0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Clinical Review | Clinician's Corner

Oral Antiplatelet Therapy in Cerebrovascular Disease, Coronary Artery Disease, and Peripheral Arterial Disease FREE

Huyen Tran, MBBS, FRACP, FRCPA; Sonia S. Anand, MD, PhD, FRCPC
[+] Author Affiliations

Section Editor: Michael Lauer, MD. We encourage authors to submit papers for consideration as a “Clinical Review.” Please contact Michael Lauer, MD, at lauerm@ccf.org.

Author Affiliations: Thromboembolism Unit (Dr Tran) and Division of Cardiology (Dr Anand), Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario.

More Author Information
JAMA. 2004;292(15):1867-1874. doi:10.1001/jama.292.15.1867.
Text Size: A A A
Published online

Context Atherothrombosis is a pathophysiologic process that results in clinical ischemic events affecting the cerebral, coronary, and peripheral arterial circulation. Antiplatelet agents, used alone or in combination, are effective in preventing recurrent vascular events among individuals with established vascular disease.

Objective To summarize the current state of evidence regarding oral antiplatelet treatment in patients with cerebrovascular disease, coronary artery disease (CAD), and peripheral arterial disease.

Evidence Acquisition Using the key terms acute coronary syndrome, atherothrombosis, ischemic stroke, myocardial infarction, MI, peripheral arterial disease, TIA, transient ischemic attack, unstable angina,aspirin,ticlopidine,dipyridamole, and clopidogrel, we searched the MEDLINE database as well as the trial register of the Cochrane Groups to identify studies published from 1960 to August 2004. We manually searched journals and abstract booklets; scrutinized reference lists of trials and review articles; and reviewed meta-analyses, scientific statements, and guidelines from official societies.

Evidence Synthesis Appropriate oral first-line antiplatelet therapy is aspirin for individuals with ST-segment elevation myocardial infarction; aspirin or clopidogrel for those with TIA or stroke, chronic stable angina, or peripheral arterial disease; and aspirin combined with clopidogrel for those with non–ST-segment elevation acute coronary syndrome. Aspirin combined with dipyridamole is a possible alternative for patients who experience a first episode of TIA or stroke in the absence of clinically apparent CAD. Although ticlopidine has been shown to be of benefit in various vascular conditions, its adverse-effect profile has limited its use.

Conclusions Aspirin, ticlopidine, clopidogrel, aspirin combined with clopidogrel, and aspirin combined with dipyridamole are effective in preventing recurrent vascular events among various subgroups of patients with vascular disease. Current clinical trial evidence favors the use of aspirin or clopidogrel as first-line agents for the majority of patients with vascular disease. Clinical trials evaluating combination antiplatelet therapies will direct future practice.

Figures in this Article

Quiz Ref IDAtherothrombosis refers to the formation of thrombus superimposed on preexisting atherosclerosis.1 This common pathophysiologic process results in morbid or fatal clinical ischemic events affecting the cerebral, coronary, or peripheral arterial circulation. Because the platelet is a pivotal mediator in the initiation and propagation of thrombus formation, antiplatelet drugs have emerged as key agents for prevention of recurrent ischemic events. However, there is controversy regarding choice of oral antiplatelet therapy in patients with vascular diseases (ie, ischemic stroke, coronary artery disease [CAD], and peripheral arterial disease [PAD]). While it has been established that aspirin prevents recurrent atherothrombotic events across a wide range of high-risk patients (relative risk reduction of approximately 25%),2 it is less clear if other antiplatelet agents, such as clopidogrel or dipyridamole, alone or added to aspirin, are more effective.

This uncertainty is reflected in clinical practice: neurologists prefer to use aspirin combined with dipyridamole for patients with transient ischemic attacks (TIAs) or ischemic strokes3; cardiologists use aspirin, clopidogrel, or their combination for patients with CAD; and there are few data regarding optimal antiplatelet treatment choices in patients with PAD. This heterogeneity in clinical practice suggests that clinicians believe that each vascular condition is different,4 despite ev dence from epidemiologic studies and findings at necropsy that atherothrombosis and atherosclerosis are systemic diseases.57 To address this apparent paradox between clinical practice and the general understanding of atherothrombosis, clinical trials have been initiated to compare various combinations of antiplatelet agents (including aspirin with clopidogrel or aspirin with dipyridamole) vs each other or vs monotherapy (aspirin or clopidogrel) in a wide variety of patients.

The purpose of this critical review is to summarize the current state of evidence regarding antiplatelet treatment in patients with cerebrovascular disease, CAD, and PAD, and to provide reasonable recommendations for clinical practice at this time.

We sought to identify all studies that (1) were published between 1960 and August 2004; (2) were randomized; (3) recruited patients with established vascular disease (ie, TIA, ischemic stroke, CAD, and PAD); (4) compared an antiplatelet regimen (defined as a drug whose primary effect is to inhibit platelet activation, aggregation, or both) with placebo or one antiplatelet regimen with another; and (5) assessed treatment for at least 10 days. To do this, combinations of key words related to antiplatelet agents (eg, aspirin, ticlopidine, dipyridamole, clopidogrel), and vascular disease (eg, acute coronary syndrome, atherothrombosis, ischemic stroke, myocardial infarction MI, peripherial arterial disease, transient ischemic attack TIA, unstable angina) were used to search the MEDLINE database and trial registers of the Cochrane Groups. Journals and abstract booklets were manually searched, and reference lists of trials and review articles were scrutinized to ensure that no important studies were missed. Meta-analyses and scientific statements or guidelines from official societies (eg, the American College of Cardiology) were also reviewed. Oral glycoprotein IIb/IIIa antagonists were not included in our literature search because clinical trials in patients with CAD have reported increased mortality.810 In addition to reviewing published randomized controlled trials identified in our literature search, we also critically examined a diverse array of studies including prospective cohort studies, mechanistic studies, meta-analyses, systematic overviews, and scientific statements from official societies. Data extraction was performed by one of the authors (H.T.).

