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Department of Medicine, Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care Medicine, Westchester Medical Center/New York Medical College, Valhalla.
Address correspondence to Wilbert S. Aronow, MD, New York Medical College, Cardiology Division, Macy Pavilion, Room 138, Valhalla, NY 10595. E-mail: wsaronow{at}aol.com
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THERAPY FOR ATHEROTHROMBOTIC DISEASE |
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 TopAbstract Therapy For Atherothrombotic... Antiplatelet DrugsAcute MIAcute Coronary SyndromesPrior MI And Stable...StrokePADPCIOral Antiplatelet Agents...Oral Antiplatelet SummaryReferences |
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ANTIPLATELET DRUGS |
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The antiplatelet action of dipyridamole remains unclear but may be related to phosphodiesterase inhibition with an increase of cyclic adenosine monophosphate within the platelet (9). The final common pathway of platelet aggregation is mediated by activation of platelet glycoprotein IIb/IIIa receptors by a platelet agonist such as adenosine diphosphate, collagen, or thrombin followed by cross-linking of activated receptors by circulating fibrinogen molecules (10). Although intravenous platelet glycoprotein IIb/IIIa inhibitors are effective in treating patients with acute coronary syndromes (11), oral platelet glycoprotein IIb/IIIa inhibitors have been found to increase mortality in patients with CAD (12).
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ACUTE MI |
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On the basis of the available data, the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend that patients with an acute MI should be treated with 162.5–325 mg of aspirin and aspirin continued indefinitely (14). The initial dose of aspirin should be administered as soon as possible after the onset of acute MI and the nonenteric-coated form used to ensure rapid absorption. The first dose of aspirin should be chewed rather than swallowed.
Of 10,018 persons aged 65 years and older with acute MI and no contraindications to aspirin use, 6140 persons (61%) were treated with aspirin during the first 2 days of hospitalization (15). In this retrospective study, use of aspirin was associated with a significant 22% reduction in 30-day mortality (15).
Clopidogrel Plus Aspirin
In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), 45,852 Chinese patients with acute MI (93% with ST-elevation MI) were randomized to aspirin 162 mg daily plus placebo or to aspirin 162 mg daily plus clopidogrel 75 mg daily (16). At 15-day follow-up, the incidence of death, recurrent MI, or stroke was 9.2% in patients treated with aspirin plus clopidogrel and 10.1% in patients treated with aspirin plus placebo, with clopidogrel causing a 9% significant reduction in death, recurrent MI, or stroke (16). No significant excess in fatal, transfused, or cerebral bleeding occurred in patients treated with clopidogrel including those patients older than 70 years (16).
In the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–Thrombolysis in Myocardial Infarction (TIMI) 28 study, 3491 patients, mean age 58 years (up to 75 years of age), with acute ST-elevation MI treated with aspirin and fibrinolytic therapy were randomized within 12 hours after the onset of acute MI to clopidogrel or to placebo and underwent coronary angiography 48–192 hours later (17). At 8-day follow-up, the incidence of an occluded infarct-related artery, death, or recurrent MI was significantly reduced 36% by clopidogrel from 21.7% in the placebo group to 15.0% in the clopidogrel group (17). At 30-day follow-up, the incidence of cardiovascular death, recurrent MI, or recurrent ischemia leading to urgent revascularization was significantly reduced 20% from 14.1% to 11.6% by clopidogrel (17). The rates of major bleeding and of intracranial hemorrhage were similar in the placebo and clopidogrel groups.
In the CLARITY–TIMI 28 study, 1863 patients underwent percutaneous coronary intervention (PCI) (18). Pretreatment with clopidogrel significantly reduced the incidence of cardiovascular death, MI, or stroke following PCI by 46% from 6.2% to 3.6%. At 30-day follow-up, pretreatment with clopidogrel significantly reduced cardiovascular death, MI, or stroke by 41% from 12.0% to 7.5% (18).
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ACUTE CORONARY SYNDROMES |
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Clopidogrel Plus Aspirin
The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial randomized 12,562 patients within 24 hours after the onset of an acute coronary syndrome (unstable angina pectoris or non-ST-elevation MI) to aspirin 75–325 mg daily plus clopidogrel (300 mg immediately followed by 75 mg daily) or to aspirin plus placebo (20). At 9-month follow-up, the primary outcome of cardiovascular death, nonfatal MI, and nonfatal stroke was significantly reduced from 11.4% to 9.3% in patients treated with clopidogrel plus aspirin, a relative risk reduction of 20% and an absolute risk reduction of 2.1% (20). The primary outcome plus refractory myocardial ischemia was significantly reduced from 18.8% to 16.5% in patients treated with clopidogrel plus aspirin, a relative risk reduction of 14% and an absolute risk reduction of 2.3% (20).
