Stroke is a leading cause of death and the primary

A View on Combination Antiplatelet Agents in Ischemic Stroke Bhargava M Vyasa*, RD Dave*, PS Daniel*, IS Anand*, CN Patel* Abstract The evaluation of antiplatelet agents for prevention of ischemic stroke is being focused as a strategy for stroke reduction. The aim of this analysis was to focus specifically on the necessity of combination antiplatelet agents for secondary prevention of ischemic strokes. Aspirin, clopidogrel, ticlopidine and the combination of aspirin plus extended-release dipyridamole are all effective in reducing the risk of recurrent ischemic strokes and transient ischemic attack. Furthermore, the combinations of all above drugs show some merits and demerits in one or more condition. National guideline endorses any of these antiplatelet agents as appropriate treatment options but more research into this strategy is needed. Choosing a single antiplatelet agent or the combination must be tailored according to patient characteristics, cost, disease condition and tolerability. Other classes of antiplatelet drugs should undergo clinical trials to optimize antiplatelet therapy. Keywords: Aspirin, clopidogrel, dipyridamole, ticlopidine, combination antiplatelet therapy, ischemic stroke Stroke is a leading cause of death and the primary cause of serious, long-term disability worldwide. Roughly, 90% of all strokes are ischemic in nature, with the remaining resulting from intracerebral hemorrhage or subarachnoid hemorrhage. Nearly, 25% of patients who experience a stroke have sustained a previous stroke, making secondary prevention of recurrent stroke an important target of pharmacotherapy. The high rates of mortality and disability associated with ischemic stroke, coupled with its prevalence, necessitate good, long-term preventive strategies. Patients suffering from a transient ischemic attack (TIA) or stroke are particularly vulnerable to secondary stroke. Available antiplatelet therapies include aspirin, clopidogrel, dipyridamole and ticlopidine. Of these options, aspirin monotherapy has been the mainstay of treatment for secondary prevention of ischemic stroke or TIA. It has been studied extensively and is relatively safe and inexpensive. Unfortunately, aspirin monotherapy has its limitations. It has been suggested that aspirin alone produces only a 10-15% relative risk (RR) reduction in stroke recurrence compared *Dept. of Pharmacology Shri Sarvajanik Pharmacy College, Mehsana, Gujarat Address for correspondence Dr Bhargava M Vyasa D/301, Ashutosh Apartments, B/h St. Xavier s Loyola School Naranpura, Ahmedabad - 380 013 E-mail: bmvyasa_1986@yahoo.co.in with placebo. Aspirin can also cause significant gastrointestinal discomfort and bleeding, and certain patients may be resistant to its antiplatelet effects. These findings have led investigators to consider alternatives to aspirin monotherapy, most notably, combination antiplatelet treatment. Combination antiplatelet therapy seeks to block platelet aggregation through multiple mechanisms. Aspirin inhibits the enzyme cyclooxygenase, thus preventing production of prostaglandins and ultimately the production of thromboxane A 2. Clopidogrel acts on platelets by irreversibly binding the adenosine diphosphate (ADP) receptor, blocking the ADP-dependent activation of the glycoprotein IIb- IIIa complex. This complex works as a receptor for fibrinogen on the surface of the platelet. Dipyridamole inhibits the uptake of adenosine into platelets, resulting in elevated local adenosine concentrations. Adenosine then acts on platelet A 2 receptors, increasing the production of cyclic adenosine monophosphate. This mechanism prevents platelet-activating factor, collagen, ADP and other stimuli from activating platelet aggregation. By blocking platelet aggregation through multiple mechanisms, it is postulated that secondary ischemic stroke prevention can be enhanced. The American Heart Association (AHA) and the American Stroke Association (ASA) published joint guidelines in 2006 for treatment of patients with a history of stroke or TIA. Indian Journal of Clinical Practice, Vol. 23, No. 11, April 2013 701

