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Controversies in antiplatelet therapy in the secondary prevention of stroke
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Pharmacology applied to geriatric medicine
Controversies in antiplatelet therapy in the secondary prevention of stroke T. Adamek * Department of Internal medicine, Thomayer Hospital, Vı´denˇska´ 800, 140 59 Prague 4, Czech Republic
A R T I C L E I N F O
A B S T R A C T
Article history: Received 25 October 2015 Accepted 14 December 2015 Available online xxx
Recurrence of stroke has been estimated at 3–4% yearly after TIA or stroke. There is no clear agreement in choosing antiplatelet therapy at this time. Europeans, Americans and British guidelines have been different. Aspirin is still used in secondary prevention of ischemic stroke, because of the longest experience with the best-achieved results in different studies and low price. Other used drugs are a combination of aspirin and dipyridamole, P2Y12 receptor antagonists – clopidogrel, ticlopidine, prasugrel and ticagrelor, or inhibitor of phosphodiesterase cilostazol, which was effective with Chinese and Japanese population. The common agreement is not to use a dual antiplatelet therapy in long term, because it does not carry a higher reduction of ischemic attacks than monotherapy. The other negative effect is causing more incidents with severe hemorrhage. According to the American recommendation, the combined therapy is promising early after having TIA and light stroke when the risk of recurrence of stroke is high. ß 2016 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Aspirin Clopidogrel Cilostazol Dipyridamole Stroke
1. Introduction Prevention of stroke is a very important topic, with consideration of having limited therapy and causing heavy health impacts. This prevention is based on correction of risk factors, in drugs prevention and intervention on carotid artery stenosis. The selection of antiplatelet therapy has still been discussed. Platelets, which have a principle role in hemostasis, are possible to inhibit in many ways (Fig. 1, Table 1). Signalling pathways – cAMP, Ca. . . 2. Aspirin Aspirin used in medicine more than 110 years achieves its antithrombotic effect through inactivation of cyclo-oxygenase (COX)-1, thereby preventing generation of thromboxane TXA2 from arachidonic acid. It is a powerful inductor of aggregation and also a vasoconstrictor. The antiplatelet therapy with aspirin in secondary prevention of stroke is the most proved and used treatment. The meta-analysis of 145 antiaggregation studies based on 55,462 people was published as early as in 1994. Average dosage of ASA with 273 mg lowered * Tel.: +420604544756. E-mail address: [email protected].
risk for heart attack by 137 cases for 10,000 people (P < 0.001) and for ischemic stroke by 39 cases for 10,000 people (P < 0.001). There were 73 people treated to prevent heart attack and 276 people to prevent stroke, the number of hemorrhagic stroke was increased by 12 for 10,000 people (P < 0.001). Sweden study SALT (Swedish aspirin low-dose trial) reached comparable results with treatment of 75 mg ASA only and reduced negative side effects [1]. Meta-analysis from year 2002 includes 287 antiaggregation studies. Overall, from 71,912 patients using ASA, 7705 (10.7%) suffered vascular event (stroke, heart attack or vascular fatal accident) compared to 72,139 risk patients using placebo 9503 (13.2%). Antiplatelet therapy managed to lower relative risk for non-fatal heart attack by 34%, for ischemic stroke by 25% [2]. Reversible inhibition of cyclo-oxygenase by indobufen is also possible, but it has higher accidents of hemorrhage complications and gastrointestinal irritations. 3. How early to administer aspirin after stroke The recommendation is coming from study CAST (Chinese acute stroke trial). CAST’s ASA therapy was started within 48 hours after diagnosis of CMP, dosage of aspirin was 160 mg/day. CAST study tested 21,106 patients. Observance period was 4 weeks. Significantly lower repetition of ischemic stroke was achieved in aspirin cure 167 (1.6%) against 215 (2.1%) in placebo cure and a little more
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Please cite this article in press as: Adamek T. Controversies in antiplatelet therapy in the secondary prevention of stroke. Eur Geriatr Med (2016), http://dx.doi.org/10.1016/j.eurger.2015.12.007
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Platelet inhibition
Thrombin inhibitors ADP receptor antagonists THROMBIN receptor
ADP receptor
Phosphodiesterase inhibitors
COX-1
Signalling pathwayscAMP, Ca
COX- 1 inhibitors TXA2
GPIIb
Fibrinogen Receptor Antagonists
IIIa
Fibrinogen Fig. 1. Platelet inhibition.
Table 1 Type of platelet inhibition. Type of inhibition
Drugs
Inactivation of plate cyclo-oxygenase COX1 Inhibition of phosphodiesterase type E5, E3 Inhibition of platelet receptors for ADP
Aspirin, indobufen, triflusal Cilostazol, dipyridamole Clopidogrel, ticlopidin, prasugrel, ticagrelor Abciximab Vorapaxar
Inhibition of glycoprotein receptors IIB/IIIA Inhibition of receptors for thrombin
immediate release, the third of patients randomized to combination cure, canceled this therapy for negative side effects, mainly headache. On the other hand, results of ESPRIT study are in agreement with results of previous ESPS-2 study (European stroke prevention study-2). ESPS-2 study from year 1996 included 6602 patients with stroke or TIA during last 3 months and they were observed through 24 months. The study evaluated 4 secondary preventive healing schemes:
of hemorrhagic stroke 115 (1.1%) in aspirin cure vs. 93 (0.9%) in placebo cure. For the composite endpoint (fatal or non-fatal stroke) during 4 weeks, there was a proportional drop of risk in aspirin cure 545 (5.3%) against 614 (5.9%) in placebo cure. The absolute difference was 6; 8 less accidents for 1000 patients [3].
combination ASA 25 mg/day + dipyridamole with longered release 2 200 mg/day; monotherapy ASA 50 mg/day; monotherapy dipyridamole 2 200 mg/day; placebo.
