Prevention of Vascular Events in Patients with Cerebrovascular Disease: Efficacy and Appropriate Duration of Antiplatelet Therapy

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1 Clin. Cardiol. 29, (2006) Prevention of Vascular Events in Patients with Cerebrovascular Disease: Efficacy and Appropriate Duration of Antiplatelet Therapy GABRIEL B. HABIB, SR., M.D., M.S., FACC, FCCP Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA Summary: Antiplatelet therapy has shown consistent benefit in the prevention of secondary stroke. The paucity of head-tohead studies of different antiplatelet regimens, assessment of comparative efficacy, and optimal treatment duration requires evaluation and comparison of clinical studies that vary extensively in design and follow-up. Evidence for aspirin benefit in secondary stroke prevention is strong, but existing studies provide little guidance with regard to treatment duration. The efficacy of clopidogrel in secondary event prevention is significantly greater than that of aspirin for patients with a history of peripheral artery disease, but does not differ from that of aspirin for patients with a history of stroke or myocardial infarction. Relative to clopidogrel alone, the addition of aspirin to clopidogrel results in increased risk for life-threatening bleeding episodes similar in absolute magnitude to the reduction of secondary event risk in patients with stroke. Benefits associated with clopidogrel occur early in the course of therapy; few data support clopidogrel use for longer than 1 year after stroke. Monotherapy with extended-release dipyridamole (ER-DP) provides reduction in secondary stroke risk similar to aspirin; however, the combination of aspirin plus ER-DP significantly reduces risk relative to either agent alone. Compared with placebo and monotherapy with either agent, risk reduction for the aspirin plus ER-DP combination continued through 24 months, with no concomitant increase in bleeding risk. Additional clinical studies should provide needed comparisons of efficacy and guidance with regard to optimal duration of therapy. This manuscript has been supported by a grant from Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA. Address for reprints: Gabriel B. Habib, Sr., M.D., M.S., F.A.C.C., F.C.C.P. Michael E. DeBakey Veterans Affairs Medical Center Section of Cardiology, Office #3C-310E 2002 Holcombe Boulevard Houston, TX 77030, USA gabehabib@yahoo.com Received: August 31, 2005 Accepted with revision: December 9, 2005 Key words: stroke, secondary prevention, extended-release dipyridamole, clopidogrel, antiplatelet Introduction Prevention of secondary stroke should be a priority for all who treat stroke patients. Approximately one-third of the 700,000 strokes that occur in the United States each year are recurrent. 1 These events are costly in terms of both morbidity and mortality. Because the factors associated with high risk for stroke also confer high risk on other forms of cardiovascular disease (CVD), including coronary artery disease (CAD), 2, 3 any patient with a history of stroke or transient ischemic attack (TIA) should be considered a high-risk cardiovascular patient. Indeed, three quarters of these patients also show evidence of heart disease. 4, 5 Given that cardiologists may be treating patients at high risk for secondary stroke, it is important to keep in mind that most cardiovascular events in patients with a history of stroke are cerebrovascular in nature. Antiplatelet agents are an important foundation of medical therapy in preventing secondary cerebrovascular events. 2 Several therapies have been evaluated in secondary stroke prevention during the past 15 years: aspirin, the thienopyridine clopidogrel, and the vasodilator dipyridamole plus aspirin. The use of these regimens has become routine, both following initial events and during and after interventional cardiovascular procedures. Each regimen has been evaluated in one or more large-scale clinical studies, with follow-up from 1 to 7 years. In addition to concerns about the efficacy of antiplatelet regimens in preventing recurrent events, there is concern about optimum duration of therapy. All drugs carry risk. The most important risk associated with antiplatelet therapies is increased bleeding. Such risk leads us to question whether treatments should be continued indefinitely. This review summarizes findings from clinical studies on the efficacy and optimum duration of antiplatelet therapies for secondary stroke prevention. Clinical Studies Aspirin Risk of bleeding events makes routine use of prophylactic aspirin problematic among asymptomatic patients at low risk