Randomized trials have established combination antiplatelet therapy as a cornerstone for secondary stroke prevention. Results from these trials enhance the recommendations from the AHA-ASA and provide the foundation for the updates in the 8th ACCP guideline. To identify pertinent combination antiplatelet trials, we performed a medline search of the literature from 1967-2007. We identified two trials - Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) and the European-Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT). Data from these two trials are important to current recommendations for secondary ischemic stroke and TIA prevention. Data from historic trials - the European Stroke Prevention Study (ESPS), the Second European Stroke Prevention Study (ESPS-2), the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events trial (CAPRIE) and the Management of Athero-Thrombosis with Clopidogrel in High-risk Patients (MATCH) - are also important to consider, as they provided the background for the AHA-ASA and most recent ACCP guidelines (Table 1). In this article, we review the evidence from randomized trials for the effectiveness and safety of established combination antiplatelet therapies for secondary prevention of ischemic stroke and TIA. We have focused on trials and meta-analysis that included patients with stroke, TIA or peripheral artery disease. Aspirin Aspirin, the most commonly used antiplatelet agent, inhibits the enzyme cyclooxygenase, reducing production of thromboxane A 2, a stimulator of platelet aggregation. This interferes with the formation of thrombi, thereby reducing the risk of stroke. The dose of aspirin in secondary stroke prevention studies ranged between 20-1,300 mg. Most studies have found that 50-325 mg/day of aspirin is as effective as higher doses. Furthermore, lower doses within this range appear to provide the same benefit as higher doses. In the ESPS-2, 50 mg of aspirin daily reduced stroke risk by 18% compared with placebo (29 strokes prevented per 1,000 treated), an effect of comparable magnitude to the other trials cited above. This benefit seen with very low-dose aspirin is consistent with laboratory observations that 30 mg of aspirin per day results in complete suppression of thromboxane A 2 production. In an analysis of data from 31 randomized, controlled trials, aspirin doses 200 mg/day were associated with a significantly lower rate of major bleeding events compared with higher doses. However, there was no difference in major bleeding when aspirin <100 mg/ day was compared with 100-200 mg/day. Aspirin <100 mg/day was associated with a lower risk compared with the 100-200 mg/day and >200 mg/day s when the overall rate of bleeding complications (including major, minor and insignificant events) was considered. A later meta-analysis of 22 randomized trials of lowdose aspirin (75-325 mg/day) versus placebo for cardiovascular prophylaxis reached similar conclusions within the low-dose range. Compared with placebo, aspirin increased the RR of any major bleeding, major gastrointestinal bleeding and intracranial bleeding Table 1. Trial Characteristics for Six Randomized Controlled Trials Trial Subjects Treatment arms Primary endpoints Results (% RRR) ESPS-1 2,500 ASA 330 mg q.d. + IR-DP 75 mg Stroke or death 33.5% reduction in stroke t.i.d. vs placebo ESPS-2 6,602 ASA 25 mg b.i.d. + ER-DP 200 mg b.i.d. or ASA 25 mg b.i.d., or ER-DP 200 mg b.i.d. vs placebo Stroke 37% with aspirin-dipyridamole, by 18% with aspirin alone, and by 16% with dipyridamole alone vs placebo CAPRIE 19,185 ASA 325 mg q.d. vs clopidogrel 75 mg q.i.d. MATCH 7,599 ASA 325 mg q.d. + clopidogrel 75 mg q.d. vs clopidogrel 75 mg q.d. CHARISMA 15,603 Clopidogrel 75 mg q.d. + ASA 75-162 mg q.i.d. vs ASA 75-162 mg q.i.d. ESPRIT 2,763 ASA 30-325 mg q.i.d. + DP 200 mg b.i.d. vs ASA 30-325 mg q.i.d. Ischemic stroke, MI or vascular death Ischemic stroke, MI, vascular death or rehospitalization for an acute ischemic event MI, stroke or death Death from vascular causes, nonfatal stroke or MI 8.7% RRR favored clopidogrel No significant difference; increased risk for bleeding in combination No significant difference; increased risk for bleeding in combination 20% RRR favored combination ASA = Aspirin; IR = Immediate release; ER = Extended-release; DP = Dipyridamole; MI = Myocardial infarction; RRR = Relative risk reduction. 702 Indian Journal of Clinical Practice, Vol. 23, No. 11, April 2013

