Reduction of Cardiovascular and Cerebrovascular Events
Clopidogrel bisulfate is used to reduce the risk of cardiovascular or cerebrovascular events (myocardial infarction [MI], stroke, and vascular death) in patients with atherosclerosis documented by recent ischemic stroke, recent MI, or established peripheral arterial disease (secondary prevention). Results of a large, randomized study (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [CAPRIE] study) suggest that clopidogrel is more effective than aspirin in reducing the risk of such cardiovascular or cerebrovascular events and has a similar overall safety profile. However, because of cost considerations, many clinicians state that aspirin should remain the drug of choice for most patients requiring long-term antiplatelet therapy for coronary artery disease, and recommend clopidogrel as an alternative in those who are unable to take aspirin because of intolerance or contraindications (e.g., allergy).
The American College of Chest Physicians (ACCP) recommends long-term antiplatelet therapy with either aspirin (75-100 mg daily) or clopidogrel (75 mg daily) in patients with established coronary artery disease (i.e., patients more than 1 year after an acute coronary syndrome, with prior revascularization, coronary stenosis greater than 50% by coronary angiogram, and/or evidence of cardiac ischemia on diagnostic testing). Long-term antiplatelet therapy also is recommended for the secondary prevention of stroke in patients with a history of noncardioembolic stroke or transient ischemic attacks (TIAs). In such patients, ACCP states that clopidogrel, aspirin, aspirin in combination with extended-release dipyridamole, or cilostazol are all acceptable options for long-term antithrombotic therapy. Based on a somewhat greater risk reduction for stroke, ACCP states that clopidogrel or the combination of aspirin with dipyridamole may be preferred over the other options for secondary prevention of noncardioembolic stroke; however, ACCP judges the evidence supporting this recommendation to be moderate in quality. Oral anticoagulation (e.g., warfarin, dabigatran) rather than antiplatelet therapy is recommended for the secondary prevention of cardioembolic stroke in patients with a history of ischemic stroke or TIA and concurrent atrial fibrillation; however, in patients who cannot or choose not to take oral anticoagulants (e.g., those with difficulty maintaining stable international normalized ratios [INRs], compliance issues, dietary restrictions, cost limitations), dual antiplatelet therapy with clopidogrel and aspirin is recommended.
ACCP and other experts also recommend antiplatelet therapy for the prevention of cardiovascular events and mortality in patients with peripheral arterial disease. Aspirin generally is suggested as the antiplatelet drug of choice for primary prophylaxis in patients with asymptomatic peripheral arterial disease. For the secondary prevention of cardiovascular events in patients with symptomatic peripheral arterial disease, including those with intermittent claudication, critical limb ischemia, or prior lower extremity procedures (e.g., peripheral artery percutaneous transluminal angioplasty, peripheral artery bypass graft surgery, amputation), long-term treatment with clopidogrel 75 mg daily or aspirin 75-100 mg daily is recommended; the addition of cilostazol may be considered in patients with refractory intermittent claudication. Dual antiplatelet therapy with clopidogrel and aspirin generally is not suggested in any of these patients with the exception of those receiving below-the-knee prosthetic bypass grafts. Clopidogrel also is recommended as an option for long-term antiplatelet therapy in patients with symptomatic carotid stenosis, including in patients who are intolerant of aspirin and those who have undergone recent carotid endarterectomy.
