Generic Name: Clopidogrel (no generic available, U.S. patent expires in early 2011)
Common Brand Name: Plavix® (Bristol-Myers Squibb/Sanofi partnership — U.S.)
Popularity: 28th most commonly prescribed drug between 2002-2009 (U.S.)
Class: Antiplatelet agent (platelet aggregation inhibitor)
Treatment Uses — To reduce mortality, incidence of reinfarction and stroke in patients with acute coronary syndromes (ACS) including acute STEMI (ST-elevation myocardial infarction), non-STEMI, unstable angina (UA), recent stroke or MI, and in patients after coronary angioplasty or cardiac bypass surgery.
In ACS, adding aspirin to clopidogrel in patients under 75 years old has been shown to improve vessel patency and decrease ischemic complications. In stroke and vascular disease patients, adding aspirin to clopidogrel did not improve outcomes, but did increase risk of bleeding.
In patients with atrial fibrillation who cannot tolerate vitamin K-antagonists (warfarin), adding clopidogrel to aspirin therapy reduces risk of stroke.
Clopidogrel is a second line drug to help reduce ischemic events (blood clots, stroke, MI) in patients at risk (from recent stroke or symptomatic peripheral vascular disease). Aspirin is considered first line therapy due to its lower cost, effectiveness, and good tolerance in most patients. Clopidogrel can be considered in aspirin intolerant patients and for aspirin failures (recurrent ischemic events despite aspirin). Some studies suggest that clopidogrel might have an edge over aspirin in patients with symptomatic peripheral vascular disease.
Clopidogrel has been shown to improve healing of some stasis ulcers. It has also been studied for preventing thrombotic events in patients with heart failure but showed no significant differences compared to warfarin or aspirin.
Dosing and Administration — The recommended starting dose of clopidogrel for adults is 75 milligrams orally once daily. For acute coronary syndromes, a 300 milligram loading dose is recommended for unstable angina in non-STEMI (UA/NSTEMI) followed by 75 milligrams once daily in combination with aspirin 81 to 325 milligrams once daily.
For STEMI, a 300 milligram loading dose is recommended for adult patients under 75 years old followed by 75 milligrams of clopidogrel once daily in combination with aspirin 162 to 325 milligrams while hospitalized followed by 81 to 162 milligrams on discharge.
Dosing is the same for patients over 75 years old except the loading dose is not recommended. Clopidogrel can be discontinued after 28 days. For PCI (percutaneous coronary interventions), a loading dose of 300 to 600 milligrams should be given as early as possible before or at the time of PCI. If a 300 milligram load was previously given, an additional 300 milligrams may be given.
PCI patients should receive 75 milligrams of clopidogrel daily. When coronary stents are placed, premature interruption of clopidogrel therapy may result in stent thrombosis (clotting) with MI. Clopidogrel should be continued for at least 12 months in patients who received bare-metal stents during PCI and may continue past 15 months for drug-eluting stents (some interventional cardiologists prefer to continue clopidogrel indefinitely with drug-eluting stents).
Following coronary artery bypass surgery (CABG), a 300 milligram loading dose of clopidogrel given 6 hours after surgery followed by 75 milligrams once daily can be considered for aspirin allergic patients.
Some cardiac surgeons use both clopidogrel and aspirin to prevent bypass graft closure. When CABG is planned, clopidogrel should be discontinued five to seven days prior to surgery. In ACS patients started on clopidogrel who then go on to require CABG, surgery may be delayed.
In stroke and vascular disease patients (and when used in atrial fibrillation), clopidogrel is continued indefinitely at the 75 milligram once daily dosing. For elective surgeries where platelet inhibition is not desirable, clopidogrel should be discontinued five days prior to the procedure.
Safety and efficacy of clopidogrel in pediatric patients has not been established. In two studies, a daily dosage regimen of 0.2 milligrams per kilogram used in pediatric patients aged 0 to 24 months at risk of arterial clots showed antiplatelet activity comparable to adults given 75 milligrams daily.
Clopidogrel can be taken without regard to meals. Dosage adjustments are not necessary in patients with kidney or liver disease, or in older patients.
Overdoses of clopidogrel will likely lead to bleeding. Platelet inhibition is not reversible; platelet transfusion may help (if given several hours after ingestion, after the drug has finished metabolizing). A single oral dose of 1500 mg/kg was lethal to mice, 2000 mg/kg lethal to rats, and 3000 mg/kg to baboons. Acute toxicity was manifest by vomiting, collapse, difficulty breathing, and GI bleeding.
