Applied Evidence

Stroke: Secondary prevention of ischemic events

J Fam Pract. 2017 July;66(7):420-422,424-427

From The Journal of Family Practice | 2017;66(7):420-422,424-427.

References

1. Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke. 2007;38:1881-1885.

2. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S76-S99.

3. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160-2236.

4. Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke. 2003;34:2741-2748.

5. Amarenco P, Bogousslavsky J, Callahan A, et al, for the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.

6. Benavente OR, Hart RG, McClure LA, et al, for the SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

7. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

8. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238-1251.

9. Diethrich EB, N’diaye M, Reid DB. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST): implications for clinical practice. In: Henry M, Diethrich EB, Polydorou A, eds. The Carotid and Supra-Aortic Trunks: Diagnosis, Angioplasty and Stenting. 2nd ed. Oxford, UK: Wiley-Blackwell; 2011.

10. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. Circulation. 2011;124:489-532.

11. SPS3 Study Group. Blood pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382:507-515.

12. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368:1092-1100.

13. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993-1003.

14. Romero JR, Morris J, Pikula A. Stroke prevention: modifying risk factors. Ther Adv Cardiovasc Dis. 2008;2:287-303.

15. Hankey GJ. Smoking and risk of stroke. J Cardiovasc Risk. 1999;6:207-211.

16. Shah RS, Cole JW. Smoking and stroke: the more you smoke the more you stroke. Expert Rev Cardiovasc Ther. 2010;8:917-932.

17. Bhat VM, Cole JW, Sorkin JD, et al. Dose-response relationship between cigarette smoking and risk of ischemic stroke in young women. Stroke. 2008;39:2439-2443.

18. Lakkur S, Judd SE. Diet and stroke: recent evidence supporting a Mediterranean-style diet and food in the primary prevention of stroke. Stroke. 2015;46:2007-2011.

19. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean dietary pattern in a randomized trial: prolonged survival and possible reduced cancer rate. Arch Intern Med. 1998;158:1181-1187.

20. Davis SM, Donnan GA. Clinical practice. Secondary prevention after ischemic stroke or transient ischemic attack. N Engl J Med. 2012;366:1914-1922.

21. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947.

22. Magid DJ, Green BB. Home blood pressure monitoring: take it to the bank. JAMA. 2013;310:40-41.

23. Diener H-C, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2004;364:331-337.

24. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706-1717.

25. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993-1003.

26. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-19.

27. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997;349:1569-1581.

28. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. 1997;349:1641-1649.

29. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol. 2015;14:361-367.

30. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet. 1993;342:1255-1262.

31. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-988.

32. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Int Med. 2007;146:857-867.

33. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy. Recent data and ideas. Stroke. 2005;36:1588-1593.

34. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest. 2010;138:1093-1100.

35. Quinn GR, Singer DE, Chang Y, et al. How well do stroke risk scores predict hemorrhage in patients with atrial fibrillation? Am J Cardiol. 2016;118:697-699.

36. Gorman EW, Perkel D, Dennis D, et al. Validation of the HAS-BLED tool in atrial fibrillation patients receiving rivaroxaban. J Atr Fibrillation. 2016;9:1461.

37. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med. 2005;118:612-617.

38. US Food and Drug Administration. FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. October 16, 2015. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm. Accessed May 26, 2017.

39. Paciaroni M, Agnelli G, Falocci N, et al. Early recurrence and cerebral bleeding in patients with acute ischemic stroke and atrial fibrillation: effect of anticoagulation and its timing: the RAF Study. Stroke. 2015;46:2175-2182.

40. Sandercock PA, Counsell C, Kane EJ. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. 2015;3:CD000024.

41. Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. Lancet. 2001;358:702-710.

42. Berge E, Abdelnoor M, Nakstad PH, et al. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Lancet. 2000;355:1205-1210.

43. Sherman DG, Albers GW, Bladin C, et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet. 2007;369:1347-1355.

44. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.

45. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321-1331.

46. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368:1083-1091.

47. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366:991-999.

