05. Stroke Prevention

Janet Chu, M.D., M.P.H.

Karl Meisel, M.D.

BOTTOM LINE

✔ All physicians can make a major impact on stroke prevention

✔ Use antiplatelet therapy, NOT anticoagulant therapy, for all non-atrial fibrillation stroke patients

✔ First-line antiplatelet agents are aspirin (either low-or-high dose), clopidogrel (Plavix) or aspirin/dipyridamole (Aggrenox).

✔ There is an increased risk of bleeding using the combination of aspirin and clopidogrel with only short-term benefit, so do not use dual antiplatelet therapy longer than 30 days unless there is a cardiac reason.

Epidemiology

  • Stroke is the 4th leading cause of death in the United States and the #1 cause of serious long-term disability.
  • 80% of strokes are ischemic and ~20% hemorrhagic
  • Major modifiable risk factors for ischemic stroke include hypertension (#1 risk factor), smoking (esp with OCPs), diabetes, hyperlipidemia, carotid disease, PAD, AF, CAD, sickle cell, HLD, poor diet, obesity, physical inactivity, and drug abuse (particularly cocaine/meth/heroin).
  • Non-modifiable risk factors include age, male sex, family history, and history of prior stroke/TIA/MI.
  • Consider SES, heavy EtOH, as minor risk factors.
  • For hemorrhagic stroke, hypertension is the major modifiable risk factor.

Primary stroke prevention

  • Counsel patients on blood pressure control (goal <140/90), smoking cessation, DM control, HLD control, diet, exercise, and weight loss
  • In the Women’s Health Study (40,000 women), those practicing lifestyle change had 55% lower stroke risk
  • Daily aspirin is recommended for those with increased risk of cardiac disease or stroke (10-year risk >10% based on the AHA/ACC CV risk calculator); it is not recommended for primary prevention in low-risk patients.
  • Statin is recommended for those with a high 10-year risk for cardiovascular events (based on the AHA/ACC CV risk calculator), particularly for those with DM
  • For AF patients with CHADS-VASC2 score ≥2 direct oral anticoagulants (apixaban, rivaroxaban, dabigatran), or warfarin with INR 2-3 is recommended for primary prevention of stroke
    • The additional risk factors are female sex, vascular disease history, and age < 75, and anticoagulation is recommended for CHADS2-VASC score > 1 (3% 1-year-rate) in conjunction with shared-decision-making with the patient.
  • For asymptomatic carotid stenosis patients, aspirin, statin, and evaluation for CEA in severe cases is recommended – screening for carotid stenosis in low-risk, asymptomatic populations is not recommended

Secondary stroke prevention

  • Definition: prevention of 2nd stroke in patients with a history of TIA or ischemic stroke
  • Important pillars include
    • A. Risk factor control: Management of HTN, HLD, DM, smoking cessation, and lifestyle changes (diet, exercise, moderating alcohol, avoiding drugs)
    • B. Source control: Management of carotid stenosis, anticoagulation in AF, and antiplatelet therapy for all other events

Risk Factor Control: Hypertension

  • Guidelines recommend initiating BP therapy after the first several days for previously untreated patients with ischemic stroke or TIA with BP ≥140 /90 mmHg
  • Resumption of BP therapy is indicated for previously treated patients with known hypertension in those who have had an ischemic stroke or TIA and are beyond the first 48 hours
  • Guidelines recommend individualizing target BP, but it is reasonable to achieve a systolic pressure <140mmgHg and a diastolic blood pressure <90mmHg
  • Diuretics +/- ACEI are reasonable first-lines but should be individualized based on other risk factors