Efficacy of clopidogrel for reduction of the risk of atherosclerotic events has been established in a multicenter, randomized, controlled study (the CAPRIE trial) in patients with atherosclerotic disease (recent [within 6 months] ischemic stroke, recent [within 35 days] MI, or symptomatic peripheral arterial disease) who received clopidogrel 75 mg once daily or aspirin 325 mg daily for an average of 1.6 years (maximum 3 years). The primary analysis of efficacy was based on the first occurrence of a new cardiovascular event (i.e., fatal or nonfatal ischemic stroke or MI, other vascular death) in all patients receiving clopidogrel or aspirin. The annual cardiovascular event rate in patients receiving clopidogrel was 5.32% compared with 5.83% in those receiving aspirin, representing an 8.7% decrease in the annual risk of a new cardiovascular event for clopidogrel-treated patients. The difference in overall risk of cardiovascular events was apparent early in the study and was maintained throughout the 3-year follow-up period. While the study was not designed to evaluate relative benefit of clopidogrel versus aspirin among patients in specific disease subgroups, most of the risk reduction associated with clopidogrel therapy occurred in patients with peripheral arterial disease, who experienced a statistically significant 23.8% decrease in risk compared with those in the same subgroup who received aspirin. Patients in the stroke subgroup who received clopidogrel experienced a relative risk reduction of 7.3%, while those in the MI subgroup experienced a relative risk reduction of -3.7% (increased relative risk compared with aspirin); neither of these relative-risk reductions was statistically significant.
Therapy with clopidogrel plus aspirin for prevention of ischemic events in a broad population of patients with established cardiovascular disease or multiple risk factors for atherosclerosis was evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial. In this large, randomized, double-blind, parallel-group study, therapy with clopidogrel (75 mg daily) and low-dose aspirin (75-162 mg daily) for approximately 2 years was not significantly more effective than low-dose aspirin alone in reducing the rate of the composite primary end point of MI, stroke, or death from cardiovascular causes. In addition, the combination of clopidogrel and aspirin was associated with an increased rate of moderate to severe bleeding.
Acute Coronary Syndrome
Clopidogrel is used in combination with aspirin for the reduction of cardiovascular and cerebrovascular events in patients with a non-ST-segment elevation acute coronary syndrome (ACS), including unstable angina and non-ST-segment-elevation MI (NSTEMI). The drug is used in patients who are to be managed medically and in those who are to be managed with coronary intervention (PCI with or without coronary artery stenting or CABG). In patients in whom elective CABG is planned, it is recommended that clopidogrel be withheld for at least 5 days (the duration of effect of clopidogrel) since the drug, when added to aspirin treatment, increases the risk of bleeding during major surgery.
Clopidogrel also is used in combination with aspirin to reduce the rate of ischemic cardiovascular events (e.g., death, reinfarction, stroke) in patients with ST-segment-elevation MI (STEMI).
Dual-drug antiplatelet therapy with a P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin is part of the current standard of care in patients with ACS. The American Heart Association (AHA), the American College of Cardiology Foundation (ACCF), the Society for Cardiovascular Angiography and Interventions (SCAI), and ACCP recommend antiplatelet therapy with a P2Y12-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in conjunction with aspirin for treatment and secondary prevention in patients with ACS. These experts generally recommend ticagrelor or clopidogrel as the P2Y12-receptor antagonist in patients with ACS who are treated medically without stent placement; because prasugrel has been studied principally in patients undergoing planned percutaneous coronary intervention (PCI), recommendations for the use of this drug are restricted to that population. In patients being managed medically, therapy with a P2Y12-receptor antagonist should be continued for up to 12 months, while aspirin should be continued indefinitely. In patients undergoing PCI with stent placement (bare-metal or drug-eluting), a loading dose of ticagrelor, clopidogrel, or prasugrel is recommended, followed by maintenance therapy with one of these agents for at least 12 months (unless the risk of bleeding outweighs the anticipated net benefit of therapy); aspirin should be continued indefinitely in such patients. While current ACCF/AHA guidelines make no recommendations regarding the P2Y12-receptor antagonist of choice in patients with ACS, ACCP suggests the use of ticagrelor over clopidogrel, regardless of whether PCI is performed. When selecting an appropriate antiplatelet regimen for patients with ACS, clinicians should consider individual risks of ischemia and bleeding as well as the specific characteristics (e.g., adverse effects, drug interaction potential) of the drugs.