Choosing medications to manage BP, cholesterol, and clotting

Optimize blood pressure control. Blood pressure (BP) plays a critical role in both the management and prevention of stroke and is considered to be the most important modifiable risk factor in both primary and secondary stroke prevention.²⁰ In the first 24 to 48 hours following a cerebral ischemic event that is not eligible for thrombolysis, permissive hypertension (treating BP only if it exceeds 220/120 mm Hg unless there is a concurrent medical illness that requires you do so) is appropriate, as hypotension or rapid fluctuations in BP can be harmful.²¹

This flexibility does not continue into the subacute phase of management (at a minimum, after the initial 48 hours) or into secondary prevention. Initiation and titration of oral agents to gradually achieve a BP <140/90 mm Hg or a reduction of 10/5 mm Hg for patients already within optimal range are the most widely recognized goals.^3,20 Patients with stroke secondary to small vessel disease may benefit from an even lower goal of <130/<80 mm Hg.¹¹ Encourage patients to monitor their BP at home for added accuracy and consistency.²²

Pharmacologic BP management is appropriate for patients who are consistently above optimal range despite attempting recommended lifestyle modifications. The data are relatively consistent with respect to the effects of different drug classes after a stroke: beta-blockers have no effect on any outcome; thiazide diuretics significantly reduce stroke and total vascular events; angiotensin-converting enzyme (ACE) inhibitors significantly reduce myocardial infarction (MI); and the combination of an ACE inhibitor and thiazide diuretic reduces stroke, MI, and combined vascular events.⁴

This has led many stroke specialists to recommend the combination of an ACE inhibitor or angiotensin II receptor blocker (ARB) and a thiazide diuretic as a first-line approach to secondary stroke prevention rather than a beta-blocker (assuming there is no additional indication for a beta-blocker). Similarly, there is ample evidence to show that the magnitude of BP reduction is proportional to the reduction in recurrent vascular events.³

Make use of statin therapy—regardless of LDL. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial⁵ explored the potential role of statin medication for secondary stroke prevention. Researchers randomly assigned almost 5000 participants who’d had a stroke or TIA one to 6 months before study entry (but had no known history of coronary artery disease) to placebo or a high-intensity statin (80 mg/d atorvastatin). The statin group demonstrated a 4.9-year absolute risk reduction in fatal or nonfatal recurrent stroke of 1.9% (NNT=53).

Given these findings and those from other studies, the AHA and ASA recommend treating patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein (LDL) level.³ Of note, statins are not indicated for the secondary prevention of hemorrhagic stroke.

Select antiplatelet therapy based on ischemic stroke subtype. Investigators are still trying to determine the optimal antiplatelet for secondary stroke prevention; it is likely that the ideal choice depends largely on the etiology of the stroke. Trials that did not select patients based on subtype of ischemic stroke have not shown a long-term benefit from dual antiplatelet therapy (clopidogrel and aspirin),^23,24 and one double-blind, multicenter trial involving more than 3000 patients with recent stroke secondary to small vessel disease demonstrated harm from such therapy in terms of a significantly increased risk of bleeding and death.⁶

Smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

However, a 2011 study compared aggressive medical management (aspirin 325 mg/d plus clopidogrel 75 mg/d for 90 days) alone to aggressive medical management plus percutaneous transluminal angioplasty and stenting (PTAS). The study involved almost 500 patients who'd had a recent TIA or stroke attributed to intracranial atherosclerotic stenosis. The authors found that the 30-day rate of stroke or death was 14.7% in the PTAS group vs 5.8% in the medical management group.²⁵

Similarly, a randomized double-blind, placebo-controlled trial published in 2013 involving over 5000 patients in China found that short-term use of dual antiplatelets (clopidogrel and aspirin for the first 21 days after an ischemic event, followed by aspirin monotherapy for 90 days) had an absolute risk reduction of 3.5% without increasing the risk of major bleeding in patients with high-risk TIA or minor stroke.²⁶

All stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin (75-325 mg); research has shown that lower doses are as effective as higher doses but with a lower risk of adverse gastrointestinal effects, including bleeding.^3,20 Aspirin 81 mg/d is a common effective dose.

For patients who cannot tolerate aspirin due to allergy, clopidogrel 75 mg/d is a reasonable alternative. Long-term studies of aspirin vs clopidogrel⁷ and clopidogrel vs extended-release dipyridamole⁸ showed no difference in secondary stroke prevention. The International Stroke Trial²⁷ and Chinese Acute Stroke Trial²⁸ both indicate that aspirin should be started as soon as possible after the onset of an acute stroke.

This special population should probably get antiplatelets, too. One recent study explored the use of an antiplatelet vs anticoagulation therapy for stroke patients with carotid artery dissection. The CADISS (Cervical Artery Dissection in Stroke Study) trial²⁹ randomized 250 patients with extracranial carotid and vertebral artery dissection with onset of symptoms within the previous 7 days to either antiplatelet or anticoagulation therapy and found no difference in the primary outcomes of recurrent stroke or death. The study also demonstrated a low risk of recurrent stroke in this population, which was 2% at 3-month follow-up.

Most patients with cervical artery dissection, therefore, are now treated with antiplatelet therapy. That said, situations may still arise in which anticoagulation can be considered, and consultation with a neurologist for guidance on choice of therapy is recommended.