The addition of clopidogrel to aspirin reduced the primary outcome in men, in women, in patients younger than 65 years from 7.6% to 5.4%, in patients older than 65 years from 15.3% to 13.3%, in patients with and without ST-segment deviation, in patients with and without diabetes mellitus, and in patients treated with and without heparin or low-molecular-weight heparin, intravenous platelet glycoprotein IIb/IIIa inhibitors, beta blockers, angiotensin-converting enzyme inhibitors, lipid-lowering therapy, and PCI or coronary artery bypass grafting (20).
The incidence of life-threatening bleeding was insignificantly increased by 1.8%–2.1% in patients treated with aspirin plus clopidogrel. The incidence of major bleeding was significantly increased from 2.7% to 3.7% in patients treated with aspirin plus clopidogrel (20). The optimal dose of aspirin in the CURE study was between 75 and 100 mg with the incidences of major bleeding being 2.6% in patients treated with aspirin plus clopidogrel and 2.0% in patients treated with aspirin plus placebo (21). The benefit of clopidogrel in the CURE trial was consistent in low-, intermediate-, and high-risk patients (stratified by TIMI risk scores) with acute coronary syndromes, supporting its use in all patients with acute coronary syndromes (22).
In the CURE study, 2658 patients, mean age 62 ± 11 years, underwent PCI (23). The primary endpoint of cardiovascular death, MI, or urgent target vessel revascularization within 30 days of PCI was significantly reduced in patients treated with clopidogrel plus aspirin from 6.4% to 4.5%, a relative risk reduction of 30% and an absolute risk reduction of 1.9% with no significant difference in major bleeding between the two groups (23). At 8-month follow-up, clopidogrel plus aspirin significantly reduced cardiovascular death or MI by 31% (23).
In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, 2116 patients, mean age 62 ± 11 years, undergoing elective PCI or deemed at high likelihood of undergoing PCI were randomized to aspirin plus clopidogrel or to aspirin plus placebo for 12 months (24). At 1-year follow-up, clopidogrel significantly reduced the incidence of death, MI, and stroke from 11.5% to 8.5%, with a relative risk reduction of 27% and an absolute risk reduction of 3.0% caused by clopidogrel (24).
In a prospective study of 768 consecutive patients, mean age 66 ± 14 years (67% with an acute coronary syndrome and 95% with symptomatic chest pain), who underwent PCI with stenting in a 6-month period, 99% were treated with aspirin, 98% with clopidogrel, 85% with beta blockers, and 96% with statins (25). The in-hospital mortality of these intensively treated patients was 0.5%. The incidence of in-hospital mortality or nonfatal MI or nonfatal stroke was 1.2% (25).
On the basis of the available data, the ACC/AHA guidelines for treating acute coronary syndromes recommend the use of aspirin as soon as possible and continuation of aspirin indefinitely (26). Clopidogrel should be administered in addition to aspirin and continued for at least 9 months (26). Aspirin and clopidogrel are the two oral antiplatelet drugs that have been approved by the Food and Drug Administration (FDA) for the treatment of acute coronary syndromes.
Because the incidence of major bleeding increases with the higher the dose of aspirin, the author prefers to use an aspirin dose of 81 mg daily. Patients older than 70 years have a higher incidence of gastrointestinal bleeding associated with antiplatelet therapy, especially aspirin, than younger patients, which is substantially reduced by the concomitant use of proton pump inhibitors (27). Comorbidities, concomitant medications, and altered pharmacokinetics in elderly persons influence the risk of major bleeding and are important elements of any therapeutic decision in using antiplatelet drugs in elderly patients.
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PRIOR MI AND STABLE ANGINA |
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Of 5490 patients aged 65 years and older who survived an acute MI, 76% received aspirin at hospital discharge (29). At 6-month follow-up of this retrospective study, aspirin users had a 23% significant reduction in mortality (29).
Of 1410 patients, mean age 81 years (range 60–100 years), with prior MI and a serum low-density lipoprotein cholesterol 
125 mg/dL, 59% were treated with aspirin (29). At 36-month follow-up of this prospective observational study, aspirin users had a 26% significant reduction in new coronary events, with a 52% significant independent reduction in new coronary events (30).