The efficacy of pretreatment with clopidogrel prior to diagnostic cardiac catheterization is controversial; while some studies have suggested a benefit in terms of decreased platelet aggregation and lower rates of periprocedural MI with clopidogrel pretreatment, other studies have found no such benefit. The potential benefit of pretreatment with clopidogrel should be balanced against the increased risk of bleeding should emergency coronary artery bypass grafting (CABG) be needed. If clopidogrel is given at hospital admission or diagnosis of ACS and the patient is subsequently scheduled for CABG, the drug should be temporarily discontinued for at least 5 days prior to CABG.
In patients with ACS who have indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical heart valves), the addition of warfarin (INR 2-3) to antiplatelet therapy is recommended; in some cases, triple antithrombotic therapy (warfarin, low-dose aspirin, and clopidogrel) is suggested. However, such triple-drug antithrombotic regimens are associated with an increased risk of bleeding, and patients should be monitored closely. Triple antithrombotic therapy with clopidogrel, aspirin, and warfarin is suggested by ACCP in patients with anterior MI and left ventricular thrombus (or at high risk for such thrombi) undergoing stent implantation; the recommended duration of such triple therapy is dependent on whether the patient has a bare-metal or drug-eluting stent.
Efficacy of clopidogrel for the long-term reduction of cardiovascular events in patients with unstable angina/NSTEMI has been established in a randomized, controlled study (the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events [CURE] trial) in patients who received clopidogrel (75 mg once daily) or placebo in addition to aspirin (75-325 mg daily) and other standard therapy (e.g., heparin) for 3-12 months. Some evidence suggests that aspirin and clopidogrel may have synergistic antithrombotic effects related to their different mechanisms of action. In the CURE study, the combined incidence of cardiovascular death, nonfatal MI, or stroke, and the combined incidence of these 3 types of events plus refractory ischemia in the clopidogrel group were reduced compared with these outcomes in the placebo group. Clopidogrel therapy also was associated with reductions in the incidences of refractory or severe ischemia, heart failure, and (during the initial period of hospitalization) revascularization procedures. In this study, aspirin and clopidogrel or placebo were administered to patients within 24 hours of symptom onset and for 3-12 months (mean: 9 months) thereafter. Although no substantial increase in life-threatening bleeding episodes occurred with clopidogrel and aspirin therapy, major bleeding (principally GI hemorrhage and bleeding at recent arterial puncture sites) was more common in patients receiving clopidogrel and aspirin (3.7%) than in patients receiving aspirin and placebo (2.7%). While clopidogrel has been administered concomitantly with aspirin for up to 1 year in clinical studies, the manufacturer states that nonsteroidal anti-inflammatory agents (NSAIAs) should be used with caution in patients receiving clopidogrel.
(See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)
ST-Segment-Elevation Myocardial Infarction
Results of randomized, controlled studies indicate that clopidogrel produces reductions in mortality and vascular events beyond those of low-dose aspirin and other standard therapy (e.g., thrombolytic agents, heparin) in patients with acute STEMI, including those undergoing subsequent PCI. In patients with suspected STEMI, experts recommend clopidogrel in addition to aspirin with or without reperfusion therapy (i.e., thrombolytic therapy, primary PCI) for 14-28 days. In patients taking clopidogrel in whom CABG is planned, ACCP suggests that the drug be withheld for at least 5 days prior to surgery.
(See Managing Antiplatelet Therapy in Patients Requiring Invasive Procedures under Dosage and Administration: Dosage.)