Relative risk reduction (%) 25 20 15 10 5 0 by 1.7- to 2.1-fold. However, the absolute annual increase in risk for any major bleeding episode (mostly gastrointestinal) and for intracranial bleeding was 0.13 and 0.03%, respectively. Furthermore, there was no evidence of an increased risk of bleeding with high low-dose aspirin (>162-325 mg/day) compared with low low-dose aspirin (75-162 mg/day) (Fig. 1). Clopidogrel Clopidogrel is a thienopyridine that inhibits ADPdependent platelet aggregation. The CAPRIE trial randomly assigned 19,000 patients with recent stroke, myocardial infarction (MI) or symptomatic peripheral arterial disease (divided roughly equally between these three enrolling diseases) to treatment with aspirin (325 mg) or clopidogrel (75 mg). The primary endpoint, a composite outcome of stroke, MI or vascular death, was significantly reduced with clopidogrel treatment compared with aspirin treatment (5.3 vs 5.8% annually, RR reduction 8.7%, 95% confidence interval [CI] 0.3-16.5%). The benefit of clopidogrel over aspirin in the CAPRIE trial varied based on enrolling disease. Most of the benefit was observed in patients with peripheral arterial disease, and the difference in composite outcome between clopidogrel and aspirin treatment in patients with recent stroke and MI was not significant. However, the strength of these observations are limited, since they are based on sub analyses. Dipyridamole Stroke, MI, Vascular death Stroke Figure 1. Comparison of antiplatelet agents. Aspirin/ Dipyridamole Ticlopidine Clopidogrel Dipyridamole impairs platelet function by inhibiting the activity of adenosine deaminase and phosphodiesterase, which causes an accumulation of adenosine, adenine nucleotides and cyclic adenosine monophosphate. Dipyridamole may also cause vasodilation. Dipyridamole is currently available in two forms: An immediate-release form, usually given as 50-100 mg three times per day. A proprietary formulation containing both extended-release dipyridamole (ER-DP) 200 mg and 25 mg aspirin, given two times per day. The effectiveness of dipyridamole monotherapy for secondary stroke prevention was established by the following studies: The ESPS-2 trial randomly assigned 6,602 patients with a recent TIA or ischemic stroke to one of 4 s: 200 mg ER-DP alone given twice-daily; 25 mg aspirin alone given twice-daily; 25 mg aspirin plus 200 mg ER- DP given twice-daily and placebo. An independent and significant benefit for stroke risk reduction was observed for both ER-DP monotherapy (odds ratio [OR] 0.81, 95% CI 0.76-0.99) and aspirin monotherapy (OR 0.79, 95% CI 0.65-0.97) compared with placebo. The benefit of combination ER-DP plus aspirin was significantly greater still than the two components alone and significantly greater than placebo (OR 0.59, 95% CI 0.48-0.73). A subsequent meta-analysis of individual patient data from all available randomized trials found that dipyridamole alone was effective for reducing recurrent stroke compared with control (OR 0.82, 95% CI 0.68-1.0). Since, the ESPS-2 trial provided 57% of the data in this meta-analysis, it is possible that ESPS-2 was the primary driver behind the results. When ESPS- 2 data were excluded, the effectiveness of dipyridamole alone compared with control did not achieve statistical significance. Whether this is related to the lower doses and immediate-release formulation used in trials other than ESPS-2 remains unclear. Ticlopidine Ticlopidine is a thienopyridine with a chemical structure and mechanism of action similar to clopidogrel. Its role in stroke prevention has been evaluated in two major trials. The CATS trial compared ticlopidine with placebo in patients who had suffered a significant stroke. At a mean of 24 months follow-up, the primary composite endpoint of stroke, MI and vascular death was significantly lower with ticlopidine compared with placebo (10.8 vs 15.3%, RR reduction 30%). Analysis by intention-to-treat gave a smaller estimate of RR reduction for stroke, MI or vascular death (23%). The TASS trial compared ticlopidine (500 mg/ Indian Journal of Clinical Practice, Vol. 23, No. 11, April 2013 703