2 G.B. Habib, Sr.: Antiplatelet therapy duration in secondary stroke prevention 245 for CVD. 6 However, among those at greater risk, the benefits of aspirin therapy appear to outweigh the risk of increased bleeding. Early studies found compelling evidence that aspirin prevents secondary stroke in patients with cerebrovascular disease. The United Kingdom Transient Ischaemic Attack (UK-TIA) trial randomized patients with a recent TIA or ischemic stroke to 1,200 mg/day aspirin, 300 mg/day aspirin, or placebo. 7 A strong trend favored aspirin for the prevention of stroke, acute myocardial infarction (AMI), or vascular death, with no difference in efficacy between the two aspirin doses, although the 1,200-mg/day dose was associated with a greater incidence of gastrotoxicity 7 (see Table I). Two trials examined the safety and efficacy of low-dose aspirin. The Dutch Transient Ischemic Attack (Dutch TIA) trial compared 30 mg/day with 283 mg/day of aspirin in patients with a recent TIA or ischemic stroke. 8 The frequency of nonfatal AMI, nonfatal stroke, or death from vascular causes was similar in both groups, but the low-dose group had significantly fewer major bleeding episodes. 8 The value of low-dose aspirin was confirmed by the Swedish Aspirin Low-dose Trial (SALT), which treated patients with 75 mg/day aspirin following an ischemic stroke, TIA, or retinal artery occlusion. 9 After a mean followup of 32 months, the relative risk (RR) of the primary outcome measure of stroke or death was reduced by 18% in aspirintreated patients versus those receiving placebo. Although aspirin therapy was associated with an increased risk of hemorrhagic stroke and a significant increased risk of fatal hemorrhagic stroke, this was outweighed by the decreased risk of ischemic stroke. 9 A meta-analysis of randomized studies of antiplatelet therapy concluded that aspirin in doses of 75 to 150 mg/day provides significant benefit against subsequent vascular events among patients with a history of stroke or TIA. 10 A mini meta-analysis of randomized studies also suggested that little incremental benefit is associated with any aspirin dose above 30 mg/day. 11 Unfortunately, few data are available on the optimum duration of aspirin therapy. Event-free survival curves from UK-TIA and SALT suggest that much of aspirin s benefit is realized within the first year, with approximately equivalent event rates thereafter. 7, 9 However, rigorous statistical comparison of these curves was performed in neither study; moreover, confidence in this interpretation is limited for UK-TIA by use of a composite endpoint and for SALT by the limited number of evaluable patients after 3 years of follow-up. 7, 9 Clopidogrel Clopidogrel s efficacy in secondary event prevention in patients with symptomatic CVD was evaluated in Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CA- PRIE), conducted in patients with recent stroke, MI, or peripheral artery disease (PAD). 12 Clopidogrel (75 mg/day) demonstrated a modest but statistically significant benefit over aspirin (325 mg/day) an 8.7% relative risk reduction (RRR) for stroke, MI, or vascular death. 12 However, this benefit was driven primarily by results found in the subgroup of patients with PAD. Although patients with PAD experienced a significant reduction in cardiovascular events, this did not occur among patients whose index event was either an MI or stroke. These results suggest that clopidogrel s efficacy in preventing recurrent vascular events may differ by index event. 12 The Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) study evaluated clopidogrel monotherapy versus clopidogrel plus aspirin in patients with recent stroke or TIA. 13 The primary endpoint was a composite of stroke, AMI, vascular death, or rehospitalization for an acute ischemic event during the 18-month treatment period. 13 Combination therapy was associated with a nonsignificant RRR of 6.4% in the primary outcome measure compared with clopidogrel monotherapy. 13 Consistent with the small reduction in risk, cumulative event curves did not diverge to a significant extent; however, it appears that any benefit from combination treatment was observed within the first 3 months. The Kaplan-Meier curves for survival free of primary intracerebral hemorrhage for each treatment group did not separate until 3 4 months after randomization, suggesting that the benefit: risk ratio may be greatest in the first few months after stroke. 