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Pharmacologic Prevention of Stroke Jonathan Raser-Schramm, MD, PhD Medical Director, Stroke Program Christiana Care Health System March 21, 2014

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Disclosures No financial relationships Will discuss off-label use of a number of antithrombotic agents

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What is a stroke? sudden onset neurological deficit attributable to a vascular cause

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What is a stroke? ICHSAHinfarction

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What is a stroke? ICHSAHinfarction 80% 15% 5%

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Modifiable stroke risk factors ICHSAHinfarction hypertension tobacco abuse

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Modifiable stroke risk factors infarction

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Atherothrombosis VASCULAR NEUROLOGY Lammie et al. Stroke (1999) thrombus atheromatous plaque

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Thromboembolism Lammie et al. Stroke (1999) thrombus atheromatous plaque

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Modifiable stroke risk factors infarction diabetes mellitus dyslipidemia

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Outline antihypertensives antilipid agents antithrombotics other pharmacologic approaches

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Two phases of stroke treatment acute stroke secondary prevention

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Two phases of stroke treatment acute stroke secondary prevention weeks to months

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Hypertension and stroke

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Who should be treated? All patients after stroke? All hypertensive patients after stroke? What about patients with non- atherosclerotic causes of stroke? Could some patients be harmed by lowering blood pressure?

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Causes of cerebral infarction small vessel disease atrial fibrillation cryptogenic large vessel disease other

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Who should be treated? All patients after stroke? Across numerous randomized studies, there has not been any subset of patients that does not clearly benefit from blood pressure reduction in stroke prevention. Yes

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Who should be treated? All hypertensive patients after stroke? Stroke prevention occurs with treatment in patients regardless of baseline blood pressure.

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Who should be treated? What about non-atherosclerotic causes of stroke? There is an argument that patients who are normotensive (120/70) and have specific causes of stroke such as atrial fibrillation, DVT with PFO, endocarditis, or hypercoagulable states may not benefit from treatment. This question is not well-studied.

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Who should be treated? Who might be harmed? large vessel disease concern for cerebral hypoperfusion

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Who should be treated? Who might be harmed? For patients with large vessel stenosis >50% (especially >70%), there is a risk of recurrent stroke with aggressive treatment. However, some studies suggest benefit with long-term, stepwise aggressive lowering of blood pressure.

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How much to lower?

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How much to lower? Some support for all these answers!! the lower, the less risk of stroke

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Which agents to choose? Diuretics Beta blockers ACE inhibitors Angiotension receptor blockers Calcium channel blockers Alpha blockers

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Which agents to choose? Diuretics Beta blockers ACE inhibitors Angiotension receptor blockers Calcium channel blockers Alpha blockers Ultimately, achieving reduction in blood pressure is likely more important than specific agent required.

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Which agents to choose? Diuretics Beta blockers ACE inhibitors Angiotension receptor blockers Calcium channel blockers Alpha blockers All these agents have safety/efficacy after stroke.

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Which agents to choose? Diuretics Beta blockers ACE inhibitors Angiotension receptor blockers Calcium channel blockers Alpha blockers Though traditionally first-line agents, in one trial HCTZ was inferior to CaCB; indapamide and chlorthalidone may have better support.

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Which agents to choose? Diuretics Beta blockers ACE inhibitors Angiotension receptor blockers Calcium channel blockers Alpha blockers Concerns about blood pressure variability and central vs peripheral effects make beta blockers not the initial preferred agents after stroke.

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Which agents to choose? Diuretics Beta blockers ACE inhibitors Angiotension receptor blockers Calcium channel blockers Alpha blockers These agents may increase the risk of stroke, despite being effective in lowering blood pressure.

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Which agents to choose? Diuretics Beta blockers ACE inhibitors Angiotension receptor blockers Calcium channel blockers Alpha blockers Ultimately, achieving reduction in blood pressure is likely more important than specific agent required.

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Antilipid therapies

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Cholesterol and stroke Relationship between high cholesterol (high LDL) and stroke is less strong than for coronary heart disease Low cholesterol has been associated with intracerebral hemorrhage However, similar mechanism from CAD strongly implied for many causes of stroke, and similar benefit expected

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Trial X stroke (vascular event) hemorrhage death treatment A treatment B 15% 10% 5% 10% 10% 10% patients enrolled

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SPARCL (2006) cerebral infarction* ICH* death atorvastatin 80 mg placebo 9% 2% 9% 12% 1% 9% stroke/TIA (LDL>100) *p

Reasons to avoid high-intensity Characteristics predisposing individuals to statin adverse effects include, but are not limited to: Multiple or serious comorbidities, including impaired renal or hepatic function. History of previous statin intolerance or muscle disorders. Unexplained ALT elevations >3 times ULN. Patient characteristics or concomitant use of drugs affecting statin metabolism. >75 years of age. Additional characteristics that may modify the decision to use higher statin intensities may include, but are not limited to: History of hemorrhagic stroke. Asian ancestry.

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What about other agents? Niacin-ER did not lower risk of cardiovascular events compared with placebo though it is effective in increasing HDL and lowering triglycerides Ezetimibe has not been shown to have any clinical benefit though it can lower LDL Omega-3 fatty acids have not been shown to benefit in stroke prevention

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Antithrombotic therapies thrombus atheromatous plaque aspirin clopidogrel prasugrel warfarin dabigatran dipyridamole rivaroxaban apixaban ticagrelor

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Antithrombotic therapies thrombus atheromatous plaque aspirin COX-inhibitor

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Antithrombotic therapies thrombus atheromatous plaque clopidogrel prasugrel P2Y 12 (ADP-R) inhibitor ticagrelor

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Antithrombotic therapies thrombus atheromatous plaque dipyridamole PDE-inhibitor

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Antithrombotic therapies thrombus atheromatous plaque warfarin vit K antagonist fII, fVII, fIX, fX

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Antithrombotic therapies thrombus atheromatous plaque rivaroxaban apixaban factor Xa inhibitor

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Antithrombotic therapies thrombus atheromatous plaque dabigatran direct thrombin inhibitor

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Antithrombotic therapies ANTIPLATELET - aspirin - clopidogrel - Aggrenox DUAL ANTIPLATELET - aspirin + clopidogrel ANTICOAGULANT - warfarin - dabigatran - apixaban - rivaroxaban - enoxaparin etc.

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How do we pick the right one? Stroke mechanism Patient preference Cost Ease of compliance Failure of prior agent Tolerability and side effects

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Causes of cerebral infarction small vessel disease atrial fibrillation/ cardioembolism cryptogenic large vessel disease other

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Atrial fibrillation

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Meta-analysis (2002) Meta-analysis (2002) stroke* major hemorrhage* death warfarinaspirin 2% 2% 5% 5% 1% 5% afib *p