We identified 111 trials, among which 22 enrolled patients with TIA or stroke (n = 30 619), 47 enrolled patients with CAD (n = 59 821), and 42 enrolled patients with PAD (n = 9214).

TIA or Stroke

Quiz Ref IDAspirin. Numerous trials have examined the efficacy of antiplatelet drugs, primarily aspirin for prevention of vascular events in patients with a prior TIA or stroke.1116 Although many were small and inconclusive, the Antiplatelet Trialists’ Collaboration (ATC) individual patient data meta-analysis reported that among more than 23 000 patients (from 21 randomized controlled trials), antiplatelet therapy (usually aspirin) compared with placebo or untreated control continued for a mean of 29 months was associated with a 22% reduction in the odds of recurrent ischemic stroke, myocardial infarction (MI), or vascular death (17.8% vs 21.4%, P<.001) (Table 1).

Table Graphic Jump LocationTable 1. Proportional Effects of Antiplatelet Therapy on Vascular Events Compared With Controls, Subdivided by Disease Categories*

Ticlopidine and Clopidogrel. Ticlopidine, a thienopyridine that blocks adenosine diphosphate–mediated platelet aggregation, has been evaluated in 2 large randomized controlled trials involving patients with TIA and stroke.17,18 In the first trial, among 1072 patients with TIA or stroke, ticlopidine (500 mg/d) compared with placebo or untreated control reduced the risk of stroke, MI, or vascular death by 23% (11.3% vs 14.0%, P = .02) after 2 years of follow up.17 In the second trial, among 3069 patients with TIA or minor stroke, ticlopidine compared with aspirin (1300 mg/d) reduced the risk of nonfatal stroke or death by 12% (17% vs 19%, P = .05) and the risk of fatal and nonfatal stroke by 21% (10% vs 13%, P = .02) after 3 years of follow up.18 However, frequent adverse effects, such as diarrhea and rash (25%), and serious hematologic adverse effects, including neutropenia (1%-2%) and thrombocytopenic thrombotic purpura (0.025%-0.05%), have been reported.1820

The Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared clopidogrel (75 mg/d) with aspirin (325 mg/d) for the long-term prevention of recurrent atherothrombotic vascular events in 19 185 patients, including 6431 with prior ischemic stroke. Among all patients, clopidogrel reduced the risk of stroke, MI, or vascular death by 8.7% (95% confidence interval [CI], 0.3 to 16.5; P = .04) (Table 2). For the subgroup of patients with prior ischemic stroke, the relative risk reduction (RRR) was similar and not statistically different from the overall result. The safety profile of clopidogrel was comparable with that of aspirin.21,22

Table Graphic Jump LocationTable 2. Results of CAPRIE Study: Treatment Effect on Outcome by Subgroup*

Recently, the results of the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) randomized trial were published. Aspirin (75 mg) added to clopidogrel (75 mg) was compared with clopidogrel alone among 7599 patients with recent TIA or ischemic stroke.23 The combination of aspirin and clopidogrel did not significantly lower the incidence of ischemic strokes, MI, or vascular death (15.7% vs 16.7%; RRR, 6.4%; 95% CI, –4.6 to 16.3; P = .24) but was associated with an increase in the risk of major (2% vs 1%, P<.001) and life-threatening bleeding (2.6% vs 1.3%; absolute risk increase, 1.3%; 95% CI, 0.64 to 1.9; P<.001).

Dipyridamole. The combination of aspirin with dipyridamole has been compared with aspirin monotherapy for stroke prevention among patients with TIA or stroke in several clinical trials.2426Quiz Ref IDDipyridamole is a pyrido-pyrimidine derivative that vasodilates coronary microvessels and inhibits platelet activation by increasing levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate. The European Stroke Prevention Study 2 (ESPS-2) evaluated this antiplatelet agent for stroke prevention in patients with TIA or stroke in the preceding 3 months.24 The study randomly assigned 6602 patients into 1 of 4 treatment groups: low-dose aspirin (25 mg twice daily) alone (n = 1649); extended-release dipyridamole (ER-DP) (200 mg twice daily) alone (n = 1654); aspirin combined with ER-DP (same doses) (n = 1650); or placebo (n = 1649). Patients were followed up for 2 years to determine the effects of these drugs on the rate of stroke and death from any cause. Compared with placebo, each of the active treatments significantly reduced the incidence of stroke (aspirin vs placebo: 12.5% vs 15%; RRR, 18.1%; P = .01; ER-DP vs placebo: 12.7% vs 15%; RRR, 16.3%; P = .04; aspirin combined with ER-DP: 9.5% vs 15%; RRR, 37.0%; P<.001) (Table 3). No significant reduction in MI or mortality was observed, although the risk reduction in ischemic events defined as stroke, MI, and sudden death confirmed the benefit of ER-DP added to aspirin. The 18% risk reduction observed with low-dose aspirin compared with placebo was consistent with the benefit observed in earlier studies of low-dose aspirin (75 mg) in patients with stroke.27 The ESPS-2 trial was the first study to show an independent statistically significant reduction in stroke risk in patients treated with ER-DP. Compared with placebo, the combination of aspirin and ER-DP was reported to be twice as effective for stroke prevention as either drug alone, indicating an additive benefit; the combination was also more effective than aspirin or ER-DP given alone (Table 3).

When the results of ESPS-2 trial are analyzed together with additional trials included in the meta-analysis by the ATC,2 10 404 patients with preexisting symptomatic atherosclerotic disease from 25 trials comparing aspirin combined with dipyridamole vs aspirin alone were combined and the addition of dipyridamole to aspirin was associated with a nonsignificant 6% risk reduction in serious vascular events (nonfatal stroke, MI, vascular deaths) (11.8% vs 12.4%; odds ratio, 0.95; 95% CI, 0.86 to 1.05; P = .32).2 The apparent reduction in nonfatal stroke was derived mainly from the ESPS-2 study24 and was not consistent with the findings for nonfatal stroke or nonfatal MI or vascular death in other studies. Possible reasons for this difference include the use of ER-DP in the ESPS-2 study vs short-acting dipyridamole in the other studies, differences in patient characteristics, or the play of chance, as no systematic biases were apparent in this trial. The extended-release form of dipyridamole has been studied in the ESPS-2 clinical trial only and replication of its effectiveness is warranted before widespread use of this antiplatelet preparation rather than aspirin or clopidogrel is advocated.