4. Combination aspirin with dipyridamole
Combination 2 years therapy achieved huge drop in recurrence of stroke by 37% (P < 0.001) in comparison with 18% (P < 0.013) with monotherapy ASA and 16% with dipyridamole monotherapy, these all against placebo. There were not shown differences in bleeding occurrences. Risk of stroke at placebo cure was 15.2%, ASA cure 12.5%, and combination of ASA + DP 9.5%. These excellent results from combination therapy were immediately frequently questioned by many study limitations. Most important was low dosage of ASA (25–50 mg) [5].
The recommended antiplatelet therapy is a combination of ASA and dipyridamole. This recommendation is based mainly on studies ESPRIT and ESPS2. The combination of dipyridamole and aspirin introduces the combination with additive antiplatelet results, when dipyridamole inhibits phosphodiesterase type 3. Study ESPRIT included 2739 patients after TIA or stroke. The first group of patients received aspirin, the second group used combination of dipyridamole with aspirin and third group received the application of oral anticoagulant treatment. Patients were monitored for 5 years. The primary endpoints were fatal accidents from any blood vessel cause, repetition of stroke and IM or huge bleeding complication. Existence of these accidents was in the group with ASA (16%) and 13% in the group ASA + DP. It means a drop in the absolute risk by 3% and yearly NNT 102 [4]. Study ESPRIT is by all means controversial. Forty percent patients used aspirin in dosage 30 mg/day, 17% patients used dipyridamole with
5. Clopidogrel, ticlopidine, prasugrel, ticagrelor Study PROFESS (Prevention regiment for effectively avoiding second strokes) compared combination ASA and dipyridamole with clopidogrel (75 mg/day). The study included 20,332 patients who recently suffered stroke. They were monitored for 2.5 years on average. The result showed recurrence of stroke for 916 (9%) patients treated with the combination therapy and 898 (8.8%)
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patients treated with clopidogrel only. No significant difference in a number of all major cardiovascular episodes was found. The combination method resulted in increased numbers of bleeding (HR = 1,15), including number of intracranial hemorrhage (HR = 1,42) [6]. The study CAPRIE (Clopidogrel vs. aspirin in patients at risk of ischemic events) is based on evaluation of advantages of clopidogrel over ASA, in patients suffered atherothrombotic events. Clopidogrel reduced a relative risk of overall clinical elements – strokes, heart attacks, and vascular deaths. The benefit of clopidogrel over aspirin was most pronounced for patients in the peripheral arterial disease subgroup (3.71% vs. 4.86% per year; P = 0.0028). The benefit of clopidogrel was not statistically significant for the 6431 patients in the stroke subgroup (7.15% vs. 7.71% per year; P > 0.2). Risks of hemorrhage were similar between the groups. Although the overall relative benefit of clopidogrel over aspirin in the CAPRIE trial was modest (absolute risk reduction of 0.5% per year) and there was no statistically significant benefit over aspirin for the stroke patients in this study, clopidogrel has become an important treatment option for patients with stroke [7].
6. Dual antiplatelet therapy – clopidogrel and aspirin This combination therapy is effective for acute coronary syndrome, but not for long-term therapy after stroke (MATCH and CHARISMA study). The MATCH study randomized 7600 people after TIA and stroke. One group was treated with 75 mg of clopidogrel, the second with 75 mg clopidogrel and 75 mg ASA. The combination of clopidogrel and ASA did not achieve a significant reduction of ischemic episodes. The group treated with clopidogrel and ASA shows evidence of ischemic episodes for 596 people (15,7%), the group treated with clopidogrel 636 (16,7%) people. The study also shows more fatal bleeding in the group with combination (96 [2,6%] patients vs. 49 [1,3%] clopidogrel monotherapy) [8]. The CHARISMA study (Clopidorel for high atherothrombotic risk and ischemic stabilization) included 15,603 people with high risk of atherosclerotic diseases, one quarter of them underwent stroke. One group was treated with ASA (75–162 mg/day) + clopidogrel, the second group was treated with ASA + placebo. Dual antiplatelet therapy did not achieve a significant drop to decrease a number of heart attacks, strokes, and cardiovascular deaths. As a result of analysis, the dual therapy in coherence with light increase of not serious bleeding is not to be supported [9]. An alternative to clopidogrel is ticlopidine, whose benefit was analyzed in three randomized studies. One study pronounced its superiority over placebo, the other superiority over aspirin and the third no benefit over aspirin. TASS study (Ticlopidine aspirin stroke study) compared ticlopidine with high-dose aspirin (650 mg) in 3069 patients with TIA or stroke. There was a 12% reduction in the primary endpoint of non-fatal stroke or death in patients receiving ticlopidine compared with those receiving aspirin (17% vs. 19%; P = 0.048). Most of this benefit was attributable to the effect of ticlopidine on stroke (10% compared with 13%; P = 0.024). Clopidogrel has mostly replaced the use of ticlopidine due to its more favorable hematologic adverse event profile [10,11]. Newer P2Y12 receptor antagonists are prasugrel and ticagrelor. PLATO compared combination ASA and clopidogrel with ASA and ticagrelor. The study included 18,624 patients who were hospitalized for acute coronary syndromes. They were monitored for 6– 12 months, the primary composite endpoint (cardiovascular death, myocardial infarction, stroke) occurred in fewer patients in the ticagrelor group than in the clopidogrel group. Patients randomized to ticagrelor had 1057 total primary endpoint events versus