14 Moreover, this small reduction in event rate was accompanied by a highly significant increase in life-threatening, major and minor bleeding episodes. 13 Just released at the 55th Annual Scientific Session of the American College of Cardiology were the results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. 15 A total of 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors received clopidogrel 75 mg plus low-dose aspirin ( mg/day) or placebo plus low-dose aspirin. The primary efficacy endpoint was a composite of MI, stroke, or death from cardiovascular causes. There was no overall significant difference in the primary efficacy endpoint (6.8% with clopidogrel plus aspirin vs. 7.3% with placebo plus aspirin; RR 0.93; 95% confidence interval [CI], 0.83 to 1.05; p = 0.22) and there was a nonsignificant trend for a higher risk of severe bleeding with clopidogrel (1.7 and 1.3%, respectively; RR 1.25; 95% CI, 0.97 to 1.61; p = 0.09). Among patients with multiple risk factors but no clinically evident cardiovascular disease, the primary endpoint was not significantly different (6.6% with clopidogrel and 5.5% with placebo; RR 1.2; 95% CI, 0.91 to 1.59; p = 0.20), but cardiovascular mortality was significantly higher with clopidogrel (3.9 vs. 2.2%, p = 0.01). Both MATCH and CHARISMA trials suggest that the combination of clopidogrel and aspirin does not provide greater benefit than aspirin or clopidogrel alone, has a higher bleeding risk, and is thus not recommended at this time. Dipyridamole plus Aspirin The first large study of the dipyridamole plus aspirin combination in preventing secondary stroke, the European Stroke Prevention Study (ESPS), enrolled 2,500 patients with a recent

3 246 Clin. Cardiol. Vol. 29, June 2006 TABLE I Findings from major antiplatelet trials for secondary prevention of stroke Statistical significance No. of of major differences Trial patients Therapy Duration Key findings in primary endpoint UK-TIA (7) 2,435 1,200 mg ASA, 1 7 Years Strong but nonsignificant RRR: 15% 300 mg ASA, trend for less stroke, AMI, 95% CI: 29 to 3% or vascular death in ASA-treated patients with no difference between two ASA doses; higher gastrotoxicity at higher ASA dose Dutch TIA (8) 3, or 283 mg 31 Months Similar risk of nonfatal AMI, OR: 0.91 ASA mean nonfatal stroke, death from 95% CI: follow-up vascular causes, but fewer Primary endpoint: 14.7 vs. bleeding episodes in 15.2% (30 vs. 283 mg low-dose ASA group) SALT (9) 1, mg ASA 32 Months Significant reduction in RRR: 18% mean stroke or death in 95% CI: , follow-up ASA-treated patients p = 0.02 CAPRIE (12) 19, mg 1.91 Years Significant but small reduction RRR: 8.7%, p = 0.043; clopidogrel mean of stroke, AMI, or vascular RRR for PAD: 23.8%, or follow-up death with clopidogrel p = ; 325 mg ASA compared with ASA; RRR for stroke: 7.3%, benefit is limited to the p = 0.26; annual stroke, subgroup with PAD and MI, or vascular death rate: is not evident in patients 5.32 vs. 5.83% (clopidogrel with AMI or stroke vs. ASA group) MATCH (13) 7, mg clopidogrel 18 Months No difference in stroke, RRR: 6.4% primary EP + 75 mg ASA AMI, vascular death, or 95% CI: , or 75 mg rehospitalization for p = 0.244; life-threatening clopidogrel acute ischemic event bleeding: 3 vs. 1%, + placebo but significant increase p < in life-threatening bleeding ESPS (16) 2,500 Dipyridamole 24 Months Significant reduction in RRR: 38.1%, p < for 75 mg t.i.d. all strokes, fatal strokes, all strokes; RRR: 45.7%, + ASA and death in DP + p < 0.01 for fatal strokes; 330 mg t.i.d. ASA treated patients RRR: 30.6%, p < 0.01 for death ESPS-2 (17) 6,602 ER-DP 200 mg 24 Months Significant reduction in ASA + ER-DP b.i.d. + ASA 25 stroke and stroke or death RRR for stroke: 37%, mg b.i.d., ASA in ER-DP + ASA compared p < 0.001; RRR for monotherapy, with ASA or ER-DP stroke or death: ER-DP monotherapy 24%, p < monotherapy, Abbreviations: ASA = aspirin, ER-DP = extended-release dipyridamole, AMI = acute myocardial infarction, RRR = relative risk reduction, CI = confidence interval, OR = odds ratio, PAD = peripheral artery disease, UK-TIA = United Kingdom Transient Ischaemic Attack trial, Dutch- TIA = Dutch Transient Ischemic Attack trial, SALT = Swedish Aspirin in Low-dose Trial, CAPRIE = Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events, MATCH = Management of Atherothrombosis with Clopidogrel in High-Risk Patients, ESPS = European Stroke Prevention Study.

