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

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

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

What is a stroke? ICHSAHinfarction

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

Modifiable stroke risk factors ICHSAHinfarction hypertension tobacco abuse

Modifiable stroke risk factors infarction

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

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

Modifiable stroke risk factors infarction diabetes mellitus dyslipidemia

Outline antihypertensives antilipid agents antithrombotics other pharmacologic approaches

Two phases of stroke treatment acute stroke secondary prevention

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

Hypertension and stroke

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?

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

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

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

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.

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

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.

How much to lower? <140/90 <130/80 <120/70 As much as possible Until it causes a problem

How much to lower? Some support for all these answers!! the lower, the less risk of stroke <120/70 is likely too low and associated in at least one study with worse outcomes. <130/80 if tolerated is likely the ideal range One reasonable guideline: <140/90 for all patients, and <130/80 for patients with diabetes

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

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.

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.

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.

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.

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.

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.

Antilipid therapies

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

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

SPARCL (2006) cerebral infarction* ICH* death atorvastatin 80 mg placebo 9% 2% 9% 12% 1% 9% stroke/TIA (LDL>100) *p<0.05

ACC recommendations (2013) stroke = ASCVD

Statin intensity

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.

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

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

Antithrombotic therapies thrombus atheromatous plaque aspirin COX-inhibitor

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

Antithrombotic therapies thrombus atheromatous plaque dipyridamole PDE-inhibitor

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

Antithrombotic therapies thrombus atheromatous plaque rivaroxaban apixaban factor Xa inhibitor

Antithrombotic therapies thrombus atheromatous plaque dabigatran direct thrombin inhibitor

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

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

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

Atrial fibrillation

Meta-analysis (2002) Meta-analysis (2002) stroke* major hemorrhage* death warfarinaspirin 2% 2% 5% 5% 1% 5% afib *p<0.05

ACTIVE-A (2009) stroke* major bleeding* death aspirin aspirin + clopidogrel 11% 4% 22% 8% 7% 22% atrial fibrillation not warfarin candidate *p<0.05

ACTIVE-W (2006) stroke* major hemorrhage death warfarin aspirin + clopidogrel 2% 3% 5% 3% 3% 5% atrial fibrillation *p<0.05

Novel anticoagulants vs warfarin RE-LY dabigatran 150 mg bid ROCKET AF rivaroxaban 20 mg qhs ARISTOTLE apixaban 5 mg bid stroke or embolism +0+ ischemic stroke +00 ICH +++ bleeding 00+ death 00+

Considerations long-term aspirin and clopidogrel has no clear benefit over single antiplatelet therapy in any subgroup studied long-term aspirin and clopidogrel may have a bleeding risk that is similar to that of warfarin in patients with atrial fibrillation

Heart failure (EF ≤ 30%)

WARCEF (2012) ischemic stroke* ICH death warfarinaspirin 2% 0% 14% 4% 0% 14% CHF (without afib) *p<0.05

Subgroup analysis For patients with prior ischemic stroke, those under 60, and those with EF ≤ 15%, there is likely a substantial benefit to the use of warfarin rather than aspirin. For patients who survived longer than 4 years in the trial, warfarin was superior to aspirin.

ARCH (2014?) stroke (vascular event) hemorrhage death warfarin aspirin + clopidogrel aortic arch athero STOPPED FOR FUTILITY

Cardioembolic stroke Anticoagulation is standard of care for patients with atrial fibrillation and prior stroke. The benefits of anticoagulation for heart failure remain dependent on individual patient characteristics.

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

Large vessel disease Cervical stenosis Intracranial stenosis

WASID (2005) - intracranial ischemic stroke major bleeding* death* warfarinaspirin 17% 8% 10% 20% 4% 3% *p<0.05

SAMMPRIS (2011) - intracranial stroke* death stenting medical treatment 22% 14% 3% intracranial stenosis 3% *p<0.05

SAMMPRIS medical therapy aspirin 325 mg daily clopidogrel 75 mg daily for 3 months aggressive antihypertensive therapy SBP < 140 (130 for diabetics) aggressive antilipid therapy rosuvastatin to achieve LDL < 100 HgbA1c < 7.0% for diabetics

CARESS (2005) stroke* any bleeding aspirin aspirin + clopidogrel 21% 2% 10% 4% carotid stenosis *p<0.05

Large vessel disease Aspirin and clopidogrel for a short-term period may be beneficial, but otherwise, there is no evidence that long-term therapy should be any different than other non- cardioembolic types of stroke.