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1225 for patients on clopidogrel (P = 0.003), but not significant difference in number of recurrence of stroke (P = 0,22). The similar results brought study TRITON-TIMI 38, which compared combination ASA and clopidogrel with ASA and prasugrel. Study SOCRATES compares ticagrelor with aspirin in early period (90 days) after ischemic stroke, the results will be awaited in year 2016 [12,13]. 7. Cilostazol Larger study with cilostazol is CSPS II, done in Japan. It observed 2672 patients after ischemic stroke. They were split in two groups, one was treated with cilostazol 200 mg/day and second with aspirin 81 mg/day. Yearly incidents of stroke in cilostazol group were significantly lower (2.76%) compared to aspirin group (3.71%), Relative reduction risk was 25.7%, (P = 0.0004). The subanalysis between subtypes of ischemic stroke showed that annual incidence of hemorrhagic stroke was much lower in the cilostazol group (0.36%) than in the aspirin group (1.20%) among patients with lacunar stroke (P = 0.003) [14,15]. Meta-analysis (including nine studies involving 6328 patients) with cilostazol was published by Tan in 2015 [16]. Stroke recurrence (hemorrhagic and ischemic) with cilostazol use was 5.3% (157) versus 8.3% (248) in control group (risk ratio 0.63). Poststroke intracranial hemorrhage was 0.5% (16) with cilostazol versus 1.6% (46) in control group. Cilostazol, alone or in combination with aspirin, significantly reduces stroke recurrence, poststroke intracranial hemorrhage, and extracranial bleeding in patients with a prior ischemic stroke as compared with other antiplatelet therapies [16]. Study SPAD was the study that evaluated effectiveness of dual antiplatelet cure with aspirin and cilostazol. Patients with previous ischemic stroke or TIA who had been taking aspirin 100 mg/day with peripheral arterial disease based on ankle-brachial index (ABI < 1.0) will be randomized into the treatment group with cilostazol 200 mg/day (n = 403) or placebo (n = 403). Observance period was 12 months. This study proved slowing down the progression of atherosclerosis in the group with combination cure, but no reduction of ischemic accidents [17]. Study CATHARSIS involved 165 patients after stroke with intracranial arterial stenosis more than 50%. Eighty-three patients were treated with cilostazol 200 mg/day + aspirin 100 mg/day, 82 patients with aspirin 100 mg/day. Primary endpoint was progression of intracranial stenosis during 2 years, significant difference was not found. Contrary to other studies, smaller progression IC stenosis was caused by a good control of risk factors. Secondary endpoints were any vascular events, and the differences were not significant [18]. 8. Triflusal and terutroban TAPIRSS (Triflusal vs aspirin for prevention of cerebral infarction) study was performed in Argentina during the years 1996–1999. Four hundred and twenty-nine patients, who had had an ischemic stroke or TIA within the previous 6 months were enrolled and randomized to receive aspirin 325 mg daily or triflusal 600 mg daily for average time of 586 days. No difference was found in primary endpoint (the incidence of vascular death, stroke, non-fatal myocardial infarction or major hemorrhage) in aspirin group 13.9% vs. triflusal group 12.7%. In a post hoc analysis, the overall incidence of major and minor hemorrhagic events was significantly lower in triflusal-treated patients (aspirin 8.3% vs. triflusal 2.8%) [19]. The trial PERFORM (19,000 patients who had an ischemic stroke or TIA in the previous 3 months, randomized to receive 30 mg/day
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Table 2 Advantages and disadvantages of antiplatelet drugs in prevention of stroke. Drug
Advantages and disadvantages
Study
Aspirin Triflusal Aspirin + dipyridamole Clopidogrel Prasugrel Ticagrelor Cilostazol
Best cost/benefit Less hemorrhagic events than aspirin, small experiences, worse cost/benefit Better results than aspirin, but worse tolerated – non compliance Better risk/benefit, worse cost/benefit than aspirin Not better than clopidogrel, worse cost/benefit than clopidogrel Not better than clopidogrel, worse cost/benefit than clopidogrel Better results in China than aspirin, must be examined for other races
Antithrombotic Trailists’ Collaboration [2] TAPIRSS [19] ESPRIT and ESPS2 [4,5] CAPRIE [7] PLATO [12] TRITON-TIMI 38 CSPS II [14,16]
terutroban or 100 mg aspirin) did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban [20].
receive clopidogrel + aspirin or aspirin alone, begin treatment within 12 hours of new ischemic symptoms and will be followed 90 days after randomization [26]. 11. Dual antiplatelet therapy in long periods
9. Combination ASA with inhibitors of receptor GpIIb/IIIa Another tested combination was ASA with inhibitors of receptor GpIIb/IIIa. This combination brought significant drop in serious vascular occurrences by 19%, which prevents 20 recurrences of stroke for 1000 treated patients during the first month. On the other site, it discovered 23 extracranial hemorrhages at 1000 patients. Study stage III evaluated safety and efficiency of abciximab and included 808 patients. It stopped early because of higher existence of hemorrhage with abciximab against placebo (5.5 vs. 0.5%; P = 0.002) [21].