Risk Factor Control: Hyperlipidemia

  • All stroke patients should be on intensive lipid-lowering therapy with a statin, starting in the acute setting.
  • Atorvastatin 80mg was the agent/dose studied in the influential 2006 SPARCL trial. It is not clear if the benefit was due to a class effect or unique to atorvastatin. Many neurologists will use atorvastatin if able, but current guidelines assume that the benefit is likely a class effect.
  • LDL goals should be less than 70 for maximal benefit or <50% reduction of prior LDL
  • It is not clear when it is best to start statins after a stroke, but in practice, most stroke centers will start the medication within the first day or two – often initially at maximal dose though some will subsequently titrate the dose down based on LDL (if less than 100).
  • KEY TRIALS: The 2006 SPARCL trial (N Engl J Med (2006) 355:549 –559) showed a 2.2% 5-year absolute risk reduction (13.1% down to 11.2%) in stroke patients randomized to atorvastatin 80mg vs placebo. The end-point was recurrent stroke, and the study drug was started within 1-6 months of the first stroke.

Risk Factor Control: Diabetes Mellitus

  • A reasonable goal of therapy is an A1C value of ≤7 percent for most patients.
  • However, evidence has not demonstrated a consistent beneficial effect of intensive glucose-lowering therapy or lifestyle modification for macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes

Source Control: Carotid artery stenosis

  • Atherosclerotic plaque at the carotid bifurcation is a common cause of stroke, as plaques can thrombosis, travel downstream, and occlude a more distal artery. Only rarely does carotid stenosis cause symptomatic flow-limiting lesions. Treatment options are either carotid endarterectomy/carotid stenting or medical management with a statin and antiplatelet agents
  • Carotid ultrasound is usually the initial test. CT Angiography and MR Angiography (with gadolinium) also likely provide clinically accurate measurements. Conventional angiography is rarely needed unless occlusion versus severe stenosis is uncertain.
  • Symptomatic stenosis – defined as having had a stroke or TIA attributable to the ipsilateral carotid– has about a 13% annual stroke risk, whereas asymptomatic stenosis has about a 2% annual stroke risk. The general consensus is that symptomatic patients with a greater than 70% stenosis should be referred for endarterectomy or stenting (if they have a life expectancy of greater than 5 years and the mortality risk estimated <6%). There is a much smaller benefit in symptomatic patients with 50-69% stenosis so CEA is not recommended; there is no indication for endarterectomy for low-grade stenosis (i.e. <50%).
  • When CEA is indicated, the benefit is greatest if the surgery is done within 2 weeks of symptoms (TIA/Stroke) if no surgical contraindications.
  • KEY TRIALS: The North American NASCET trial (N Engl J Med (1991) 325(7):445-53) showed a 17% absolute risk reduction (26% down to 9%) with endarterectomy compared to medical management in symptomatic patients with 70-99% stenosis in the 2-year risk of ipsilateral stroke. The European ECST study (Lancet (1991) 337(8752):1235-43) showed a similar benefit (16.8% down to 2.8%) with endarterectomy compared to medical management (aspirin) in the risk of recurrent ipsilateral stroke at 3 years.
  • Carotid artery stenting is another alternative especially if there are contraindications to surgery: CREST trial – Carotid Revascularization Endarterectomy versus Stent Trial – prospective RCT comparing CAS with CEA showed comparable 30-day stroke and death rates, with greater efficacy of CAS in patients < 70 years and greater efficacy of CEA in patients > 70 years. CAS should be considered if CEA is not safe (prior radiation to the neck) or stenosis location is not anatomically appropriate for CEA (distal ICA).

Source Control: Detection of Occult Atrial Fibrillation

  • Two recent trials in the NEJM found that paroxysmal atrial fibrillation was common among patients with a recent cryptogenic stroke or TIA who were 55 years or older
  • Non-invasive ambulatory ECG monitoring for 30 days significantly improved the detection of occult atrial fibrillation as opposed to the standard practice of short-term ambulatory ECG monitoring
  • These trials have shifted the standard of care towards longer ambulatory EKG monitoring (> 1 week, ideally up to 30 days) within 6 months of the index event to detect paroxysmal atrial fibrillation in patients who do not have another obvious cause of stroke.