In a randomized, controlled study in approximately 3500 patients with STEMI who were scheduled to receive therapy with a thrombolytic agent, unfractionated heparin or a low molecular weight heparin when appropriate, and aspirin (Clopidogrel as Adjunctive Reperfusion Therapy [CLARITY] study), addition of clopidogrel (300-mg loading dose followed by 75 mg once daily) was associated with a 36% reduction in the risk of the primary composite end point (occluded infarct-related artery at angiography 2-8 days later or death or recurrent MI prior to angiography); at 30 days, clopidogrel therapy had reduced the composite end point of cardiovascular death, recurrent MI, or recurrent ischemia requiring urgent revascularization by 20%. Rates of major bleeding, including intracranial hemorrhage, were similar with or without adjunctive clopidogrel therapy. In a prospective analysis of a subset of patients from the CLARITY study who underwent PCI after angiography (PCI-Clopidogrel as Adjunctive Reperfusion Therapy [CLARITY] study), pretreatment before PCI with clopidogrel (300-mg loading dose followed by 75 mg once daily) in addition to initial standard therapy (e.g., thrombolytic agents, aspirin) during hospitalization for acute STEMI was associated with a reduction of 38% in recurrent MI and stroke compared with standard therapy; considering cardiovascular events before and after PCI through 30 days after randomization in patients undergoing coronary artery stenting, adjunctive clopidogrel therapy reduced cardiovascular death, MI, and stroke by 41%.
In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) in approximately 45,000 patients with acute STEMI, treatment with clopidogrel (75 mg once daily without a loading dose) in addition to aspirin (162 mg daily) beginning at hospital admission and continuing during hospitalization for up to 4 weeks (mean treatment duration: 14.9 days) was associated with a 9% reduction in death, reinfarction, or stroke (the primary composite end point) compared with aspirin therapy. In addition, death from any cause was reduced by 7%, and fatal or nonfatal reinfarction by 14%, in patients receiving adjunctive clopidogrel. Clopidogrel treatment was associated with a small increase in minor bleeding but no excess in major (i.e., transfused, cerebral, or fatal) bleeding complications.
In patients with STEMI who have undergone diagnostic cardiac catheterization and in whom PCI is planned, experts recommend a loading dose of a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) before or at the time of PCI in conjunction with aspirin therapy. Therapy with a P2Y12-receptor antagonist should be continued for at least 12 months after stent (bare-metal or drug-eluting) placement, unless the risk of bleeding outweighs the anticipated net benefit of therapy; aspirin should be continued indefinitely in such patients.
The American Diabetes Association (ADA) suggests that clopidogrel may be used for prevention of a first MI (primary prevention) as an alternative to aspirin in aspirin-allergic patients with type 1 or type 2 diabetes mellitus who are at high risk for cardiovascular events (i.e., family history of CHD, smoking, hypertension, obesity, albuminuria, elevated blood cholesterol or triglyceride concentrations).
Prevention of Stent Thrombosis
Clopidogrel has been used in combination with aspirin (dual-drug therapy) to prevent stent thrombosis following implantation of coronary artery stents.
Compared with bare-metal stents, implantation of drug-eluting stents has been associated with a reduction in the frequency of restenosis and repeat revascularization without evidence of excess MI or death in randomized controlled trials evaluated for US Food and Drug Administration (FDA) approval of these stents (in clinically stable patients without other serious medical conditions who had newly diagnosed coronary lesions less than 28-30 mm in length). Previous recommendations based on clinical trials in such patients advised dual-drug therapy with aspirin and a thienopyridine derivative (i.e., clopidogrel, ticlopidine) for at least 3 or 6 months following implantation of a sirolimus- or paclitaxel-eluting stent, respectively. However, with expanded use of drug-eluting stents to include patients with high-risk coronary lesions and coexisting medical conditions (e.g., diabetes, renal dysfunction), an increase in the incidence of late (e.g., 1-12 months or more post-implantation) stent thrombosis has been noted in patients with drug-eluting stents compared with bare-metal stents, often coincident with discontinuance of clopidogrel after initially recommended durations of dual-drug antiplatelet therapy.