A more recent meta-analysis by De Schryver et al28 included randomized trials of individuals who were within 6 months after presentation of arterial vascular disease and who were treated for at least 1 month.28 Starting therapy consisted of dipyridamole (in any dose) alone or added to another antiplatelet drug compared with placebo or antiplatelet drug(s) other than dipyridamole. Dipyridamole alone or in combination with another antiplatelet agent compared with placebo reduced vascular events such as nonfatal stroke or nonfatal MI (dipyridamole vs placebo: RRR, 0.90; 95% CI, 0.83 to 0.98; aspirin combined with dipyridamole vs aspirin alone: RRR, 0.90; 95% CI, 0.80 to 1.00).28 There was no evidence that dipyridamole alone was more efficacious than aspirin.

To resolve some of the controversy regarding the effectiveness of aspirin and dipyridamole, this combination is currently being evaluated in ongoing clinical trials, such as the European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) (n = 4500; ER-DP [400 mg/d] added to aspirin [any dose between 30 and 325 mg/d] vs aspirin alone) for patients who have experienced a TIA or minor ischemic stroke, and the Prevention Regimen for Effectively Avoiding Second Strokes (ProFESS) trial (n = 15 500; clopidogrel added to aspirin vs ER-DP added to aspirin) for patients with ischemic TIA or stroke. Results from these studies will clarify the role of combined aspirin and ER-DP compared with other antiplatelet combinations.

Coronary Artery Disease

The pathophysiological spectrum of CAD includes stable angina, unstable angina, ST-segment elevation MI (STEMI), and non–ST-segment elevation MI (NSTEMI). Patients with CAD who become unstable by virtue of developing a change in the pattern of angina are classified as having acute coronary syndrome (ACS) and include patients with unstable angina, STEMI, and NSTEMI.

STEMI ACS.Aspirin. Initial randomized trials conducted in the 1970s and early 1980s did not consistently demonstrate a benefit of aspirin compared with placebo in patients with acute MI.2932 However, these were relatively small and likely underpowered. The Second International Study of Infarct Survival (ISIS-2) trial randomly assigned 17 187 patients presenting within 24 hours of onset of suspected acute MI to receive streptokinase, aspirin 162.5 mg/d for 30 days, both, or neither.33 At the end of 5 weeks, aspirin reduced the risk of death by 23% and nonfatal MI or stroke by 49% and 46%, respectively, with no increase in major or intracranial bleeding. The survival benefits of aspirin in patients with acute MI were also seen in patients receiving concomitant heparin therapy and were additive to the benefits of streptokinase. A recently published long-term follow-up of patients randomized in the ISIS-2 trial demonstrated that the benefits of aspirin remained evident even after 10 years.34

The efficacy of aspirin as an adjunct to thrombolytic therapy and for the long-term management of patients with MI treated has recently been summarized by the ATC.2 Among more than 19 000 patients randomized in 15 trials, antiplatelet therapy (primarily aspirin) compared with placebo or untreated control and continued for a mean of 1 month after the acute event was associated with a 30% reduction in the odds of stroke, recurrent MI, or vascular death (10.4% vs 14.2%, P<.001). Among more than 20 000 patients with a history of MI randomized in 12 trials, antiplatelet therapy (again, primarily aspirin) compared with placebo or untreated control and continued for a mean of 27 months was associated with a 25% reduction in the odds of stroke, recurrent MI, or vascular death (13.5% vs 17%, P<.001).

Clopidogrel and Ticlopidine. No studies have compared clopidogrel or ticlopidine with placebo or untreated control as an adjunct to thrombolytic therapy for the acute treatment of patients with STEMI ACS. The combination of clopidogrel with aspirin compared with aspirin alone is currently being evaluated in the Clopidogrel Metoprolol Myocardial Infarction Trial (COMMIT) (n = 30 000) and the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) study (n = 2200).

As mentioned before, the CAPRIE trial21 of 19 185 patients with a history of symptomatic atherothrombosis included 6302 with prior MI. When all patients with prior MI, including those from the stroke and PAD subgroups, were considered together (n = 8446), the risk reduction with clopidogrel vs aspirin was similar to the overall treatment effect (RRR, 7.4%; 95% CI, –5.2 to 18.6) (Table 2). Clopidogrel compared with aspirin was associated with a significantly lower risk of gastrointestinal bleeding (2.0% vs 2.7%; P<.002), although the overall safety profile of clopidogrel was comparable to that of aspirin.21,22

NSTEMI ACS.Aspirin. Randomized trials have demonstrated the benefits of aspirin compared with placebo or untreated control for the management of patients with NSTEMI ACS.3541 Aspirin (75-1300 mg/d) reduced the risk of MI by about 50% at 2 years3739,41 and progression to severe angina requiring cardiac catherization by 30% at 1 year.40

The ATC meta-analysis of antiplatelet therapy (primarily aspirin) in more than 5000 patients with unstable angina reported a 46% reduction in the odds of stroke, MI, or vascular death with antiplatelet therapy (primarily aspirin) vs placebo or untreated control (8.0% vs 13.3%, P<.001) (Table 1).