Dual antiplatelet antiplatelet therapy (DAPT) for the prevention of recurrent ischemic stroke is not better than single antiplatelet therapy in long therapy. Nine randomized controlled trials were included in the meta-analysis enrolling a total of 45,136 patients. DAPT did not significantly reduced risk of stroke recurrence (risk ratio 0.89, P = 0.10) but when compared with single agent therapy, the risk of intracerebral hemorrhage was significantly higher with DAPT (risk ratio 1.31; P = 0.004) [27]. 12. Lacunar ischemic stroke
10. Importance of combined therapy in early period Recurrence risk of strokes occurs 3–4% yearly and the most risky appears to be in early period after TIA or ischemic stroke. Therefore, the more aggressive therapy is suggested in this period. A study evaluating a combination therapy, ASA and clopidogrel in early period after stroke, was the study FASTER (Fast assessment of stroke and transient ischemic attack to prevent early recurrence). This study randomized 392 patients, up to 24 hours after TIA or stroke. All patients were on aspirin, 198 patients of them on clopidrogel (300 mg first dosage and then 75 mg/day), 194 on placebo. Therapy lasted 90 days. Fourteen patients (7.1%) on clopidogrel suffered by stroke in 90 days against 21 patients (10.8%) on placebo, which represents the absolute risk reduction of 3.8% (P = 0.19). Two patients treated with clopidogrel suffered with intracranial hemorrhage against zero on placebo, the absolute risk reduction grows of 1% (P = 0.5) [22]. A study CHANCE (from China) randomized 5171 patients within 24 hours after the onset of minor ischemic stroke or TIA. One group of patients received clopidogrel 300 mg first day, 75 mg clopidogrel from 2 to 90 day, and 75 mg aspirin for the first 21 days, the second group was treated with aspirin 75 mg for 90 days. The primary outcome (ischemic + hemorrhagic stroke) occurred in 8.2% of patients in the clopidogrel + aspirin group, as compared with 11.7% of those in the aspirin group (P < 0.001). Moderate or severe hemorrhage was similar in both groups, the rate of hemorrhagic stroke was 0,3% in each group [23]. High and variable blood pressure, high percentage of smokers in China, together with high existence of obesity were identified as reasons for higher number of ischemic and mainly hemorrhagic stroke occurrences [24,25]. In Euro-American population is the treatment of hypertension, diabetes and dyslipidemie on much higher level. We can expect lower effect of aspirin and clopidogrel in this population than in China. Study POINT (Platelet-oriented inhibition in new TIA and minor ischemic stroke) will explain this problem. This study will recruit 5840 subjects in years 2014–2018 and will be randomized to
Overview of long-term antiplatelet therapy after lacunar ischemic stroke brings meta-analysis published by Kwok in 2015 [28]. Lacunar stroke presents 25% of ischemic strokes. Kwok used meta-analysis for 17 randomized studies with antiplatelet therapy which involved 42,234 patients with observation time from 4 weeks to 3.5 years. Any antiplatelet agent was associated with a significant reduction in recurrence of any stroke. When other antiplatelet agents (ticlodipine, cilostazol, and dipyridamole) were compared with aspirin, there was no consistent reduction in stroke recurrence. Dual antiplatelet therapy also did not bring clear benefit against monotherapy [28]. 13. Conclusion There is no doubt about the effectiveness of antiplatelet therapy in the secondary prevention of ischemic stroke, which has to be applied in 48 hours after the event, but there is no unity of its selection, we are looking for the best risk/benefit and cost/benefit. Aspirin, even with many reservations, is still dominant in some states. Aspirin combined with dipyridamole has a little bit of better results when consistently used, but this combination is badly tolerated which lowers the compliance and therefore effectivity. Clopidogrel is better tolerated and is preferred in British guidelines, but the benefit of clopidogrel was not statistically significant in the stroke subgroup of trial CAPRIE. Ticlopidin is substituted by clopidogrel because of its hematologic side effects. Prasugrel and ticagrelor are not better than clopidogrel for prevention of stroke. Cilostazol appears to be a promising drug in China and Japan, but it must be examined farther for other races (Table 2). Dual antiplatelet therapy is not recommended over monotherapy because of increased risk of hemorrhage during long-term usage and no reduction of ischemic events. American guidelines consider this method for treatment during first 90 days. Choosing the right therapy will ask for detailed etiology analysis of stroke and individualized therapy.
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Disclosure of interest The author declares that he has no competing interest. References [1] The SALT Collaborative Group. SALT, Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991;338:1345–9. [2] Antithrombotic Trailists’ Collaboration. Collaborative meta-analysis of randomied trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high-risk patients. BMJ 2002;324:71–86. [3] CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997;349:1641–9. [4] Halkes P, van Gijn J, Kappelle L, Koudstaal P, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665–73. [5] Diener H, 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. [6] Diener H, Sacco R, Yusuf S, Cotton D, Ounpuu S, Lawton W, et al. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 2008;7:875–84. [7] CAPRIE steering comittee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348: 1329–39. [8] Skvortsova V, Shamalov N. The results of the MATCH study evidence for advantages of clopidogrel monotherapy as secondary prophylaxis in cerebrovascular pathology. Zh Nevrol Psikhiatr Im S S Korsakova 2004;11:7–12. [9] Hankey G, Johnston S, Easton J, Hacke W, Mas J, Brennan D, et al. Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial. Int J Stroke 2011;6:3–9. [10] Hass W, Easton J, Adams H, 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;321:501–7. [11] Europen Stroke Organisation (ESO) Executive Committee, ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457–507. [12] Kohli P, Wallentin L, Reyes E, Horrow J, Husted S, Angiolillo D, et al. Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO Study. Circulation 2013;127:673–80. [13] Pieske B. Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES). Eur J Heart Fail 2014;16:1026–38.