4 G.B. Habib, Sr.: Antiplatelet therapy duration in secondary stroke prevention 247 TIA, transient neurologic deficit, or stroke. 16 After 24 months of treatment with placebo or dipyridamole (75 mg t.i.d.) plus aspirin (330 mg t.i.d.), highly significant risk reductions were observed in all strokes, fatal strokes, and death. 10, 16 The second European Stroke Prevention Study (ESPS-2) differed from ESPS in several ways: ESPS-2 used extendedrelease dipyridamole (ER-DP; 200 mg b.i.d.), a lower dose of aspirin (25 mg b.i.d.), and a 2 2 factorial design that incorporated a placebo arm, an ER-DP monotherapy arm, and an aspirin monotherapy arm in addition to the aspirin/er-dp combination. 17 Over 6,600 patients with a recent stroke or TIA enrolled. After 24 months, the risk of stroke and stroke or death were significantly reduced in both aspirin and ER-DP monotherapy arms compared with placebo. 17 However, aspirin/er-dp provided a greater reduction than either monotherapy regimen compared with placebo in the risk of stroke and stroke or death. The effects of the two agents in combination were nearly additive with respect to risk reduction, reducing the RR of stroke over aspirin alone by 23%. 17 Compared with aspirin alone, aspirin/er-dp did not increase bleeding risk. Overall and severe or fatal bleeding event rates were similar in patients treated with ER-DP and those receiving placebo; they were also similar in patients receiving aspirin/er-dp and those receiving aspirin alone. 17 With regard to treatment effect over time, RR for stroke and for stroke plus death in the aspirin/er-dp group diverged within 1 month from placebo and from the monotherapy groups. Stroke risk reduction continued to diverge over the entire 24-month study. 17 A post hoc subgroup analysis of ESPS-2 has shown that the treatment benefit associated with aspirin/er-dp is particularly great among certain high-risk patients. 18 Patients with a history of hypertension, MI, TIA, or stroke prior to the index event, or any CVD, as well as patients who were smokers at baseline, showed greater benefit than low-risk patients when aspirin/er-dp was compared with aspirin alone. 18 Discussion The most recent guidelines for therapy following ischemic stroke strongly recommend antiplatelet treatment. 19 While acknowledging the efficacy of aspirin monotherapy, the guidelines currently recommend either aspirin/dipyridamole (evidence grade 2A) or clopidogrel (evidence grade 2B) as preferable to aspirin. 19 However, the guidelines have acknowledged the limited number of comparative studies versus aspirin and the absence of head-to-head studies between clopidogrel and aspirin/er-dp. 19 In general, the evidence presented here supports the use of aspirin to prevent recurrent cerebrovascular events in highrisk patients. Clopidogrel monotherapy appears to provide the same degree of efficacy as aspirin among patients with a history of stroke or TIA. However, clopidogrel plus aspirin does not yield significant additive benefit over clopidogrel alone and confers substantially greater risk of serious bleeding. 13 In contrast, aspirin/er-dp reduces the risk of recurrent stroke significantly more than either agent alone, with a reduction similar in magnitude to the additive benefit of both agents. 17 Notably, this benefit is achieved with a bleeding episode risk comparable to that of aspirin alone. With regard to treatment duration, it is difficult to make a specific recommendation for aspirin, as existing studies provide little information on the temporal development of either risk reduction or cumulative incidence of bleeding events. It is certainly prudent to use the lowest possible dose of aspirin when considering long-term or indefinite treatment to minimize the risk of bleeding and gastrointestinal complications. For clopidogrel monotherapy, the short duration of CA- PRIE and the absence of event curves for efficacy or bleeding episodes specific to stroke also make it difficult to provide recommendations for optimal treatment duration for stroke survivors. 12 However, the overall efficacy curve from CAPRIE suggests that most clinical benefits occur within a year of clopidogrel initiation. In addition, the pattern of intracranial bleeding episodes observed in MATCH indicates an increased incidence beginning around 9 months. 13 Taken together, these findings suggest that it may be prudent to limit clopidogrel therapy after a cerebrovascular event to 1 year, at least until more specific information becomes available. In contrast, benefit of aspirin/er-dp continued to diverge from aspirin and ER-DP monotherapy over the course of ESPS-2, suggesting that the clinical benefit of this combination continues for at least 24 months. 16, 17 The risk of bleeding attributable to aspirin remained constant throughout the study. 17 The aspirin/er-dp combination should be considered in the same light as aspirin monotherapy, with no clear time threshold at which clinical benefit is known to abate while a low ongoing risk of bleeding persists. Additional evidence may be provided by an ongoing clinical trial comparing clopidogrel with aspirin plus ER-DP in patients with a history of recent stroke. The 18,500-patient Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study will be the largest prospective secondary stroke prevention trial to date. Patients with a recent history of ischemic stroke will be randomized to treatment in a 2 2 factorial design, with aspirin/er-dp or clopidogrel, either alone or with telmisartan, an angiotensin II receptor blocker. Time to the first recurrent stroke is the primary endpoint, with a composite CVD as the secondary endpoint. The understanding of event patterns and treatment benefit among high-risk patients following ischemic stroke continues to develop. It is hoped that CHARISMA and PRoFESS will provide physicians with greater information on the relative benefit of the various antiplatelet agents as well as the most appropriate duration for such therapy. References 1. American Heart Association. Heart Disease and Stroke Statistics 2005 Update. Dallas, Texas: American Heart Association, Wolf PA, Clagett GP, Easton JD, Goldstein LB, Gorelick PB, Kelly-Hayes M, Sacco RL, Whisnant JP: Preventing ischemic stroke in patients with pri-

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