Clopidogrel and Ticlopidine. No studies have compared clopidogrel with placebo/control (in the absence of aspirin) in patients with NSTEMI ACS. One open-label study of 652 patients with unstable angina demonstrated that ticlopidine compared with control reduced the risk of death or MI by 46% at 6 months (P = .009).42

The Clopidogrel in Unstable Angina to Prevent Recurrent Events in Patients with Acute Coronary Syndromes Without ST-Segment Elevation (CURE) study of 12 562 patients demonstrated that the combination of clopidogrel (300-mg loading dose followed by 75 mg/d) and aspirin (75-325 mg/d) was superior to aspirin alone (75-325 mg/d) in preventing stroke, MI, and vascular death (RRR, 0.80; 95% CI, 0.72 to 0.90; P<.001).43 The combination of clopidogrel and aspirin was associated with an increased risk of major bleeding (3.7% vs 2.7%; RRR, 1.38; 95% CI, 1.13 to 1.67; P = .001) but no significant excess in life-threatening bleeding (2.1% vs 1.8%, P = .13). The incidence of bleeding with clopidogrel was lower in patients receiving an aspirin dose of less than 100 mg/d compared with those receiving higher doses.44

Chronic Stable Angina

Aspirin. Randomized trials have demonstrated the benefits of aspirin compared with placebo or untreated control for the management of patients with stable angina. The Swedish Angina Pectoris Aspirin Trial (SAPAT) randomly assigned 2035 patients with stable angina to receive 75 mg of aspirin daily or placebo.45 The SAPAT investigators reported a 34% reduction in MI and sudden death (95% CI, 24% to 49%; P = .003). The meta-analysis of antiplatelet therapy (primarily aspirin) by the ATC group included 2920 patients with stable angina and reported a 33% reduction in the odds of serious vascular events (stroke, MI, or vascular death) with antiplatelet therapy vs placebo or untreated control (9.9% vs 14.1%, P<.001)2 (Table 1). Taken together in patients with CAD, antiplatelet therapy (primarily aspirin) is associated with a 29% reduction in the odds of serious vascular events (11.4% vs 15.3%, P <.001) (Table 1).

Percutaneous Coronary Intervention.Quiz Ref IDPercutaneous coronary intervention involves the use of 1 or more revascularization devices designed to remove (eg, rotational atherectomy), ablate (eg, excimer laser angioplasty), or scaffold (eg, stents) atherosclerotic plaque.46 This results in local vascular trauma, exposing highly thrombogenic subendothelium to the circulating blood and leading to local thrombus formation. The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for Percutaneous Coronary Intervention 200147 recommend that aspirin 80 to 325 mg be given at least 2 hours prior to the procedure in combination with either ticlopidine or clopidogrel for at least 72 hours prior to the procedure when possible. Because of its more favorable safety profile, clopidogrel should be used in preference to ticlopidine. Aspirin should be continued indefinitely, and per the results of the Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) study48 and the Clopidogrel for the Reduction of Events During Observation (CREDO) trial,49 clopidogrel should be continued for approximately 12 months, and possibly longer, depending on physicians’ estimates of their patients’ risk.

Peripheral Arterial Disease

Aspirin. No individual randomized controlled trial has conclusively demonstrated that aspirin reduces cardiovascular events among patients with PAD. The ATC meta-analysis of antiplatelet therapy (primarily aspirin) in more than 9000 patients with PAD demonstrated a 23% reduction in the odds of serious vascular events (5.8% vs 7.1%, P<.004), with similar benefits observed among patients with intermittent claudication, those having peripheral grafts, and those who have undergone peripheral angioplasty2 (Table 1).

Ticlopidine. Ticlopidine has been reported to reduce cardiovascular and thrombotic events in patients with intermittent claudication. The Swedish Ticlopidine Multicenter Study enrolled 687 patients and compared ticlopidine (250 mg twice daily) with placebo. A significant 34% reduction in coronary and cerebrovascular events (25.7% vs 29.0%; RRR, 0.66; 95% CI, 0.45 to 0.96) was observed.50 Despite these results, potential adverse effects associated with ticlopidine, in particular neutropenia and thrombotic thrombocytopenic purpura, have limited its use.

Clopidogrel. In addition to the overall benefit of clopidogrel among patients with a history of symptomatic atheroclerosis in the CAPRIE study, clopidogrel was associated with a risk reduction of approximately 24% (95% CI, 8.9 to 36.2; P = .003) compared with aspirin in a subgroup analysis of more than 6000 patients with PAD.21 Compared with the MI and ischemic stroke subgroups, the risk reduction was significantly higher (Table 2). Furthermore, a test of heterogeneity of the 3 treatment effects for clopidogrel was statistically significant (P = .04), suggesting that the true benefit of clopidogrel vs aspirin might be much greater in patients with PAD. Based on these results, clopidogrel was approved in 1997 by the US Food and Drug Administration for the reduction of ischemic events in patients with PAD.

TIA or Stroke

The weight of current evidence supports the use of aspirin or clopidogrel as first-line therapy after a first episode of TIA or stroke. Clopidogrel may be preferred in patients with aspirin intolerance. Extended-release dipyridamole (400 mg/d) combined with aspirin (50 mg/d) is a possible alternative. However, the evidence supporting its use comes from a single trial,4 and its routine use in patients with concomitant symptomatic CAD is questionable. For patients who develop recurrent TIA or stroke while taking aspirin, options for changes in therapy include the use of clopidogrel alone or aspirin combined with ER-DP in the absence of CAD.23 In patients who develop recurrent TIA or stroke while taking clopidogrel, an option for second-line therapy can be aspirin combined with ER-DP; for patients who develop ACS, aspirin combined with clopidogrel should be used (Figure 1).

Figure 1. Recommended Initial Antiplatelet Therapy for Patients With Transient Ischemic Attack or Ischemic Stroke and Subsequent Therapy for Recurrent Ischemic Events
Graphic Jump Location

Abbreviations: ACS indicates acute coronary syndrome; TIA, transient ischemic attack.
*Per the Antithrombotic Trialists’ Collaboration.21,2
†Per the CAPRIE Steering Committee.21
‡Per Diener et al24 and De Schryver et al.28
§Without coronary artery disease.

The limiting factor in recommending more widespread use of dipyridamole is its potential to cause coronary vasodilatation resulting in increased blood flow to nonstenosed coronary arteries and possible myocardial ischemia during exercise. Current ACC/AHA guidelines (2002) recommend that dipyridamole not be used in patients with stable angina.51 However, this recommendation was based on short-acting dipyridamole.52 No increase in cardiac events has been observed with the use of ER-DP in patients with prior ACS.53 Given that other effective options exist for patients with clinically apparent CAD who experience TIA or stroke, the combination of ER-DP with aspirin should be avoided until this issue is resolved by current clinical trials.