Conflicting data have been reported regarding the risks of cardiovascular events in patients receiving drug-eluting stents, which may be related to variable definitions of stent thrombosis and differences in patient characteristics and coronary lesions in the populations studied. Some observational studies have indicated an increased risk of late cardiovascular events (e.g., death or death and MI) in patients with drug-eluting stents following discontinuance of dual-drug antiplatelet therapy with aspirin and clopidogrel, or just the clopidogrel component of such therapy. In a study in patients who had stopped taking clopidogrel (75 mg once daily) after 6 months but continued low-dose aspirin therapy (100 mg daily) and were without major adverse events 6 months after stent placement, the incidence of late cardiac events (defined as cardiac death or documented nonfatal MI in months 7-18 of follow-up) was higher in patients with drug-eluting stents versus bare-metal stents (4.9 versus 1.3% of patients, respectively). Thrombosis-related events, including late stent thrombosis and death related to stent thrombosis or target-vessel MI, were twice as frequent in patients with drug-eluting stents versus bare-metal stents (2.6 versus 1.3%, respectively). Overall rates of cardiac death and nonfatal MI during the entire 18-month follow-up period (6 months of clopidogrel therapy and 1 year of subsequent aspirin therapy) were not different in patients with either type of stent. Target vessel revascularizations related to restenosis were less frequent in patients with drug-eluting stents. In another observational study, patients with drug-eluting stents who were event-free (no death, MI, or revascularization) and who reported continued clopidogrel use at 6 or 12 months after stent implantation had lower rates of death, nonfatal MI, or the combined end point of death or MI at 24 months' follow-up than patients with drug-eluting stents who did not report continued use of clopidogrel. In contrast, rates of these cardiac events at 24 months in patients with bare-metal stents were similar regardless of reported clopidogrel use. A subgroup analysis by reported aspirin use did not alter the effect of clopidogrel on cumulative rates of death or combined death or MI in patients with drug-eluting stents except that event rates were lower.
A pooled analysis of data from a large patient records database in Sweden covering 3 years of follow-up revealed an increased rate of death beginning 6 months after stent implantation in patients with drug-eluting stents compared with bare-metal stents. An increase of 18% in the relative long-term risk of death was found in patients with drug-eluting stents at 3 years, corresponding to an absolute increase in the risk of death of 0.5% per year after the initial 6 months. However, results of 2 pooled analyses of data from randomized controlled trials that served as the basis for approval of drug-eluting stents in the US indicate a similar incidence of death or MI over long-term follow-up (4 years) in patients with sirolimus- or paclitaxel-eluting stents compared with bare-metal stents. Another pooled analysis of data from 14 randomized trials that included patients with high-risk features (e.g., diabetes, prior MI, long or complex coronary lesions) who received sirolimus-eluting or bare-metal stents also found similar outcomes with respect to the risk of death or the combined risk of death or MI. While the overall incidence of stent thrombosis was not increased with sirolimus-eluting versus bare-metal stents over the entire period of follow-up (approximately 1-5 years) in this analysis, the risk of stent thrombosis was greater with the drug-eluting stents after the first year following stent implantation (0.6 or 0.05% with the sirolimus-eluting or bare-metal stent, respectively), which coincided with the protocol-specified discontinuance of dual-drug antiplatelet therapy in these trials.
Because of evidence suggesting an increased incidence of late stent thrombosis and cardiovascular events (e.g., cardiac death, nonfatal MI) in patients with drug-eluting stents following discontinuance of dual-drug antiplatelet therapy with aspirin and clopidogrel, or just the clopidogrel component of such therapy
(see Unstable Angina/NSTEMI under Uses: Acute Coronary Syndrome), a broad range of experts recommend that patients who have undergone placement of a drug-eluting stent and who are not at high risk for bleeding receive clopidogrel for at least 12 months in conjunction with low-dose aspirin therapy. Current expert guidelines recommend a treatment duration of at least 12 months for patients with any type of coronary artery stent (bare-metal or drug-eluting). While a minimum duration of therapy of 1 month may be acceptable in patients receiving a bare-metal stent for a non-ACS indication, clopidogrel should ideally be given up to 12 months for these patients as well unless the patient is at increased risk of bleeding; in such a case, clopidogrel should be administered for a minimum of 2 weeks. There is some evidence suggesting that an even longer duration of dual antiplatelet therapy (for more than 12 months) may be beneficial in some patients with drug-eluting stents to reduce the risk of late stent thrombosis and other cardiovascular events, but such prolonged therapy may be associated with an increased risk of bleeding.