day) to aspirin (1,300 mg/day) in 3,069 patients with a recent TIA or mild stroke. At 3-year followup, ticlopidine was associated with a significant reduction in the primary endpoint (nonfatal stroke or death) compared with aspirin (17 vs 19%). Ticlopidine treatment was also associated with a significant reduction in the rate of fatal and nonfatal stroke compared with aspirin (10 vs 13%, respectively; RR reduction 21% [95% CI, 4-38]). Aspirin Plus Clopidogrel The combined use of aspirin and clopidogrel does not offer greater benefit for stroke prevention than either agent alone but does substantially increase the risk of bleeding complications. This conclusion is supported by results from the MATCH trial. This study enrolled 7,599 patients with stroke or TIA who also had some additional high-risk feature, defined as prior MI, prior stroke (in addition to the index event), diabetes, angina or symptomatic peripheral artery disease (PAD). The primary endpoint was a composite of ischemic stroke, MI, vascular death or rehospitalization for acute ischemia. Patients were randomly assigned to the combination of clopidogrel (75 mg daily) plus aspirin (75 mg daily) versus clopidogrel (75 mg daily) alone. Follow-up was 18 months. The following observations were reported: Aspirin plus clopidogrel treatment did not reduce the risk of major vascular events compared with clopidogrel alone (RR reduction 6.4%, 95% CI -4.6 to 16.3%). Aspirin plus clopidogrel was associated with a significant increase in life-threatening bleeding complications, mainly intracranial and gastrointestinal, compared with clopidogrel alone. Over the 18-month trial period, there was an absolute excess of 1.3% for life-threatening hemorrhage (95% CI 0.6-1.9) and an additional 1.3% for major hemorrhage in patients assigned combination therapy. Overall, treatment with aspirin and clopidogrel compared with clopidogrel alone might prevent 10 ischemic events per 1,000 treated (not statistically significant) at the cost of 13 life-threatening hemorrhages per 1,000 treated. Several authors have noted limitations of MATCH. For instance, 54% of MATCH subjects qualified for trial entry because of a lacunar stroke, a stroke subtype that has the lowest recurrence risk. Furthermore, data regarding interaction between treatment and stroke mechanism were not reported, raising the question of whether combination therapy might still play a role in particular stroke subtypes. The combination of aspirin and clopidogrel has been shown to have benefit over aspirin alone in patients with acute coronary syndromes. However, there are important differences between patients with coronary and cerebrovascular disease, and between short-term therapy initiated in the acute setting, and longer term preventative therapy. The results of the MATCH trial serve to emphasize these differences. In contrast to the MATCH trial, which evaluated aspirin plus clopidogrel versus clopidogrel alone in patients with stroke or TIA, the CHARISMA trial evaluated aspirin plus clopidogrel versus aspirin alone in patients with symptomatic cardiovascular disease or asymptomatic multiple cardiovascular risk factors. In this patient population, the combination of aspirin plus clopidogrel was not more effective than aspirin alone for reducing the rate of MI, stroke or death from cardiovascular causes. CHARISMA enrolled 15,603 patients with either documented cardiovascular disease (coronary, ischemic cerebrovascular or peripheral arterial) or, in 21% of patients, multiple atherothrombotic risk factors (e.g., diabetes, hypertension, primary hypercholesterolemia, current smoking, asymptomatic carotid stenosis 70%) and randomly assigned them to low-dose aspirin (75-162 mg/day) plus either clopidogrel (75 mg/day) or placebo. The following observations were reported at a median of 28 months: Combined aspirin plus clopidogrel treatment did not reduce the risk of the composite primary endpoint (MI, stroke