Coronary Artery Disease

In patients with chronic stable angina, there are increasing numbers of oral antiplatelet therapies that have been proven to be effective for acute or long-term therapy. Aspirin is the mainstay of treatment in this population of patients as it is effective, relatively safe, and inexpensive. Aspirin should be started as soon as the diagnosis is suspected and continued indefinitely. Among patients who have recently undergone coronary artery stenting, aspirin and clopidogrel should be given in combination for up to a year.48,49

STEMI ACS.Quiz Ref IDThe ACC/AHA guidelines for the management of patients with acute MI (1999) recommend that aspirin (160-325 mg/d) be given on day 1 of AMI and continued indefinitely in all patients.54 Clopidogrel or another oral antiplatelet agent, such as ticlopidine, is recommended as an alternative to aspirin only when there is a contraindication or intolerance to aspirin (Figure 2).

Figure 2. Recommended Initial Antiplatelet Therapy for Patients With Stable Coronary Artery Disease and Subsequent Therapy for Recurrent Ischemic Events
Graphic Jump Location

Abbreviations: ACS indicates acute coronary syndrome; TIA, transient ischemic attack.
*Per the Antithrombotic Trialists’ Collaboration.2
†Per the CAPRIE Steering Committee.21

NSTEMI ACS. For patients with unstable angina and NSTEMI, the combination of aspirin and clopidogrel should be started as soon as possible after presentation in the absence of contraindications. This recommendation is reasonable since clopidogrel reduces the risk of ischemic events irrespective of whether an early interventional strategy is used and the majority of bleeding episodes are reversible. Aspirin should be continued indefinitely and clopidogrel should be continued for up to 9 to 12 months43 and possibly longer, depending on the physician’s estimate of the patient’s risk.

Peripheral Arterial Disease

Patients with symptomatic PAD are at high risk of vascular death due to coronary or cerebrovascular causes.55 Therefore, in addition to modification of cardiovascular risk factor(s), aggressive antiplatelet therapy should be considered. Based on available evidence, the first-line oral antiplatelet therapy should be aspirin (160-325 mg/d) or clopidogrel (75 mg/d), and clopidogrel is recommended when aspirin is contraindicated or not tolerated. Combination antiplatelet therapy with aspirin and clopidogrel should be initiated if a patient experiences a recurrent vascular event while receiving monotherapy. Given the high proportion of patients with PAD who have coexisting CAD,21 aspirin combined with ER-DP should be avoided when such a patient experiences a TIA or stroke until more efficacy and safety data of this combination in high-risk vascular patients has been accrued (Figure 3).

Figure 3. Recommended Initial Antiplatelet Therapy for Patients With Peripheral Arterial Disease and Subsequent Therapy for Recurrent Ischemic Events
Graphic Jump Location

Abbreviations: ACS indicates acute coronary syndrome; TIA, transient ischemic attack.
*Per the Antithrombotic Trialists’ Collaboration.2
†Per the CAPRIE Steering Committee.21
‡Per Diener et al24 and De Schryver et al.28

Corresponding Author: Sonia S. Anand, MD, PhD, FRCP, Department of Medicine, McMaster University Medical Center, 1200 Main St W, Room 3W28a, Hamilton, Ontario, Canada, L8N 3Z5 (anands@mcmaster.ca).

Author Contributions: Dr Tran had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses.

Study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content: Tran, Anand.

Statistical analysis: Tran.

Funding/Support: Dr Tran receives salary support funding from Hamilton Health Sciences, Canada. Dr Anand receives funding from the Canadian Institutes of Health Research for salary support.

Role of the Sponsors: The funding organizations had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; the preparation of the data; or the preparation, review, or approval of the manuscript.

Financial Disclosure: Dr Anand has received speaking honoraria from Sanofi and Bristol-Myers Squibb, the makers of clopidogrel.