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

Stroke in general Small vessel disease Cryptogenic stroke Other causes

ESPS-2 (1996) stroke* severe bleeding death aspirin aspirin + dipyridamole 13% 1% 11% 10% 11% prior stroke/TIA 2% *p<0.05

ESPRIT (2006) ischemic stroke* major bleeding death aspirin aspirin + dipyridamole 8% 4% 8% 7% 3% 7% TIA/minor stroke *p<0.05

PRoFESS (2008) stroke major hemorrhage death clopidogrel aspirin + dipyridamole 9% 4% 7% 9% 4% 7% ischemic stroke

Considerations long-term aspirin and dipyridamole ER may be more effective than aspirin alone cost, convenience, and side effects may mitigate increased efficacy increased risk of intracranial hemorrhage with combination therapy may be present

CURE (2001) stroke major bleeding death aspirin aspirin + clopidogrel 1% ACS (NSTEMI) 1% 3% 6% 6% 4%

CHARISMA (2006) stroke severe bleeding death aspirin aspirin + clopidogrel 2% vascular disease or risk 2% 1% 5%5% 2% *p<0.05

MATCH (2004) ischemic stroke life-threatening hemorrhage death clopidogrel aspirin + clopidogrel 8% 1% 5% 8% 3% 5% recent stroke/TIA *p<0.05

SPS3 (2012) recurrent stroke major hemorrhage* death* aspirin aspirin + clopidogrel 9% 4% 5% 8% 7% 7% lacunar stroke *p<0.05

FASTER (2007) stroke symptomatic hemorrhage aspirin aspirin + clopidogrel 11% 7% 3% TIA/minor stroke

CHANCE (2013) stroke mod-severe hemorrhage death aspirin aspirin + clopidogrel 12% 8% TIA/minor stroke in China

Considerations short-term aspirin and clopidogrel may have a benefit in select subgroups: - symptomatic carotid stenosis - symptomatic intracranial stenosis - minor stroke or high-risk TIA (China) long-term aspirin and clopidogrel offers the potential for harm without benefit

Real life is complicated Many patients have both coronary atherosclerosis and stroke Do we treat them independently? When might too much be too much?

Common clinical scenario ischemic stroke due to atrial fibrillation stable ischemic heart disease Is warfarin* alone adequate to prevent recurrent ischemic heart disease? Is the added risk of bleeding with the addition of aspirin worth any putative benefit?

Meta-analysis (Dentali, 2007) 10 randomized controlled trials comparing aspirin + oral anticoagulant (OAC) vs. OAC alone indication for OAC varied INR/TT goal varied across trials only 4 studies rated as high quality

Meta-analysis (2007) arterial thromboembolism major bleeding death anticoagulant aspirin + anticoagulant 9% 3% 7% 6% 4% 7% any indication for anticoagulation

Consideration heterogeneity across studies results driven by mechanical valve as indication for anticoagulation For patients with stable coronary artery disease and atrial fibrillation, warfarin alone may be sufficient therapy; the addition of aspirin clearly increases the risk of bleeding.

Common clinical scenario ischemic stroke due to atrial fibrillation acute ischemic heart disease with stent Is the added risk of bleeding with the addition of warfarin to aspirin and clopidogrel worth any putative benefit? Can warfarin and a single antiplatelet agent substitute for dual antiplatelet therapy?

WOEST (2013) MI major bleeding* death* clopidogrel+ anticoagulant aspirin + clopidogrel + anticoagulant 3% 3% 3% 5% 6% 6% PCI (25% ACS) *p<0.05

Considerations some patients might benefit from triple antithrombotic therapy (?) there is very little data regarding the appropriateness of prasugrel or ticagrelor in this context, but they might carry an elevated risk of intracerebral hemorrhage

After ischemic stroke antihypertensives – YES antilipid agents – STATIN antithrombotics – YES, DEPENDS other pharmacologic approaches – ?

Questions/Discussion