of any cause or death from cardiovascular causes) compared with aspirin alone (6.8 vs 7.3%, RR 0.93, 95% CI 0.83-1.05) Combination therapy compared with aspirin alone was associated with a significant increase in moderate bleeding (2.1 vs 1.3%) and a nonsignificant increase in severe bleeding (1.7 vs 1.3%). Aspirin Plus Dipyridamole The beneficial effects of aspirin and dipyridamole for secondary stroke prevention appear to be additive such that the combination of aspirin and ER-DP is significantly more effective than aspirin alone for stroke prevention. The data supporting this conclusion come from the following randomized trials: 704 Indian Journal of Clinical Practice, Vol. 23, No. 11, April 2013

In a meta-analysis of six randomized trials with 7,648 patients, stroke risk was significantly reduced with aspirin plus dipyridamole (including immediate and extended-release formulations) compared with aspirin alone (RR 0.77, 95% CI 0.67-0.89). Nearly, 80% of the patients in this metaanalysis came from just two trials, ESPS-2 and ESPRIT. In the ESPS-2 trial, the stroke rate at 24 months of follow-up was significantly reduced in the aspirin plus ER-DP compared with the aspirin alone (9.9 vs 12.9%; RR reduction 23%, 95% CI 9.2-37.0). There was no significant difference in the risk of death between the two s. The risk of bleeding complications was not significantly different between the aspirin plus ER-DP and the aspirin monotherapy, whereas both s experienced a greater frequency of bleeding complications than the placebo. In the later ESPRIT trial, 2,739 patients within six months of a TIA or minor stroke of presumed arterial origin were randomly assigned to openlabel treatment with aspirin (30-325 mg/day) alone or aspirin plus dipyridamole (200 mg twicedaily). The median aspirin dose was 75 mg/day in both treatment s, and the dipyridamole formulation used by most patients (83%) was extended-release rather than immediate release. Over a mean follow-up of 3.5 years, the composite primary outcome (death from all vascular causes, nonfatal stroke, nonfatal MI or major bleeding complication) was significantly less frequent in the aspirin plus dipyridamole than the aspirin (13 vs 16%, hazard ratio 0.80, 95% CI 0.66-0.98, absolute risk reduction 1.0% per year). ESPRIT included patients using aspirin doses ranging from 30 to 325 mg daily, allaying concerns that the very low aspirin dose (25 mg twice-daily) used in ESPS-2 was in part responsible for the benefit of combined aspirin plus ER-DP over aspirin alone. The specific dipyridamole preparation may be important. In the meta-analysis cited above, the combination of aspirin and immediate-release dipyridamole was nonsignificantly better than aspirin alone for secondary prevention of stroke (RR 0.83, 95% CI 0.59-1.15). In contrast, ER-DP was used in all or the vast majority of patients in the much larger ESPS-2 and ESPRIT trials, and aspirin plus ER-DP was associated with a significant reduction in stroke risk compared with aspirin alone (RR 0.76, 95% CI 0.65-0.89). Table 2. A Semi-quantitative Evaluation of Antiplatelets for the Prevention of Stroke and other Vascular Events ASA Clopidogrel Ticlopidine ASA/ Dipyridamole Efficacy Tolerability Routine No No Yes No monitoring Dosing o.d. o.d. b.i.d. b.i.d. frequency Cost Triple Therapy As we know that two antiplatelet agents are beneficial to single, then three agents with different modes of action might be better still, providing bleeding risk doesn t become vulnerable. The efficacy of combining three antiplatelet drugs (aspirin, dipyridamole and clopidogrel) on inhibiting platelet aggregation, the formation of platelet-leukocyte conjugates and leukocyte activation has been demonstrated in vitro. However, in human beings, for prevention of secondary ischemic stroke, short-term triple therapy was no more effective. Recurrent cerebrovascular events ceased with triple therapy over a period of 5-23 months follow-up and no episodes of intracranial hemorrhage or major extracranial bleeding have occurred to date. Comparison of Antiplatelet Agents A semi-quantitative evaluation of antiplatelets for the prevention of stroke and