Nenci G. Unifying concept of arterial vascular disease.  Eur Heart J. 1999;1:(suppl A)  A27-A30
Antithrombotic Trialists’ Collaboration.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients.  BMJ. 2002;324:71-86
PubMed   |  Link to Article
Jonas S, Grieco G. Potential value of triple antiplatelet therapy for secondary stroke prevention.  Stroke. 2003;34:e182-e183
PubMed   |  Link to Article
van Gijn J, Algra A. Aspirin and stroke prevention.  Thromb Res. 2003;110:349-353
PubMed   |  Link to Article
Aronow WS, Ahn C. Prevalence of coexistence of coronary artery disease, peripheral arterial disease, and atherothrombotic brain infarction in men and women > or=62 years of age.  Am J Cardiol. 1994;74:64-65
PubMed   |  Link to Article
Mautner GC, Mautner SL, Roberts WC. Amounts of coronary arterial narrowing by atherosclerotic plaque at necropsy in patients with lower extremity amputation.  Am J Cardiol. 1992;70:1147-1151
PubMed   |  Link to Article
Chimowitz MI, Mancini GB. Asymptomatic coronary artery disease in patients with stroke.  Stroke. 1992;23:433-436
PubMed   |  Link to Article
SYMPHONY Investigators.  Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial.  Lancet. 2000;355:337-345
PubMed   |  Link to Article
Topol EJ, Easton D, Harrington RA.  et al.  Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease.  Circulation. 2003;108:399-406
PubMed   |  Link to Article
Cannon CP, McCabe CH, Wilcox RG.  et al.  Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial.  Circulation. 2000;102:149-156
PubMed   |  Link to Article
Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia.  Stroke. 1977;8:301-314
PubMed   |  Link to Article
Guiraud-Chaumeil B, Rascol A, David J.  et al.  Prevention of recurrences of cerebral ischemic vascular accidents by platelet antiaggregants. [in French].  Rev Neurol (Paris). 1982;138:367-385
PubMed
Sorensen PS, Pedersen H, Marquardsen J.  et al.  Acetylsalicylic acid in the prevention of stroke in patients with reversible cerebral ischemic attacks: a Danish cooperative study.  Stroke. 1983;14:15-22
PubMed   |  Link to Article
 High-dose acetylsalicylic acid after cerebral infarction.  Stroke. 1987;18:325-334
PubMed   |  Link to Article
Boysen G, Sorensen PS, Juhler M.  et al.  Danish very-low-dose aspirin after carotid endarterectomy trial.  Stroke. 1988;19:1211-1215
PubMed   |  Link to Article
Acheson J, Danta G, Hutchinson EC. Controlled trial of dipyridamole in cerebral vascular disease.  BMJ. 1969;1:614-615
PubMed   |  Link to Article
Gent M, Blakely JA, Easton JD.  et al.  The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke.  Lancet. 1989;1:1215-1220
PubMed   |  Link to Article
Hass WK, Easton JD, Adams HP Jr.  et al. Ticlopidine Aspirin Stroke Study Group.  A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients.  N Engl J Med. 1989;321:501-507
PubMed   |  Link to Article
Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K.  et al.  Thrombotic thrombocytopenic purpura associated with ticlopidine.  Ann Intern Med. 1998;128:541-544
PubMed   |  Link to Article
Hankey GJ, Sudlow CL, Johnson CL. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients.  Cochrane Database Syst Rev. 2000;2:CD001246
PubMed
CAPRIE Steering Committee.  A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).  Lancet. 1996;348:1329-1339
PubMed   |  Link to Article
Harker LA, Boissel JP, Pilgrim AJ, Gent M.CAPRIE Steering Committee and Investigators.  Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE.  Drug Saf. 1999;21:325-335
PubMed   |  Link to Article
Diener HC, Bogousslavsky J, Brass LM.  et al.  Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH).  Lancet. 2004;364:331-337
PubMed   |  Link to Article
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study, 2: Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.  J Neurol Sci. 1996;143:1-13
PubMed   |  Link to Article
American-Canadian Co-Operative Study Group.  Persantine Aspirin Trial in Cerebral Ischemia, Part II: endpoint results.  Stroke. 1985;16:406-415
PubMed   |  Link to Article
Bousser MG, Eschwege E, Haguenau M.  et al.  “AICLA” controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia.  Stroke. 1983;14:5-14
PubMed   |  Link to Article
SALT Collaborative Group.  Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.  Lancet. 1991;338:1345-1349
PubMed   |  Link to Article
De Schryver EL, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease.  Cochrane Database Syst Rev. 2004;1:CD001820
PubMed
Elwood PC, Williams WO. A randomized controlled trial of aspirin in the prevention of early mortality in myocardial infarction.  J R Coll Gen Pract. 1979;29:413-416
PubMed
Elwood PC. Early use of aspirin.  Lancet. 1990;335:486
PubMed   |  Link to Article
Verheugt FW, Kupper AJ, Galema TW, Roos JP. Low dose aspirin after early thrombolysis in anterior wall acute myocardial infarction.  Am J Cardiol. 1988;61:904-906
PubMed   |  Link to Article
 Randomized factorial trial of high-dose intravenous streptokinase, of oral aspirin and of intravenous heparin in acute myocardial infarction.  Eur Heart J. 1987;8:634-642
PubMed
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.  Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.  Lancet. 1988;2:349-360
PubMed
Baigent C, Collins R, Appleby P.  et al. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.  ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither.  BMJ. 1998;316:1337-1343
PubMed   |  Link to Article
Cairns JA, Theroux P, Lewis HD Jr, Ezekowitz M, Meade TW. Antithrombotic agents in coronary artery disease.  Chest. 2001;119:(1 suppl)  228S-252S
PubMed   |  Link to Article
Nyman I, Larsson H, Wallentin L.Research Group on Instability in Coronary Artery Disease in Southeast Sweden.  Prevention of serious cardiac events by low-dose aspirin in patients with silent myocardial ischaemia.  Lancet. 1992;340:497-501
PubMed   |  Link to Article
Lewis HD Jr, Davis JW, Archibald DG.  et al.  Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina.  N Engl J Med. 1983;309:396-403
PubMed   |  Link to Article
Cairns JA, Gent M, Singer J.  et al.  Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial.  N Engl J Med. 1985;313:1369-1375
PubMed   |  Link to Article
Theroux P, Ouimet H, McCans J.  et al.  Aspirin, heparin, or both to treat acute unstable angina.  N Engl J Med. 1988;319:1105-1111
PubMed   |  Link to Article
Wallentin LC.Research Group on Instability in Coronary Artery Disease in Southeast Sweden.  Aspirin (75 mg/day) after an episode of unstable coronary artery disease.  J Am Coll Cardiol. 1991;18:1587-1593
PubMed   |  Link to Article
RISC Group.  Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.  Lancet. 1990;336:827-830
PubMed   |  Link to Article
Balsano F, Rizzon P, Violi F.  et al. Studio della Ticlopidina nell'Angina Instabile Group.  Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter clinical trial.  Circulation. 1990;82:17-26
PubMed   |  Link to Article
Yusuf S, Zhao F, Mehta SR.  et al.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med. 2001;345:494-502
PubMed   |  Link to Article
Peters RZ, Lewis B. Aspirin dose and bleeding events in the CURE study.  Circulation. 2002;106:2258a
Juul-Moller S, Edvardsson N, Jahnmatz B.  et al. Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.  Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.  Lancet. 1992;340:1421-1425
PubMed   |  Link to Article
Popma JJ, Ohman M, Weitz J.  et al.  Antithrombotic therapy in patients undergoing percutaneous coronary intervention.  Chest. 2001;119:321-336
Link to Article
Smith SC, Dove JT, Jacobs AK.  et al.  ACC/AHA Guidelines for Percutaneous Coronary Intervention: Executive Summary and Recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 2001;103:3019-3041
Link to Article
Mehta SR, Yusuf S, Peters RJ.  et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention.  Lancet. 2001;358:527-533
PubMed   |  Link to Article
Steinhubl SR, Berger PB, Mann JT.  et al. CREDO Investigators.  Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention.  JAMA. 2002;288:2411-2420
PubMed   |  Link to Article
Janzon L, Bergqvist D, Boberg J.  et al.  Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine.  J Intern Med. 1990;227:301-308
PubMed   |  Link to Article
Gibbons RJ, Abrams J, Chatterjee K.  et al.  ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 2003;107:149-158
PubMed   |  Link to Article
Tsuya T, Okada M, Horie H, Ishikawa K. Effect of dipyridamole at the usual oral dose on exercise-induced myocardial ischemia in stable angina pectoris.  Am J Cardiol. 1990;66:275-278
PubMed   |  Link to Article
Diener HC, Darius H, Bertrand-Hardy JM, Humphreys M. Cardiac safety in the European Stroke Prevention Study 2 (ESPS2).  Int J Clin Pract. 2001;55:162-163
PubMed
Ryan TJ, Antman EM, Brooks NH.  et al.  1999 update: ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction: Executive Summary and Recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 1999;100:1016-1030
PubMed   |  Link to Article
Criqui MH, Langer RD, Fronek A.  et al.  Mortality over a period of 10 years in patients with peripheral arterial disease.  N Engl J Med. 1992;326:381-386
PubMed   |  Link to Article