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[14] Uchiyama S. Results of the Cilostazol Stroke Prevention Study II (CSPS II): a randomized controlled trial for the comparison of cilostazol and aspirin in stroke patients. Rinsho Shinkeigaku 2010;50:832–4. [15] Uchiyama S, Shinohara Y, Katayama Y, Yamaguchi T, Handa S, Matsuoka K, et al. Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2. Cerebrovasc Dis 2014;37:296–303. [16] Tan L, Margaret B, Hu R, Yin Y, Cao L, Feng H, et al. Efficacy and safety of cilostazol therapy in ischemic stroke: a meta-analysis. J Stroke Cerebrovasc Dis 2015;24:930–8. [17] Jeng J, Sun Y, Lee J, Lin R, Chen C, Po H, et al. The efficacy and safety of cilostazol in ischemic stroke patients with peripheral arterial disease (SPAD): protocol of a randomized, double-blind, placebo-controlled multicenter trial. Int J Stroke 2015;10:123–7. [18] Uchiyama S, Sakai N, Toi S, Ezura M, Okada Y, Takagi M, et al. Final results of cilostazol-aspirin therapy against recurrent stroke with intracranial artery stenosis (CATHARSIS). Cerebrovasc Dis Extra 2015;5:1–13. [19] Culebras A, Rotta-Escalante R, Vila J, Domı´nguez R, Abiusi G, Famulari A, et al. Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology 2004;62:1073–80. [20] Hennerici M, PERFORM Study Investigators. Rationale and design of the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) Study. Cerebrovasc Dis 2009;3:28–32. [21] Adams H, Effron M, Torner J, Davalos A, Frayne J, Teal P, et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III, trial. Abciximab in emergency treatment of stroke trial (AbESTT-II). Stroke 2008;39:87–99. [22] Kennedy J, Hill M, Ryckborst K, Eliasziw M, Demchuk A, Buchan A, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER):a randomised controlled pilot trial. Lancet Neurol 2007;6: 961–9. [23] Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013;369:11–9. [24] Walter N, Kernan W, Ovbiagele B, Black H, Bravata D, Chimowitz M, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic stroke. Stroke 2014;45:2160–236. [25] Feldmann E, Daneaul N, Kwan E, Ho K, Pessin M, Langenberg P, et al. Chinesewhite differences in the distribution of occlusive cerebrovascular disease. Neurology 1990;40:1541–5. [26] Johnston S, Easton J, Farrant M, Barsan W, Battenhouse H, Conwit R, et al. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: rationale and design. Int J Stroke 2013;8:479–83. [27] Salih M, Elmasry Y, Spinetto P, Kawsar H, Somberg J. Use of dual antiplatelet versus single antiplatelet therapy for prevention of recurrent ischemic stroke: meta-analysis of randomized controlled trials. J Am Coll Cardiol 2015;65(10_S). http://dx.doi.org/10.1016/S0735-1097(15)61488-7. [28] Kwok C, Shoamanesh A, Copley H, Myint P, Loke Y, Benavente O. Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomized trials. Stroke 2015;46:1014–23.
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EURGER-710; No. of Pages 5 European Geriatric Medicine xxx (2016) xxx–xxx
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Pharmacology applied to geriatric medicine
Controversies in antiplatelet therapy in the secondary prevention of stroke T. Adamek * Department of Internal medicine, Thomayer Hospital, Vı´denˇska´ 800, 140 59 Prague 4, Czech Republic
A R T I C L E I N F O
A B S T R A C T
Article history: Received 25 October 2015 Accepted 14 December 2015 Available online xxx
Recurrence of stroke has been estimated at 3–4% yearly after TIA or stroke. There is no clear agreement in choosing antiplatelet therapy at this time. Europeans, Americans and British guidelines have been different. Aspirin is still used in secondary prevention of ischemic stroke, because of the longest experience with the best-achieved results in different studies and low price. Other used drugs are a combination of aspirin and dipyridamole, P2Y12 receptor antagonists – clopidogrel, ticlopidine, prasugrel and ticagrelor, or inhibitor of phosphodiesterase cilostazol, which was effective with Chinese and Japanese population. The common agreement is not to use a dual antiplatelet therapy in long term, because it does not carry a higher reduction of ischemic attacks than monotherapy. The other negative effect is causing more incidents with severe hemorrhage. According to the American recommendation, the combined therapy is promising early after having TIA and light stroke when the risk of recurrence of stroke is high. ß 2016 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Aspirin Clopidogrel Cilostazol Dipyridamole Stroke
1. Introduction Prevention of stroke is a very important topic, with consideration of having limited therapy and causing heavy health impacts. This prevention is based on correction of risk factors, in drugs prevention and intervention on carotid artery stenosis. The selection of antiplatelet therapy has still been discussed. Platelets, which have a principle role in hemostasis, are possible to inhibit in many ways (Fig. 1, Table 1). Signalling pathways – cAMP, Ca. . . 2. Aspirin Aspirin used in medicine more than 110 years achieves its antithrombotic effect through inactivation of cyclo-oxygenase (COX)-1, thereby preventing generation of thromboxane TXA2 from arachidonic acid. It is a powerful inductor of aggregation and also a vasoconstrictor. The antiplatelet therapy with aspirin in secondary prevention of stroke is the most proved and used treatment. The meta-analysis of 145 antiaggregation studies based on 55,462 people was published as early as in 1994. Average dosage of ASA with 273 mg lowered * Tel.: +420604544756. E-mail address: [email protected].
risk for heart attack by 137 cases for 10,000 people (P < 0.001) and for ischemic stroke by 39 cases for 10,000 people (P < 0.001). There were 73 people treated to prevent heart attack and 276 people to prevent stroke, the number of hemorrhagic stroke was increased by 12 for 10,000 people (P < 0.001). Sweden study SALT (Swedish aspirin low-dose trial) reached comparable results with treatment of 75 mg ASA only and reduced negative side effects [1]. Meta-analysis from year 2002 includes 287 antiaggregation studies. Overall, from 71,912 patients using ASA, 7705 (10.7%) suffered vascular event (stroke, heart attack or vascular fatal accident) compared to 72,139 risk patients using placebo 9503 (13.2%). Antiplatelet therapy managed to lower relative risk for non-fatal heart attack by 34%, for ischemic stroke by 25% [2]. Reversible inhibition of cyclo-oxygenase by indobufen is also possible, but it has higher accidents of hemorrhage complications and gastrointestinal irritations. 3. How early to administer aspirin after stroke The recommendation is coming from study CAST (Chinese acute stroke trial). CAST’s ASA therapy was started within 48 hours after diagnosis of CMP, dosage of aspirin was 160 mg/day. CAST study tested 21,106 patients. Observance period was 4 weeks. Significantly lower repetition of ischemic stroke was achieved in aspirin cure 167 (1.6%) against 215 (2.1%) in placebo cure and a little more
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Please cite this article in press as: Adamek T. Controversies in antiplatelet therapy in the secondary prevention of stroke. Eur Geriatr Med (2016), http://dx.doi.org/10.1016/j.eurger.2015.12.007
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Platelet inhibition
Thrombin inhibitors ADP receptor antagonists THROMBIN receptor
ADP receptor
Phosphodiesterase inhibitors
COX-1
Signalling pathwayscAMP, Ca
COX- 1 inhibitors TXA2
GPIIb
Fibrinogen Receptor Antagonists
IIIa
Fibrinogen Fig. 1. Platelet inhibition.