In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, 19,185 patients, mean age 63 ± 11 years, with a recent MI or recent ischemic stroke or symptomatic PAD were randomized in a blinded trial to clopidogrel 75 mg daily or to aspirin 325 mg daily (31). Median follow-up was 1.9 years. At 1.9-year follow-up, the incidence of vascular death, MI, and ischemic stroke was 5.83% in patients on aspirin and 5.32% in patients on clopidogrel, with clopidogrel causing a significant 9% relative risk reduction and a 0.51% absolute risk reduction in vascular death, MI, and ischemic stroke (31). Intracranial hemorrhage occurred in 0.35% of patients treated with clopidogrel and in 0.49% of patients treated with aspirin. Gastrointestinal bleeding occurred in 1.99% of patients treated with clopidogrel and in 2.66% of patients treated with aspirin (p <.05) (31).
In the CAPRIE trial, the incidence of vascular death, MI, and ischemic stroke was not significantly different in patients with an MI treated with aspirin or clopidogrel (31). However, compared with aspirin, clopidogrel caused a 20% significant reduction in the incidence of new MI (32).
In the CAPRIE trial, 1480 patients had a history of cardiac surgery (33). In these 1480 patients, compared with aspirin, clopidogrel caused a 32% significant relative risk reduction in vascular death, MI, and stroke, with an absolute risk reduction of 3.3% per year (33). A meta-analysis of antiplatelet drugs used in patients at high risk for vascular events showed that, compared with aspirin, clopidogrel significantly reduced vascular death, MI, or ischemic stroke by 10% (13).
In high-risk patients the reduction in vascular death, MI, or stroke was 19% in 34 trials using an aspirin dose of 500–1500 mg daily, 26% in 19 trials using an aspirin dose of 160–325 mg daily, 32% in 12 trials using an aspirin dose of 75–150 mg daily, 13% in 3 trials using an aspirin dose <75 mg daily, and 23% in 65 trials using any aspirin dose (13).
The ACC/AHA guidelines recommend that all patients should receive aspirin indefinitely after MI unless there is a contraindication to its use (14). Clopidogrel 75 mg daily or warfarin to maintain an International Normalized Ratio between 2.0 and 3.0 should be administered indefinitely if aspirin is contraindicated in post-MI patients (14). Aspirin and clopidogrel are the two oral antiplatelet drugs approved by the FDA for treatment of patients after MI.
An educational program may need to be utilized in getting physicians to prescribe antiplatelet drugs to patients with CAD (34–36). In 200 patients with CAD seen at the New York Medical College Cardiology Clinic, use of antiplatelet therapy increased from 69% prior to an intensive educational program to 99% 9–20 months after the onset of the educational program (36).
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STROKE |
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The Ticlopidine Aspirin Stroke study randomized 3069 patients, mean age 63 years, with a recent transient or mild persistent focal cerebral or retinal ischemia to aspirin 1300 mg daily or to ticlopidine 500 mg daily (37). The 3-year event rates for death from any cause or nonfatal stroke were 17% for patients treated with ticlopidine and 19% for patients treated with aspirin, with a significant 12% risk reduction by ticlopidine. The 3-year incidences of fatal and nonfatal stroke were 10% for patients treated with ticlopidine and 13% for patients treated with aspirin, with a significant 21% reduction by ticlopidine (37).
Severe neutropenia occurred in 0.9% of patients treated with ticlopidine and in none of the patients (0%) treated with aspirin. The most common adverse effects from ticlopidine are diarrhea and rash (37). Ticlopidine may also cause severe aplastic anemia (38).
On the basis of these data, the author would use ticlopidine in treating patients with a history of stroke or transient ischemic attack who cannot tolerate aspirin or clopidogrel. Ticlopidine is also contraindicated in patients with severe hepatic impairment.
In patients at high risk for vascular events, the reduction in vascular death, recurrent MI, or ischemic stroke was similar in patients treated with aspirin plus dipyridamole versus aspirin alone (13). This meta-analysis (13) demonstrated that, of 25 studies, only the European Stroke Prevention Study (ESPS-2) (39) showed that dipyridamole plus low-dose aspirin significantly reduced stroke more than low-dose aspirin alone.
In the ESPS-2 trial, 6602 patients with prior stroke or transient ischemic attack were randomized to placebo, aspirin 50 mg daily, extended release dipyridamole 400 mg daily, or to aspirin 50 mg plus dipyridamole 400 mg daily (39). At 2-year follow-up, compared with placebo, low-dose aspirin alone significantly reduced the risk of stroke by 18%, dipyridamole alone significantly reduced the risk of stroke by 14%, and dipyridamole plus aspirin significantly reduced the risk of stroke by 37%. Compared with low-dose aspirin alone, dipyridamole plus aspirin significantly reduced the risk of stroke by 25% and insignificantly increased the risk of death by 3% (39).