Pharmacology/Pharmacokinetics/Stability — Clopidogrel is rapidly absorbed from the gut, with the active metabolite reaching peak blood levels in 30 to 60 minutes. Initial platelet inhibition is seen within 2 hours. Loading doses produce peak platelet inhibition within 2 to 5 hours.
Following repeated 75 milligram daily doses of clopidogrel, inhibition of platelet aggregation reaches a steady state (40 to 60 percent) between three and seven days. Following a single dose, platelet inhibition can be seen for up to 72 hours. With repeated doses, effects last for five to seven days after discontinuation. While loading doses accelerate peak response, effects are dose limited and appear to peak at 600 milligrams.
Clopidogrel is extensively metabolized in the liver. About 50 percent of metabolites are excreted by the kidneys and 46 percent in the feces. The molecular weight of clopidogrel makes it theoretically possible for the drug or metabolites to be excreted in breast milk.
Clopidogrel is excreted in breast milk of rats. There is not adequate human data to assess infant risk with clopidogrel use by breastfeeding mothers. Potential benefits of treatment must be weighed against possible risks.There are no human studies of clopidogrel use during pregnancy. Animal studies using much higher than comparable human doses have not demonstrated fetal harm.
Clopidogrel works in the body by breaking down into metabolites, one of which binds irreversibly to a receptor on platelets that prevents the platelets from aggregating (forming clots). Because the bonds are irreversible, this effect lasts the entire seven to 10 day life of the platelet.
Clopidogrel 75 milligram tablets are pink, round, biconvex, film coated, debossed with “75" on one side and “1171" on the other. The 300 milligram tablets are pink, oblong, film coated, and debossed with “300" on one side and “1332" on the other. They should be stored at room temperature (68-77 F) with excursions to 59-86 F permitted.
Cautions and Warnings — Clopidogrel should not be given to actively bleeding patients (gastrointestinal bleeding, intracranial hemorrhage, etc.). The U.S. Food and Drug Administration (FDA) added a boxed warning to clopidogrel in March 2010 that some patients are poor metabolizers of clopidogrel and may not exhibit platelet inhibition.
It is possible to assess this with a blood test; clinicians are advised to use alternative antiplatelet agents in these patients. It was believed that increasing clopidogrel dosing would achieve sufficient platelet inhibition in poor metabolizers but very recent data suggests this is not the case.
Important Side Effects and Interactions — Bleeding is the most commonly reported adverse effect of clopidogrel (major bleeding 4 percent, minor bleeding 5 percent). Using clopidogrel with other anticoagulating agents (NSAIDs, warfarin, aspirin) increases risk of bleeding. Gastrointestinal bleeding risks increase significantly when clopidogrel users take oral NSAIDs. Other commonly reported side effects include bruising (5 percent), nosebleeds (3 percent), rash (4 percent), itching (3 percent), and GI upset (<1 percent).
Currently, there are 145 drugs reported to interact with clopidogrel. Of these, the most significant is a marked reduction (45 percent) in serum concentrations of the active clopidogrel metabolite when taken with the proton pump inhibitor (PPI) omeprazole.
This occurs when the drugs are taken together and even when separated by 12 hours. While there is not sufficient information about interactions with other PPIs, it seems logical that they should also be avoided. If a PPI is absolutely necessary, pantoprazole may have the least inhibitory activity on clopidogrel although significant inhibition was observable in studies.
Cimetidine (an H2 antagonist) also interferes with the antiplatelet activity of clopidogrel; there is no evidence implicating other H2 blockers. This information is important since both PPIs and H2 blockers are readily available over the counter (OTC) and patients may unknowingly be using these with prescribed clopidogrel. EMS providers should ask patients about OTC drug use.
A rarely reported side effect called thrombotic thrombocytopenic purpura (TTP) has occurred with clopidogrel. TTP is characterized by low platelet count (thrombocytopenia), destruction of red blood cells (hemolytic anemia), kidney and neurological dysfunction, and fever. While rare, TTP typically occurs within the first two weeks of clopidogrel therapy and can be fatal. Treatment may include plasma exchange.
Average Costs — U.S.
• 75 mg tablet/ 300 mg tablet (brand name Plavix)*
Patient cost: $7.32 each
Large Hospital cost: $5.30 each
*(Wal Mart® and Target don’t include this med in their $4/month programs)
References:
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed November, 2010).
2. Albany Medical Center Pharmacy, Albany, New York.