In a randomized, placebo-controlled, double-blind study (Dual Antiplatelet Therapy [DAPT] study), patients who received 30 months of dual antiplatelet therapy (aspirin plus clopidogrel or prasugrel) following placement of a drug-eluting stent had substantially reduced rates of stent thrombosis and major adverse cardiovascular and cerebrovascular events compared with those who received 12 months of dual antiplatelet therapy. Preliminary data from the study indicated that a longer duration of therapy was associated with a higher incidence of moderate to severe bleeding and also an unexpected finding of an increased rate of noncardiovascular mortality (principally related to trauma or cancer); however, these adverse mortality findings were not observed during FDA's final review of the DAPT study and other randomized, controlled clinical studies. FDA review of the DAPT study and additional long-term studies of clopidogrel, including meta-analyses conducted by FDA, concluded that there is no evidence of either a harmful or beneficial effect of clopidogrel on all-cause mortality or cancer-related deaths in a population with, or at risk for, coronary artery disease. The results of the FDA-conducted meta-analyses indicated that long-term (12 months or longer) dual antiplatelet therapy with clopidogrel and aspirin does not appear to change the overall risk of death when compared to short-term (6 months or less) clopidogrel and aspirin therapy, or aspirin alone. Additionally, there was no apparent increase in the risks of cancer-related deaths or cancer-related adverse effects with such long-term treatment.
Because of the potentially life-threatening consequences of premature discontinuance of dual-drug antiplatelet therapy in patients with drug-eluting stents, AHA/ACC/SCAI, the American College of Surgeons, and the American Dental Association currently state that implantation of a drug-eluting stent should be performed only in patients who can tolerate and are highly likely to comply with such prolonged combination therapy. For management of patients with coronary stents who require additional invasive procedures,
see Managing Antiplatelet Therapy in Patients Requiring Invasive Procedures, under Dosage and Administration: Dosage.
Chronic Stable Angina
Clopidogrel may be used as an alternative to aspirin in patients with symptomatic chronic stable angina who cannot tolerate aspirin.
Embolism Associated with Atrial Fibrillation and/or Valvular Heart Disease
Clopidogrel has been used in combination with aspirin as an alternative to warfarin anticoagulation for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Dual antiplatelet therapy with clopidogrel and aspirin was evaluated as a potential alternative to warfarin in a randomized controlled study in patients with atrial fibrillation at high risk of stroke. The study was terminated early because of clear evidence of superiority of warfarin over antiplatelet therapy for the primary outcome of stroke, systemic embolism, MI, or vascular death. Results of another study comparing dual antiplatelet therapy (clopidogrel and aspirin) with aspirin monotherapy in patients with atrial fibrillation who had an increased risk of stroke but were unable to take warfarin showed that the combination of clopidogrel and aspirin was more effective than aspirin in reducing the risk of stroke; however, dual antiplatelet therapy was also associated with an increased risk of bleeding. Based on these findings, ACCP and other experts recommend the use of clopidogrel and aspirin rather than aspirin alone as an alternative to oral anticoagulation in patients with atrial fibrillation at increased risk of stroke who cannot or choose not to take oral anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations). Because the risk of bleeding with combination aspirin and clopidogrel therapy is similar to the risk of bleeding with warfarin, such combination therapy is not recommended in patients with a hemorrhagic contraindication to warfarin.
In patients with atrial fibrillation and mitral stenosis who cannot or choose not to take warfarin therapy (for reasons other than concerns about major bleeding), ACCP recommends combination therapy with aspirin and clopidogrel rather than aspirin alone.
While the risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation, the risk has been estimated to be less than that for atrial fibrillation but greater than that for sinus rhythm. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.