currently there is no evidence that one way is better than the other.

Also, a New England Journal of Medicine study published in 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.[4]

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 patients taking clopidogrel and those taking aspirin in regard to episodes of life-threatening bleeding.[5]

A further analysis of the trial mentioned immediately above found that in patients with acute coronary syndrome taking aspirin, adding clopidogrel was beneficial, compared to placebo, in reducing major cardiovascular events.[6] However, it has been noted that beyond 30 days there was no significant advantage to treatment with clopidogrel over placebo in regard to cardiovascular death or nonfatal heart attack. The long-term role of clopidogrel remains unclear.[7]

In 2013, the medical journal 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 to those who used both clopidogrel and aspirin.[8]

Effect decreased when combined with omeprazole (PRILOSEC)

A study published in 2008 investigating the effect of the heartburn drug omeprazole (PRILOSEC, PRILOSEC OTC, ZEGERID, ZEGERID OTC), a proton pump inhibitor, on the action of clopidogrel plus aspirin therapy found that omeprazole significantly decreased the effect of clopidogrel, possibly making it less effective in preventing strokes and heart attacks.

In 2009 the FDA issued a safety alert stating that 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 [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].”[9]

Blood disorder — thrombotic thrombocytopenic purpura

Ticlopidine, a close chemical relative of clopidogrel, has been linked to a life-threatening blood disorder called thrombotic thrombocytopenic purpura (TTP).[10] Clopidogrel has also been linked to TTP. TTP was identified in 11 patients soon after they started clopidogrel in a two-year period between March 1998 and March 2000.[11] Between the end of 1997 and the fourth quarter of 2001 the FDA received 16 reports of TTP associated with use of clopidogrel. It is not known if these 16 reports included the 11 mentioned above.

Bleeding ulcers and other GI bleeding

Research published in the Jan. 20, 2005, New England Journal of Medicine found “an astonishingly high rate of bleeding ulcers” in patients taking clopidogrel 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.

Combining clopidogrel with non-steroidal anti-inflammatory drugs also increases the risk of gastrointestinal bleeding.

Regulatory actions surrounding clopidogrel

In 2005, in response to a 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 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.”[12]

In March 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.

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.[13]

Clopidogrel is given routinely to patients after a DES is implanted, usually after a heart attack, to reduce future such events. 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 a year following the implantation of a DES offers no further benefit, in terms of reduced death from cardiac causes, heart attack or other thrombotic events, compared to 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.

A decision by the FDA on our petition is pending.

What You Can Do

Do not use clopidogrel if you have or have had intracranial hemorrhage or peptic ulcer disease.

If you have been taking clopidogrel for more than a year following implantation of a DES, you should contact your cardiologist or primary care provider and discuss discontinuation of the drug.

Before taking clopidogrel, tell your doctor if you have or have ever had an allergy to this drug, bleeding problems, liver disease or stomach ulcers; are pregnant or breast-feeding; or had recent surgery or trauma. Also tell your doctor about any other drugs you take, including aspirin, herbs, vitamins and other non-prescription products.

When taking clopidogrel, tell any doctor, dentist, emergency medical technician, pharmacist or surgeon you see that you take clopidogrel. This is especially important for any surgery, including dental.

If you miss a dose, take it as soon as you remember, but skip it if it is almost time for the next dose. Do not take double doses.

Call your doctor immediately if you experience any of the following symptoms while taking clopidogrel: black, tarry stools; blood in urine or stools; chest pain; fainting; frequent, painful or difficult urination; blood in the urine; generalized pain; sudden or severe headache; irregular heartbeat; sudden joint pain and swelling; nosebleed; red or purple spots on the skin; shortness of breath; skin blistering, flaking or peeling; severe stomach pain; swelling of feet or lower legs; ulcers, sores or white spots in the mouth; unusual bleeding or bruising; vomiting of blood or material that looks like coffee grounds; or sudden weakness.

Call your doctor if you develop these symptoms while taking clopidogrel and they persist: abdominal or stomach pain, anxiety, back pain, constipation, cough, diarrhea, depression, dizziness, fever, chills, headache, heartburn, insomnia, itching, joint pain, leg cramps, muscle aches, nausea or vomiting, numbness or tingling, runny nose, sneezing or skin rash.


[1] CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). The Lancet. Nov 16, 1996;348:1329-1339.

[2] Gorelick PB, Born GV, D'Agostino RB, Hanley DF, Moye L, Pepine CJ. Therapeutic benefit: Aspirin revisited in light of the introduction of clopidogrel. Stroke. Aug 1999;30:1716-1721.

[3] Haffer AST. Food and Drug Administration Warning - Plavix (clopidogrel) Advertising, May 9, 2001.

[4] Bhatt DL. Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events. New England Journal of Medicine. Apr 20, 2006:1706-1717.

[5] Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New England Journal of Medicine. Aug 16, 2001;345:494-502.

[6] Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. The Lancet. Aug 18, 2001;358:527-533.

[7] Stables RH. Clopidogrel in invasive management of non-ST-elevation ACS. The Lancet. Aug 18, 2001; 358: 520 - 521.

[8] DeWilde W, Oirbans T, Verheugt FW. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. The Lancet. March 30, 2013; 381:1107-1115.

[9] Food and Drug Administration. FDA Safety Alert: Clopidogrel (marketed as Plavix) and Omeprazole (marketed as Prilosec) - Drug Interaction, Jan 26, 2009.

[10] Bennett CL, Davidson CJ, Raisch DW, Weinberg PD, Bennett RH, Feldman MD. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Archives of Internal Medicine. Nov 22, 1999; 159: 2524 - 2528.

[11] Bennett CL, Connors JM, Carwile JM, Moake JL, Bell WR, Tarantolo SR, McCarthy LJ, Sarode R, Hatfield AJ, Feldman MD, Davidson CJ, Tsai HM. Thrombotic thrombocytopenic purpura associated with clopidogrel. New England Journal of Medicine. Jun 15, 2000; 342: 1773 - 1777.

[12] Food and Drug Administration. Letter to Sanofi-Synthelabo Inc. Re: Labeling Changes to Plavix (clopidogrel bisulfate), Apr 26, 2005.

[13] Wolfe S, Holtzman NA. Petition to the Food and Drug Administration requesting a black-box warning for clopidogrel addressing the increased risk of bleeding with use beyond twelve months following implantation of drug-eluting coronary artery stents. http://www.citizen.org/documents/2149.pdf. Accessed April 24, 2014.