Source Control: Anticoagulation in Atrial Fibrillation and Valvular Disease

  • In valvular AF, anticoagulation with warfarin (goal INR 2-3) is recommended
  • In nonvalvular AF, anticoagulation with warfarin (goal INR 2-3), apixaban, rivaroxaban, or dabigatran, is recommended in stroke patients with paroxysmal or permanent AF based on CHADS2-VASC score as above
  • ASA is recommended in patients with contraindication to anticoagulation
  • If patients have mechanical/rheumatic valves, bridging therapy with LMWH is recommended if oral warfarin needs to be interrupted. Of note, do NOT bridge patients in the setting of acute stroke.
  • For patients with mechanical valves & a history of stroke or TIA, anticoagulation with warfarin (goal INR 2.5 – 3.5) is recommended
  • There is no additional benefit for anticoagulation in patients with severe systolic function, according to the recent WARCEF (Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction) trial.
  • The combination of oral anticoagulation with antiplatelet therapy is not recommended for all patients after ischemic stroke or TIA but may be reasonable in patients with CAD
  • As above, decisions about anticoagulation should be made with shared decision-making with the patient

Source Control: Antiplatelet Therapy for Non-Cardioembolic Strokes 

  • Use antiplatelet therapy, NOT anticoagulant therapy, for all non-cardioembolic stroke patients
  • Aspirin monotherapy (between 81-325mg PO daily), combination ASA 25-dipyridamole 200mg PO bid (i.e. Aggrenox), and clopidogrel 75mg PO daily are all acceptable first-line options.
  • Dual antiplatelet therapy with aspirin and clopidogrel for stroke patients is reasonable for about 21 days after minor stroke or TIA then a single antiplatelet should be used to avoid hemorrhagic complications.
  • Often, if patients have a stroke/TIA are already on aspirin switch to clopidogrel or aspirin/dipyridamole
    • A. Aspirin
      • Both the “baby” 81mg dose or the regular 325mg dose appears to work equally well.
    • B. Aspirin/Dipyridamole (Aggrenox)
      • This only comes as a combination pill of extended-release dipyridamole (200mg) and aspirin (25mg) given twice daily. Immediate-release dipyridamole did not show the same clinical benefit in the initial trials so should not be substituted.
      • Up to one-third of patients may have to discontinue this combination due to headache (which sometimes goes away after a few weeks if patients continue the med).
      • KEY TRIALS: The 2006 ESPRIT trial (Lancet 2006; 367(9523):1665-1673) found a 1% absolute risk reduction for the combination of aspirin and dipyridamole compared to aspirin alone (median aspirin dose 75mg, range 30-325mg). The 1996 ESPS-2 trial (J Neurol Sci 1996; 143(1-2):1-13) comparing ASA to ASA/dipyridamole reported a 3% absolute risk reduction (37% relative risk reduction) in preventing recurrent stroke. The 2008 PRoFESS trial (N Engl J Med 2008 359) of 20,332 patients showed that neither aspirin/dipyridamole nor clopidogrel had superior efficacy when compared head-to-head.
    • C. Clopidogrel (Plavix)
      • Once-daily 75mg dosing. Should not be paired with aspirin unless there is a strong cardiac indication given increased bleeding risk.
      • KEY TRIALS:
        • The 1996 CAPRIE trial (Lancet 1996; 348(9038):1329-39) showed a decrease in the composite risk of stroke, MI, or peripheral vascular death from 5.83% to 5.32% with clopidogrel compared to aspirin. CAPRIE enrolled patients with prior MI, stroke, or peripheral vascular disease, and some have argued that only the PVD patients accounted for the marginal benefit of clopidogrel.
        • Also see the discussion above on the 2008 PRoFESS trial, which found that neither aspirin/dipyridamole nor clopidogrel was superior.
        • The 2004 MATCH trial (Lancet 2004; 364: 331–337) showed an increase in life-threatening bleeding to 2.6% from 1.3% with combination ASA/clopidogrel vs. ASA alone without any benefit to offset this risk.
        • The 2006 CHARISMA trial (N Engl J Med 2006; 354:1706-1717) showed an increased risk of moderate bleeding with the combination of aspirin and clopidogrel compared to aspirin alone.
        • In the 2012 SPS3 trial, a double-blinded randomized multicenter trial of 3020 patients with recent symptomatic lacunar infarcts, patients were randomized to clopidogrel 75mg+aspirin 325mg or aspirin 325mg daily. The addition of clopidogrel to aspirin showed no significant reduction in the risk of recurrent stroke but did significantly increase the risk of bleeding and death. (N Engl J Med 2012; 367:817-825).
        • The 2013 CHANCE trial (N Engl J Med 2013; 369:11-19) showed that the combination of clopidogrel and aspirin is superior to aspirin alone in patients with TIA or minor stroke who can be treated within 24 hours of the onset of symptoms patients in reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage.
        • More recently, in the 2018 POINT trial, a randomized trial of 4881 patients, those with minor ischemic stroke or high-risk TIA who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone (N Engl J Med 2018; 379:215-225).