Table 1 Type of platelet inhibition. Type of inhibition
Drugs
Inactivation of plate cyclo-oxygenase COX1 Inhibition of phosphodiesterase type E5, E3 Inhibition of platelet receptors for ADP
Aspirin, indobufen, triflusal Cilostazol, dipyridamole Clopidogrel, ticlopidin, prasugrel, ticagrelor Abciximab Vorapaxar
Inhibition of glycoprotein receptors IIB/IIIA Inhibition of receptors for thrombin
immediate release, the third of patients randomized to combination cure, canceled this therapy for negative side effects, mainly headache. On the other hand, results of ESPRIT study are in agreement with results of previous ESPS-2 study (European stroke prevention study-2). ESPS-2 study from year 1996 included 6602 patients with stroke or TIA during last 3 months and they were observed through 24 months. The study evaluated 4 secondary preventive healing schemes:
of hemorrhagic stroke 115 (1.1%) in aspirin cure vs. 93 (0.9%) in placebo cure. For the composite endpoint (fatal or non-fatal stroke) during 4 weeks, there was a proportional drop of risk in aspirin cure 545 (5.3%) against 614 (5.9%) in placebo cure. The absolute difference was 6; 8 less accidents for 1000 patients [3].
combination ASA 25 mg/day + dipyridamole with longered release 2 200 mg/day; monotherapy ASA 50 mg/day; monotherapy dipyridamole 2 200 mg/day; placebo.
4. Combination aspirin with dipyridamole
Combination 2 years therapy achieved huge drop in recurrence of stroke by 37% (P < 0.001) in comparison with 18% (P < 0.013) with monotherapy ASA and 16% with dipyridamole monotherapy, these all against placebo. There were not shown differences in bleeding occurrences. Risk of stroke at placebo cure was 15.2%, ASA cure 12.5%, and combination of ASA + DP 9.5%. These excellent results from combination therapy were immediately frequently questioned by many study limitations. Most important was low dosage of ASA (25–50 mg) [5].
The recommended antiplatelet therapy is a combination of ASA and dipyridamole. This recommendation is based mainly on studies ESPRIT and ESPS2. The combination of dipyridamole and aspirin introduces the combination with additive antiplatelet results, when dipyridamole inhibits phosphodiesterase type 3. Study ESPRIT included 2739 patients after TIA or stroke. The first group of patients received aspirin, the second group used combination of dipyridamole with aspirin and third group received the application of oral anticoagulant treatment. Patients were monitored for 5 years. The primary endpoints were fatal accidents from any blood vessel cause, repetition of stroke and IM or huge bleeding complication. Existence of these accidents was in the group with ASA (16%) and 13% in the group ASA + DP. It means a drop in the absolute risk by 3% and yearly NNT 102 [4]. Study ESPRIT is by all means controversial. Forty percent patients used aspirin in dosage 30 mg/day, 17% patients used dipyridamole with
5. Clopidogrel, ticlopidine, prasugrel, ticagrelor Study PROFESS (Prevention regiment for effectively avoiding second strokes) compared combination ASA and dipyridamole with clopidogrel (75 mg/day). The study included 20,332 patients who recently suffered stroke. They were monitored for 2.5 years on average. The result showed recurrence of stroke for 916 (9%) patients treated with the combination therapy and 898 (8.8%)
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patients treated with clopidogrel only. No significant difference in a number of all major cardiovascular episodes was found. The combination method resulted in increased numbers of bleeding (HR = 1,15), including number of intracranial hemorrhage (HR = 1,42) [6]. The study CAPRIE (Clopidogrel vs. aspirin in patients at risk of ischemic events) is based on evaluation of advantages of clopidogrel over ASA, in patients suffered atherothrombotic events. Clopidogrel reduced a relative risk of overall clinical elements – strokes, heart attacks, and vascular deaths. The benefit of clopidogrel over aspirin was most pronounced for patients in the peripheral arterial disease subgroup (3.71% vs. 4.86% per year; P = 0.0028). The benefit of clopidogrel was not statistically significant for the 6431 patients in the stroke subgroup (7.15% vs. 7.71% per year; P > 0.2). Risks of hemorrhage were similar between the groups. Although the overall relative benefit of clopidogrel over aspirin in the CAPRIE trial was modest (absolute risk reduction of 0.5% per year) and there was no statistically significant benefit over aspirin for the stroke patients in this study, clopidogrel has become an important treatment option for patients with stroke [7].