other vascular events based on selected criteria and available evidence is shown in Table 2. All the antiplatelet agents except for ticlopidine are acceptable for initial therapy but because of its efficacy, safety and cost, ASA should probably be used first in most circumstances for ischemic stroke prevention. Alternatives to ASA for second choice would include clopidogrel or the combination of ASA/dipyridamole. The combination of ASA and clopidogrel cannot be recommended for long-term stroke prevention both because of a lack of efficacy and increased risk of intracranial hemorrhage. Conclusion Antiplatelet therapy has major role in secondary prevention of ischemic stroke is undeniable. Effectiveness of single drug aspirin in contrast to combination with other antiplatelet agents is questionable according Indian Journal of Clinical Practice, Vol. 23, No. 11, April 2013 705

to various studies. Further, the potential of newer antiplatelets and their combination for reducing ischemic stroke is to be explored before arriving at decisive relative effectiveness of various combinations. Suggested Reading 1. Vande Griend JP, Saseen JJ. Combination antiplatelet agents for secondary prevention of ischemic stroke. Pharmacotherapy 2008;28(10):1233-42. 2. Katzan IL. Antiplatelet agents in secondary stroke prevention. The Cleveland Clinic 2009. 3. Sprigg N, Gray LJ, England T, Willmot MR, Zhao L, Sare GM, et al. A randomised controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility. PLoS One 2008;3(8):e2852. 4. Sacco RL, Elkind MS. Update on antiplatelet therapy for stroke prevention. Arch Intern Med 2000;160(11):1579-82. 5. Cucchiara B, et al. Antiplatelet therapy for secondary prevention of stroke. Up To Date 2009. 6. Leonardi-Bee J, Bath PM, Bousser MG, Davalos A, Diener HC, Guiraud-Chaumeil B, et al; Dipyridamole in Stroke Collaboration (DISC). Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials. Stroke 2005;36(1):162-8. 7. O Donnell MJ, Hankey GJ, Eikelboom JW. Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: a critical review. Stroke 2008;39(5):1638-46. 8. Côté R, David M, Deveber G, Teal P, Roussin A, Sharma M. Prevention of ischemic stroke. The Thrombosis Interest Group of Canada. February 19, 2007. 9. Antiplatelet chemoprevention of occlusive vascular events and death. Int Soc Drug Bull Therapeut Lett 2000;37a-37b. 10. Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989;321(8):501-7. 11. Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989;1(8649):1215-20. 12. Fong JK. Update on Secondary Ischemic Stroke Prevention. Med Bull 2004;9:5-7. 13. Thijs V, Lemmens R, Fieuws S. Network meta-analysis: simultaneous meta-analysis of common antiplatelet regimens after transient ischaemic attack or stroke. Eur Heart J 2008;29(9):1086-92. 14. Kirshner HS. Therapeutic interventions for prevention of recurrent ischemic stroke. Am J Manag Care 2008;14(6 Suppl 2):S212-26. 15. Kirshner HS. Secondary stroke prevention, and the role of antiplatelet therapies. Clinical Medicine: Therapeutics 2009;1:601-12. 16. Zhao L, Heptinstall S, Bath PM. Antiplatelet therapy for stroke prevention. Br J Cardiol 2005;12(1):57-60. 17. McCabe DJ, Brown MM. Prevention of ischaemic stroke - antiplatelets. Br Med Bull 2000;56(2):510-25. 18. Cote R. Prevention of ischemic stroke. Canadian J CME 2001;193-8. 19. Flemming KD, Wiebers DO. Optimizing antiplatelet therapy to prevent ischemic stroke. Emerg Med 2002;34:28-37. Tamiflu Resistance may be Rising The pandemic H1N1 influenza A strain -- now circulating as seasonal flu - appears to be developing resistance to oseltamivir (Tamiflu) in Australia, a researcher is reporting at the annual meeting of the Australasian Society for Infectious Diseases. (Source: Medpage Today) Postpartum Depression Underidentified, Undertreated Postpartum depression is increasingly common, new research suggests. In a study of 10,000 women who had recently given birth, 14% or roughly 1 in 7 - screened positive for recurrent episodes of major depression. And of these, more than 19% reported having considered harming themselves. (Source: Medscape) 706 Indian Journal of Clinical Practice, Vol. 23, No. 11, April 2013