Figures

Figure 1. Recommended Initial Antiplatelet Therapy for Patients With Transient Ischemic Attack or Ischemic Stroke and Subsequent Therapy for Recurrent Ischemic Events
Graphic Jump Location

Abbreviations: ACS indicates acute coronary syndrome; TIA, transient ischemic attack.
*Per the Antithrombotic Trialists’ Collaboration.21,2
†Per the CAPRIE Steering Committee.21
‡Per Diener et al24 and De Schryver et al.28
§Without coronary artery disease.

Figure 2. Recommended Initial Antiplatelet Therapy for Patients With Stable Coronary Artery Disease and Subsequent Therapy for Recurrent Ischemic Events
Graphic Jump Location

Abbreviations: ACS indicates acute coronary syndrome; TIA, transient ischemic attack.
*Per the Antithrombotic Trialists’ Collaboration.2
†Per the CAPRIE Steering Committee.21

Figure 3. Recommended Initial Antiplatelet Therapy for Patients With Peripheral Arterial Disease and Subsequent Therapy for Recurrent Ischemic Events
Graphic Jump Location

Abbreviations: ACS indicates acute coronary syndrome; TIA, transient ischemic attack.
*Per the Antithrombotic Trialists’ Collaboration.2
†Per the CAPRIE Steering Committee.21
‡Per Diener et al24 and De Schryver et al.28

Tables

Table Graphic Jump LocationTable 1. Proportional Effects of Antiplatelet Therapy on Vascular Events Compared With Controls, Subdivided by Disease Categories*
Table Graphic Jump LocationTable 2. Results of CAPRIE Study: Treatment Effect on Outcome by Subgroup*