6. Dual antiplatelet therapy – clopidogrel and aspirin This combination therapy is effective for acute coronary syndrome, but not for long-term therapy after stroke (MATCH and CHARISMA study). The MATCH study randomized 7600 people after TIA and stroke. One group was treated with 75 mg of clopidogrel, the second with 75 mg clopidogrel and 75 mg ASA. The combination of clopidogrel and ASA did not achieve a significant reduction of ischemic episodes. The group treated with clopidogrel and ASA shows evidence of ischemic episodes for 596 people (15,7%), the group treated with clopidogrel 636 (16,7%) people. The study also shows more fatal bleeding in the group with combination (96 [2,6%] patients vs. 49 [1,3%] clopidogrel monotherapy) [8]. The CHARISMA study (Clopidorel for high atherothrombotic risk and ischemic stabilization) included 15,603 people with high risk of atherosclerotic diseases, one quarter of them underwent stroke. One group was treated with ASA (75–162 mg/day) + clopidogrel, the second group was treated with ASA + placebo. Dual antiplatelet therapy did not achieve a significant drop to decrease a number of heart attacks, strokes, and cardiovascular deaths. As a result of analysis, the dual therapy in coherence with light increase of not serious bleeding is not to be supported [9]. An alternative to clopidogrel is ticlopidine, whose benefit was analyzed in three randomized studies. One study pronounced its superiority over placebo, the other superiority over aspirin and the third no benefit over aspirin. TASS study (Ticlopidine aspirin stroke study) compared ticlopidine with high-dose aspirin (650 mg) in 3069 patients with TIA or stroke. There was a 12% reduction in the primary endpoint of non-fatal stroke or death in patients receiving ticlopidine compared with those receiving aspirin (17% vs. 19%; P = 0.048). Most of this benefit was attributable to the effect of ticlopidine on stroke (10% compared with 13%; P = 0.024). Clopidogrel has mostly replaced the use of ticlopidine due to its more favorable hematologic adverse event profile [10,11]. Newer P2Y12 receptor antagonists are prasugrel and ticagrelor. PLATO compared combination ASA and clopidogrel with ASA and ticagrelor. The study included 18,624 patients who were hospitalized for acute coronary syndromes. They were monitored for 6– 12 months, the primary composite endpoint (cardiovascular death, myocardial infarction, stroke) occurred in fewer patients in the ticagrelor group than in the clopidogrel group. Patients randomized to ticagrelor had 1057 total primary endpoint events versus
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1225 for patients on clopidogrel (P = 0.003), but not significant difference in number of recurrence of stroke (P = 0,22). The similar results brought study TRITON-TIMI 38, which compared combination ASA and clopidogrel with ASA and prasugrel. Study SOCRATES compares ticagrelor with aspirin in early period (90 days) after ischemic stroke, the results will be awaited in year 2016 [12,13]. 7. Cilostazol Larger study with cilostazol is CSPS II, done in Japan. It observed 2672 patients after ischemic stroke. They were split in two groups, one was treated with cilostazol 200 mg/day and second with aspirin 81 mg/day. Yearly incidents of stroke in cilostazol group were significantly lower (2.76%) compared to aspirin group (3.71%), Relative reduction risk was 25.7%, (P = 0.0004). The subanalysis between subtypes of ischemic stroke showed that annual incidence of hemorrhagic stroke was much lower in the cilostazol group (0.36%) than in the aspirin group (1.20%) among patients with lacunar stroke (P = 0.003) [14,15]. Meta-analysis (including nine studies involving 6328 patients) with cilostazol was published by Tan in 2015 [16]. Stroke recurrence (hemorrhagic and ischemic) with cilostazol use was 5.3% (157) versus 8.3% (248) in control group (risk ratio 0.63). Poststroke intracranial hemorrhage was 0.5% (16) with cilostazol versus 1.6% (46) in control group. Cilostazol, alone or in combination with aspirin, significantly reduces stroke recurrence, poststroke intracranial hemorrhage, and extracranial bleeding in patients with a prior ischemic stroke as compared with other antiplatelet therapies [16]. Study SPAD was the study that evaluated effectiveness of dual antiplatelet cure with aspirin and cilostazol. Patients with previous ischemic stroke or TIA who had been taking aspirin 100 mg/day with peripheral arterial disease based on ankle-brachial index (ABI < 1.0) will be randomized into the treatment group with cilostazol 200 mg/day (n = 403) or placebo (n = 403). Observance period was 12 months. This study proved slowing down the progression of atherosclerosis in the group with combination cure, but no reduction of ischemic accidents [17]. Study CATHARSIS involved 165 patients after stroke with intracranial arterial stenosis more than 50%. Eighty-three patients were treated with cilostazol 200 mg/day + aspirin 100 mg/day, 82 patients with aspirin 100 mg/day. Primary endpoint was progression of intracranial stenosis during 2 years, significant difference was not found. Contrary to other studies, smaller progression IC stenosis was caused by a good control of risk factors. Secondary endpoints were any vascular events, and the differences were not significant [18]. 8. Triflusal and terutroban TAPIRSS (Triflusal vs aspirin for prevention of cerebral infarction) study was performed in Argentina during the years 1996–1999. Four hundred and twenty-nine patients, who had had an ischemic stroke or TIA within the previous 6 months were enrolled and randomized to receive aspirin 325 mg daily or triflusal 600 mg daily for average time of 586 days. No difference was found in primary endpoint (the incidence of vascular death, stroke, non-fatal myocardial infarction or major hemorrhage) in aspirin group 13.9% vs. triflusal group 12.7%. In a post hoc analysis, the overall incidence of major and minor hemorrhagic events was significantly lower in triflusal-treated patients (aspirin 8.3% vs. triflusal 2.8%) [19]. The trial PERFORM (19,000 patients who had an ischemic stroke or TIA in the previous 3 months, randomized to receive 30 mg/day
Please cite this article in press as: Adamek T. Controversies in antiplatelet therapy in the secondary prevention of stroke. Eur Geriatr Med (2016), http://dx.doi.org/10.1016/j.eurger.2015.12.007
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Table 2 Advantages and disadvantages of antiplatelet drugs in prevention of stroke. Drug
Advantages and disadvantages
Study
Aspirin Triflusal Aspirin + dipyridamole Clopidogrel Prasugrel Ticagrelor Cilostazol
Best cost/benefit Less hemorrhagic events than aspirin, small experiences, worse cost/benefit Better results than aspirin, but worse tolerated – non compliance Better risk/benefit, worse cost/benefit than aspirin Not better than clopidogrel, worse cost/benefit than clopidogrel Not better than clopidogrel, worse cost/benefit than clopidogrel Better results in China than aspirin, must be examined for other races
Antithrombotic Trailists’ Collaboration [2] TAPIRSS [19] ESPRIT and ESPS2 [4,5] CAPRIE [7] PLATO [12] TRITON-TIMI 38 CSPS II [14,16]
terutroban or 100 mg aspirin) did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban [20].