A meta-analysis from the Antithrombotic Trialists' Collaborative study showed that, in high-risk patients, there were 183 nonfatal strokes on aspirin plus dipyridamole versus 236 nonfatal strokes on aspirin alone, 150 nonfatal MIs on aspirin plus dipyridamole versus 134 nonfatal MIs on aspirin alone, and 286 vascular deaths on aspirin plus dipyridamole versus 279 vascular deaths on aspirin alone (13). Dipyridamole also causes a coronary steal syndrome and should not be administered to patients with CAD.
The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) was a prospective study which randomized patients within 6 months of a transient ischemic attack or minor ischemic stroke to aspirin 30–325 mg daily (median dose 75 mg) with (n = 1363) or without (n = 1376) dipyridamole 200 mg twice daily (40). At 3.5-year follow-up, the incidence of vascular death, nonfatal stroke, nonfatal MI, or major bleeding was significantly reduced 20% by dipyridamole plus aspirin, compared with aspirin alone, from 16% to 13% (absolute reduction 1% per year) (40). The open design of this study which was not double-blind might have introduced bias. Trial medication was also discontinued in 34% of patients treated with the combination of dipyridamole plus aspirin, mainly because of adverse effects.
In the CAPRIE trial, 12,033 patients, mean age 65 ± 11 years, with ischemic stroke were randomized to clopidogrel 75 mg daily or to aspirin 325 mg daily (31). At 1.9-year follow-up, compared with aspirin, clopidogrel insignificantly reduced vascular death, nonfatal MI, and nonfatal stroke by 7.3% (31). In the CURE trial, compared to aspirin plus placebo, aspirin plus clopidogrel significantly reduced the incidence of vascular death, nonfatal MI, and nonfatal stroke by 20% (absolute risk reduction 2.1%) in patients with no prior ischemic stroke and by 26% (absolute risk reduction 4.5%) in patients with prior ischemic stroke (31).
The FDA has approved aspirin, clopidogrel, ticlopidine, and extended release dipyridamole plus aspirin for the treatment of patients with prior ischemic stroke. Compared with clopidogrel alone, the addition of aspirin to clopidogrel in patients with recent ischemic stroke or transient ischemic attack and at least 1 additional vascular risk factor was associated at 18-month follow-up with a 6% insignificant reduction in vascular death, MI, ischemic stroke, or rehospitalization for acute ischemia (41). Warfarin was associated with a significantly higher rate of adverse events and provided no benefit over aspirin in patients with stroke or transient ischemic attack caused by intracranial arterial stenosis (42).
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PAD |
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A meta-analysis of 26 prospective randomized studies of 6263 patients with intermittent claudication due to PAD demonstrated that antiplatelet drugs significantly reduced the incidence of vascular death, nonfatal MI, and nonfatal stroke by 23% (13). A meta-analysis of 12 prospective randomized studies of 2497 patients with PAD undergoing peripheral arterial grafting showed that antiplatelet drugs significantly reduced the incidence of vascular death, nonfatal MI, and nonfatal stroke by 22% (13). A meta-analysis of four prospective randomized studies of 946 patients with PAD undergoing peripheral angioplasty demonstrated that antiplatelet drugs significantly reduced the incidence of vascular death, nonfatal MI, and nonfatal stroke by 29% (13). If one combines the 42 prospective randomized studies of 9706 patients with PAD and intermittent claudication, peripheral arterial grafting, and peripheral angioplasty, the incidence of vascular death, nonfatal MI, and nonfatal stroke at follow-up was 5.8% for patients randomized to antiplatelet drugs versus 7.1% for the control group, a significant decrease of 23% caused by antiplatelet drugs with similar benefits observed among patients with intermittent claudication, those undergoing peripheral arterial grafting, and those having peripheral angioplasty (13).
Another meta-analysis of 24 prospective studies of patients with PAD found that, compared with placebo, antiplatelet drug therapy significantly reduced the incidence of vascular death, nonfatal MI, and nonfatal stroke at follow-up by 22% (46). Long-term treatment of patients with PAD with aspirin has also been shown to improve the ankle–brachial index and slow the progression of PAD as assessed by serial angiography (47,48) and to reduce the need for arterial reconstruction when used for primary prevention of cardiovascular events in men (49). Aspirin has also been demonstrated to slow the progression of carotid atherosclerosis (50). The beneficial effect of aspirin is most likely due to prevention or retardation of platelet thrombogenesis on the surface of atherosclerotic plaques (51).