Source Control: Patent Foramen Ovale

  • Closure of PFO may be effective in reducing the risk of recurrent stroke for young patients with cryptogenic stroke. Cryptogenic stroke was defined as an ischemic stroke that does not involve large vessel stenosis or occlusion in the territory of infarct, no atrial fibrillation, no other cardioembolic source, and not a lacunar (small subcortical) infarction.
  • For patients aged ≤60 years with a cryptogenic embolic-appearing ischemic stroke who have a medium to large PFO or small with associated atrial septal aneurysm, percutaneous PFO device closure in addition to antiplatelet therapy, rather than antiplatelet therapy alone is recommended
  • For patients with cryptogenic stroke and PFO who are >60 years of age, we suggest antiplatelet therapy rather than percutaneous PFO device closure or anticoagulation (unless the patient has an indication for treatment with anticoagulation).
  • KEY TRIALS:
    • In a 2018 meta-analysis that included four trials (PC, RESPECT extended follow-up, REDUCE and CLOSE), PFO closure reduced the risk of recurrent stroke from 5.1 percent with medical therapy to 1.8 percent (Ann Intern Med 2018;168(5):335).
    • In a 2015 meta-analysis of 12 observational studies involving 2385 medically treated patients with cryptogenic stroke and PFO, there was no significant difference between treatment with oral anticoagulation compared with antiplatelet therapy for the composite outcome of recurrent stroke, TIA, or death and no difference for the outcome of recurrent stroke alone (Eur Heart J 2015 Sep;36(35):2381-9).

References

Amarenco P, et al. 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.

Antithrombotic Trialists’ Collaborative. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ, 2002;324(7329):71-86.

CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329-39.

Diener HC, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomized, double-blind, placebo-controlled trial. Lancet. 2004;364:331–337. 

European Carotid Surgery Trialists' Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet. 1991;337(8752):1235-43.

Gladstone DJ, et al. "Atrial fibrillation in patients with cryptogenic stroke." New England Journal of Medicine. 2014;370:2467-2477.

Homma S, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med. 2012;366(20):1859-69. 

Johnston SC, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med 2018; 379:215-225.

Ken DM et al. Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis. Eur Heart J. 2015 Sep;36(35):2381-9.

Kernan WN et al. AHA/ASA 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;45:2160–223.

Mantese VA, et al. The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST): Stenting Versus Carotid Endarterectomy for Carotid Disease. Stroke. 2010;41:S31-S34. 

Meschia JF, et al. Guidelines for the Primary Prevention of Stroke: A Statement for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:3754–3832

Sacc RL, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359. 

Shah R, et al. Device Closure Versus Medical Therapy Alone for Patent Foramen Ovale in Patients With Cryptogenic Stroke: A Systematic Review and Meta-analysis. Ann Intern Med. 2018;168(5):335.

The SPS3 Investigators. Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke. N Engl J Med. 2012;367:817-825.

Wang Y, et al. Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack. N Engl J Med 2013; 369:11-19.