receive clopidogrel + aspirin or aspirin alone, begin treatment within 12 hours of new ischemic symptoms and will be followed 90 days after randomization [26]. 11. Dual antiplatelet therapy in long periods
9. Combination ASA with inhibitors of receptor GpIIb/IIIa Another tested combination was ASA with inhibitors of receptor GpIIb/IIIa. This combination brought significant drop in serious vascular occurrences by 19%, which prevents 20 recurrences of stroke for 1000 treated patients during the first month. On the other site, it discovered 23 extracranial hemorrhages at 1000 patients. Study stage III evaluated safety and efficiency of abciximab and included 808 patients. It stopped early because of higher existence of hemorrhage with abciximab against placebo (5.5 vs. 0.5%; P = 0.002) [21].
Dual antiplatelet antiplatelet therapy (DAPT) for the prevention of recurrent ischemic stroke is not better than single antiplatelet therapy in long therapy. Nine randomized controlled trials were included in the meta-analysis enrolling a total of 45,136 patients. DAPT did not significantly reduced risk of stroke recurrence (risk ratio 0.89, P = 0.10) but when compared with single agent therapy, the risk of intracerebral hemorrhage was significantly higher with DAPT (risk ratio 1.31; P = 0.004) [27]. 12. Lacunar ischemic stroke
10. Importance of combined therapy in early period Recurrence risk of strokes occurs 3–4% yearly and the most risky appears to be in early period after TIA or ischemic stroke. Therefore, the more aggressive therapy is suggested in this period. A study evaluating a combination therapy, ASA and clopidogrel in early period after stroke, was the study FASTER (Fast assessment of stroke and transient ischemic attack to prevent early recurrence). This study randomized 392 patients, up to 24 hours after TIA or stroke. All patients were on aspirin, 198 patients of them on clopidrogel (300 mg first dosage and then 75 mg/day), 194 on placebo. Therapy lasted 90 days. Fourteen patients (7.1%) on clopidogrel suffered by stroke in 90 days against 21 patients (10.8%) on placebo, which represents the absolute risk reduction of 3.8% (P = 0.19). Two patients treated with clopidogrel suffered with intracranial hemorrhage against zero on placebo, the absolute risk reduction grows of 1% (P = 0.5) [22]. A study CHANCE (from China) randomized 5171 patients within 24 hours after the onset of minor ischemic stroke or TIA. One group of patients received clopidogrel 300 mg first day, 75 mg clopidogrel from 2 to 90 day, and 75 mg aspirin for the first 21 days, the second group was treated with aspirin 75 mg for 90 days. The primary outcome (ischemic + hemorrhagic stroke) occurred in 8.2% of patients in the clopidogrel + aspirin group, as compared with 11.7% of those in the aspirin group (P < 0.001). Moderate or severe hemorrhage was similar in both groups, the rate of hemorrhagic stroke was 0,3% in each group [23]. High and variable blood pressure, high percentage of smokers in China, together with high existence of obesity were identified as reasons for higher number of ischemic and mainly hemorrhagic stroke occurrences [24,25]. In Euro-American population is the treatment of hypertension, diabetes and dyslipidemie on much higher level. We can expect lower effect of aspirin and clopidogrel in this population than in China. Study POINT (Platelet-oriented inhibition in new TIA and minor ischemic stroke) will explain this problem. This study will recruit 5840 subjects in years 2014–2018 and will be randomized to
Overview of long-term antiplatelet therapy after lacunar ischemic stroke brings meta-analysis published by Kwok in 2015 [28]. Lacunar stroke presents 25% of ischemic strokes. Kwok used meta-analysis for 17 randomized studies with antiplatelet therapy which involved 42,234 patients with observation time from 4 weeks to 3.5 years. Any antiplatelet agent was associated with a significant reduction in recurrence of any stroke. When other antiplatelet agents (ticlodipine, cilostazol, and dipyridamole) were compared with aspirin, there was no consistent reduction in stroke recurrence. Dual antiplatelet therapy also did not bring clear benefit against monotherapy [28]. 13. Conclusion There is no doubt about the effectiveness of antiplatelet therapy in the secondary prevention of ischemic stroke, which has to be applied in 48 hours after the event, but there is no unity of its selection, we are looking for the best risk/benefit and cost/benefit. Aspirin, even with many reservations, is still dominant in some states. Aspirin combined with dipyridamole has a little bit of better results when consistently used, but this combination is badly tolerated which lowers the compliance and therefore effectivity. Clopidogrel is better tolerated and is preferred in British guidelines, but the benefit of clopidogrel was not statistically significant in the stroke subgroup of trial CAPRIE. Ticlopidin is substituted by clopidogrel because of its hematologic side effects. Prasugrel and ticagrelor are not better than clopidogrel for prevention of stroke. Cilostazol appears to be a promising drug in China and Japan, but it must be examined farther for other races (Table 2). Dual antiplatelet therapy is not recommended over monotherapy because of increased risk of hemorrhage during long-term usage and no reduction of ischemic events. American guidelines consider this method for treatment during first 90 days. Choosing the right therapy will ask for detailed etiology analysis of stroke and individualized therapy.
Please cite this article in press as: Adamek T. Controversies in antiplatelet therapy in the secondary prevention of stroke. Eur Geriatr Med (2016), http://dx.doi.org/10.1016/j.eurger.2015.12.007
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Please cite this article in press as: Adamek T. Controversies in antiplatelet therapy in the secondary prevention of stroke. Eur Geriatr Med (2016), http://dx.doi.org/10.1016/j.eurger.2015.12.007