References

Nenci G. Unifying concept of arterial vascular disease.  Eur Heart J. 1999;1:(suppl A)  A27-A30
Antithrombotic Trialists’ Collaboration.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients.  BMJ. 2002;324:71-86
PubMed   |  Link to Article
Jonas S, Grieco G. Potential value of triple antiplatelet therapy for secondary stroke prevention.  Stroke. 2003;34:e182-e183
PubMed   |  Link to Article
van Gijn J, Algra A. Aspirin and stroke prevention.  Thromb Res. 2003;110:349-353
PubMed   |  Link to Article
Aronow WS, Ahn C. Prevalence of coexistence of coronary artery disease, peripheral arterial disease, and atherothrombotic brain infarction in men and women > or=62 years of age.  Am J Cardiol. 1994;74:64-65
PubMed   |  Link to Article
Mautner GC, Mautner SL, Roberts WC. Amounts of coronary arterial narrowing by atherosclerotic plaque at necropsy in patients with lower extremity amputation.  Am J Cardiol. 1992;70:1147-1151
PubMed   |  Link to Article
Chimowitz MI, Mancini GB. Asymptomatic coronary artery disease in patients with stroke.  Stroke. 1992;23:433-436
PubMed   |  Link to Article
SYMPHONY Investigators.  Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial.  Lancet. 2000;355:337-345
PubMed   |  Link to Article
Topol EJ, Easton D, Harrington RA.  et al.  Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease.  Circulation. 2003;108:399-406
PubMed   |  Link to Article
Cannon CP, McCabe CH, Wilcox RG.  et al.  Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial.  Circulation. 2000;102:149-156
PubMed   |  Link to Article
Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia.  Stroke. 1977;8:301-314
PubMed   |  Link to Article
Guiraud-Chaumeil B, Rascol A, David J.  et al.  Prevention of recurrences of cerebral ischemic vascular accidents by platelet antiaggregants. [in French].  Rev Neurol (Paris). 1982;138:367-385
PubMed
Sorensen PS, Pedersen H, Marquardsen J.  et al.  Acetylsalicylic acid in the prevention of stroke in patients with reversible cerebral ischemic attacks: a Danish cooperative study.  Stroke. 1983;14:15-22
PubMed   |  Link to Article
 High-dose acetylsalicylic acid after cerebral infarction.  Stroke. 1987;18:325-334
PubMed   |  Link to Article
Boysen G, Sorensen PS, Juhler M.  et al.  Danish very-low-dose aspirin after carotid endarterectomy trial.  Stroke. 1988;19:1211-1215
PubMed   |  Link to Article
Acheson J, Danta G, Hutchinson EC. Controlled trial of dipyridamole in cerebral vascular disease.  BMJ. 1969;1:614-615
PubMed   |  Link to Article
Gent M, Blakely JA, Easton JD.  et al.  The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke.  Lancet. 1989;1:1215-1220
PubMed   |  Link to Article
Hass WK, Easton JD, Adams HP Jr.  et al. Ticlopidine Aspirin Stroke Study Group.  A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients.  N Engl J Med. 1989;321:501-507
PubMed   |  Link to Article
Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K.  et al.  Thrombotic thrombocytopenic purpura associated with ticlopidine.  Ann Intern Med. 1998;128:541-544
PubMed   |  Link to Article
Hankey GJ, Sudlow CL, Johnson CL. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients.  Cochrane Database Syst Rev. 2000;2:CD001246
PubMed
CAPRIE Steering Committee.  A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).  Lancet. 1996;348:1329-1339
PubMed   |  Link to Article
Harker LA, Boissel JP, Pilgrim AJ, Gent M.CAPRIE Steering Committee and Investigators.  Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE.  Drug Saf. 1999;21:325-335
PubMed   |  Link to Article
Diener HC, Bogousslavsky J, Brass LM.  et al.  Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH).  Lancet. 2004;364:331-337
PubMed   |  Link to Article
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study, 2: Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.  J Neurol Sci. 1996;143:1-13
PubMed   |  Link to Article
American-Canadian Co-Operative Study Group.  Persantine Aspirin Trial in Cerebral Ischemia, Part II: endpoint results.  Stroke. 1985;16:406-415
PubMed   |  Link to Article
Bousser MG, Eschwege E, Haguenau M.  et al.  “AICLA” controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia.  Stroke. 1983;14:5-14
PubMed   |  Link to Article
SALT Collaborative Group.  Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.  Lancet. 1991;338:1345-1349
PubMed   |  Link to Article
De Schryver EL, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease.  Cochrane Database Syst Rev. 2004;1:CD001820
PubMed
Elwood PC, Williams WO. A randomized controlled trial of aspirin in the prevention of early mortality in myocardial infarction.  J R Coll Gen Pract. 1979;29:413-416
PubMed
Elwood PC. Early use of aspirin.  Lancet. 1990;335:486
PubMed   |  Link to Article
Verheugt FW, Kupper AJ, Galema TW, Roos JP. Low dose aspirin after early thrombolysis in anterior wall acute myocardial infarction.  Am J Cardiol. 1988;61:904-906
PubMed   |  Link to Article
 Randomized factorial trial of high-dose intravenous streptokinase, of oral aspirin and of intravenous heparin in acute myocardial infarction.  Eur Heart J. 1987;8:634-642
PubMed
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.  Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.  Lancet. 1988;2:349-360
PubMed
Baigent C, Collins R, Appleby P.  et al. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.  ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither.  BMJ. 1998;316:1337-1343
PubMed   |  Link to Article
Cairns JA, Theroux P, Lewis HD Jr, Ezekowitz M, Meade TW. Antithrombotic agents in coronary artery disease.  Chest. 2001;119:(1 suppl)  228S-252S
PubMed   |  Link to Article
Nyman I, Larsson H, Wallentin L.Research Group on Instability in Coronary Artery Disease in Southeast Sweden.  Prevention of serious cardiac events by low-dose aspirin in patients with silent myocardial ischaemia.  Lancet. 1992;340:497-501
PubMed   |  Link to Article
Lewis HD Jr, Davis JW, Archibald DG.  et al.  Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina.  N Engl J Med. 1983;309:396-403
PubMed   |  Link to Article
Cairns JA, Gent M, Singer J.  et al.  Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial.  N Engl J Med. 1985;313:1369-1375
PubMed   |  Link to Article
Theroux P, Ouimet H, McCans J.  et al.  Aspirin, heparin, or both to treat acute unstable angina.  N Engl J Med. 1988;319:1105-1111
PubMed   |  Link to Article
Wallentin LC.Research Group on Instability in Coronary Artery Disease in Southeast Sweden.  Aspirin (75 mg/day) after an episode of unstable coronary artery disease.  J Am Coll Cardiol. 1991;18:1587-1593
PubMed   |  Link to Article
RISC Group.  Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.  Lancet. 1990;336:827-830
PubMed   |  Link to Article
Balsano F, Rizzon P, Violi F.  et al. Studio della Ticlopidina nell'Angina Instabile Group.  Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter clinical trial.  Circulation. 1990;82:17-26
PubMed   |  Link to Article
Yusuf S, Zhao F, Mehta SR.  et al.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med. 2001;345:494-502
PubMed   |  Link to Article
Peters RZ, Lewis B. Aspirin dose and bleeding events in the CURE study.  Circulation. 2002;106:2258a
Juul-Moller S, Edvardsson N, Jahnmatz B.  et al. Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.  Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.  Lancet. 1992;340:1421-1425
PubMed   |  Link to Article
Popma JJ, Ohman M, Weitz J.  et al.  Antithrombotic therapy in patients undergoing percutaneous coronary intervention.  Chest. 2001;119:321-336
Link to Article
Smith SC, Dove JT, Jacobs AK.  et al.  ACC/AHA Guidelines for Percutaneous Coronary Intervention: Executive Summary and Recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 2001;103:3019-3041
Link to Article
Mehta SR, Yusuf S, Peters RJ.  et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention.  Lancet. 2001;358:527-533
PubMed   |  Link to Article
Steinhubl SR, Berger PB, Mann JT.  et al. CREDO Investigators.  Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention.  JAMA. 2002;288:2411-2420
PubMed   |  Link to Article
Janzon L, Bergqvist D, Boberg J.  et al.  Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine.  J Intern Med. 1990;227:301-308
PubMed   |  Link to Article
Gibbons RJ, Abrams J, Chatterjee K.  et al.  ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 2003;107:149-158
PubMed   |  Link to Article
Tsuya T, Okada M, Horie H, Ishikawa K. Effect of dipyridamole at the usual oral dose on exercise-induced myocardial ischemia in stable angina pectoris.  Am J Cardiol. 1990;66:275-278
PubMed   |  Link to Article
Diener HC, Darius H, Bertrand-Hardy JM, Humphreys M. Cardiac safety in the European Stroke Prevention Study 2 (ESPS2).  Int J Clin Pract. 2001;55:162-163
PubMed
Ryan TJ, Antman EM, Brooks NH.  et al.  1999 update: ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction: Executive Summary and Recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 1999;100:1016-1030
PubMed   |  Link to Article
Criqui MH, Langer RD, Fronek A.  et al.  Mortality over a period of 10 years in patients with peripheral arterial disease.  N Engl J Med. 1992;326:381-386
PubMed   |  Link to Article
CME


You need to register in order to view this quiz.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 93

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Topics
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Example 3