Ticlopidine has been shown to be effective in reducing cardiovascular events in two prospective studies of patients with PAD (52,53) but not in a third prospective study of patients with PAD (54). Adverse hematologic effects limit the use of ticlopidine in the treatment of older persons with PAD (55).
In the CAPRIE trial, 10,592 patients with PAD, mean age 64 ± 10 years, were randomized to clopidogrel 75 mg daily or to aspirin 325 mg daily (31). At 1.9-year follow-up, compared with aspirin, clopidogrel significantly reduced the incidence of vascular death, nonfatal MI, and nonfatal stroke by 24% (31). On the basis of these data, it is reasonable to conclude that clopidogrel is superior to aspirin in the treatment of patients with PAD. Clopidogrel is also the only antiplatelet drug approved by the FDA to help reduce the risk of vascular death, nonfatal MI, and nonfatal stroke in patients with PAD (56).
In 561 PAD patients, mean age 71 ± 10 years, followed in a vascular surgery clinic at New York Medical College, 89% were treated with clopidogrel or aspirin (57). In 1006 patients, mean age 72 ± 9 years (range 60–95 years), seen at the University of Iowa General Medicine Clinic, antiplatelet drugs were used in the treatment of 178 of 209 patients (85%) with PAD (43). Finally, to avoid bleeding, caution is required when using antiplatelet drugs in combination with nonsteroidal anti-inflammatory drugs or warfarin.
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PCI |
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ORAL ANTIPLATELET AGENTS (ASPIRIN, CLOPIDOGREL) |
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The ACC/AHA and European Society of Cardiology (ESC) practice guidelines recommend clopidogrel in addition to aspirin or as an alternative in aspirin-intolerant patients with a class Ia indication (26,60). Clopidogrel should be continued for up to 9 months; however, initiation of clopidogrel is determined by its relative benefit in preventing cardiovascular events versus its bleeding risk particularly among those requiring bypass surgery (61). In the CURE trial, clopidogrel when used in addition to aspirin was associated with an additional 20% relative reduction in the composite endpoint of cardiovascular death, nonfatal MI, or stroke at 1 year in the overall trial population (20). Compared with younger patients, the subgroup older than 65 years had a similar absolute reduction (2.0% vs 2.2%) and a smaller relative reduction (13.1% vs 28.9%) with the addition of clopidogrel, although in both groups clopidogrel was significantly better than placebo (20).
In PCI-CURE, clopidogrel was associated with a 31% risk reduction in cardiovascular death or nonfatal MI at 1 year in the overall population (23). Compared with younger patients, the subgroup older than 65 years had both a smaller absolute reduction (3.5% vs 3.9%) and relative reduction (20.7% vs 39.8%) in cardiovascular death or nonfatal MI, and the trend to better outcomes with clopidogrel was not statistically significant (23). Whereas no gradient favoring a larger benefit with clopidogrel in older patients is seen in either study, the subgroups undergoing PCI with higher TIMI risk scores or prior revascularization were more likely to benefit (22,23).
From a safety perspective, the risk of bleeding increased with use of combination aspirin and clopidogrel in the CURE trial, but again was lowest with aspirin doses below 100 mg daily (21). Recent evidence has confirmed that aspirin's efficacy is not enhanced by doses in excess of 75–150 mg/day, and that higher doses increase risk for gastrointestinal toxicity and bleeding (13,21). Although no age subgroups for safety were reported, this dosing reduction may be of particular relevance to the elderly population.
In-hospital use of antiplatelet therapy decreases with advancing patient age (62–64). Between ages younger than 65 years and 85 years or older, in-hospital aspirin use decreased from 95% to 87% in the Global Registry of Acute Coronary Events (GRACE) (63), and acute use of aspirin (during the first 24 hours) decreased similarly from 93% to 89% in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) study (62). In-hospital use of clopidogrel is more notably affected by patient age—decreasing from 52% to 30% in GRACE (63) and from 45% to 30% in CRUSADE (62) between age younger than 65 years and 85 years and older. This finding is only partly explained by the lower use of PCI in elderly persons (62).
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ORAL ANTIPLATELET SUMMARY |
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Received May 7, 2006
Accepted August 14, 2006
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References |
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62 years of age. Am J Cardiol. 1994;74:64-65.[Medline]
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