# Presentation: 763471

## Clinical Overview

- Director, Stanford Stroke Center Stanford University
- Palo Alto, California

**Gregory W. Albers, MD**

## Ischemic Stroke

- 85% of strokes are ischemic
- Most ischemic strokes caused by atherosclerosis of extracranial or intracranial arteries
- Embolic or thrombotic occlusion of cerebral blood vessels by aggregated platelets, fibrin, and debris from atheromatous plaques

## The Most Frequent Sites of Arterial and Cardiac Abnormalities Causing Ischemic Stroke

**Intracranial****Atherosclerosis**

**Carotid Plaque With****Arteriogenic Emboli**

**Aortic Arch****Plaque**

**Cardiogenic****Emboli**

**Penetrating****Artery Disease**

**Flow Reducing****Carotid Stenosis**

**Atrial Fibrillation**

**Valve Disease**

**Left Ventricular****Thrombi**

- Albers et al, *Chest,* 1998.

## Transient Ischemic Attack

- Transient occlusion of an intracranial arterydue to thromboembolism
- Symptoms resolve following rapid fragmentation and dissolution of the microemboli/thrombus

## Stroke Morbidity and Mortality

- Leading cause of serious, long-term disability
- Third leading cause of death in the U.S.;second leading cause worldwide
- Accounts for >50% of all hospitalizationsfor acute neurologic disease

## Stroke Incidence

- >700,000 new or recurrent strokes per year
- ~ 4 million Americans are living with neurologic deficits due to stroke

## The High Cost of Stroke

**Annual Total**

**1998**

**Per Event***

**Direct Costs****	**$28B	$38,714**(care and treatment)**
**Indirect Costs****	**$15B	$20,520**(lost productivity)**
**Total****	****$43B****	****$59,234**

- *Based on 731,000 strokes/yr

- American Heart Association. *1998 Heart and Stroke Statistical Update*.  Dallas, TX:AHA, 1997.
- Broderick J et al. *Stroke.* 1998;29:415–421.

## Secondary Preventionof Ischemic Stroke

- Carotid endarterectomy: >50% stenosis
- Anticoagulation therapy: Cardioembolic stroke
- Antiplatelet therapy: Most common therapy

## Antiplatelet Agentsfor Stroke Prevention

- Aspirin
- Ticlopidine
- Clopidogrel
- Dipyridamole

## Efficacy of Antiplatelet Agentsfor Prevention of Stroke, MI,or Vascular Death

**Population****	****Therapy****	****Reduction (%)****	**** Reduction (%)**

- Efficacy of Antiplatelet Agentsfor Prevention of Stroke, MI,or Vascular Death

**All Vascular****	**All antiplatelet	22	27**Diseases****	**regimens
**Stroke/TIA****	**All antiplatelet	17	22	regimens
**Stroke/TIA****	**Aspirin	13	16

- Source: Antiplatelet Trialists’ Collaboration, 1994: Algra and Van Gijn 1996.

**Risk Reductions**

## Efficacy of Antiplatelet Agents vs Placebo for Prevention of Stroke, MI, or Vascular Death in Stroke/TIA Patients

**Aspirin (all doses)**	10	13
**Ticlopidine**	1	23
**Dipyridamole + ASA**	4	30
**All Antiplatelet Agents**	18	17

**	****	****Relative Risk**** Antiplatelet Agent****	****No. of Studies ****	****Reduction (%)****	**

- Source: Algra and Van Gijn 1996; Gent et al.1989; Tijssen, 1998; Antiplatelet Trialists’ Collaboration, 1994.

## Relative Risk Reductions for VascularDeath, Stroke, MI from ASA Trials vs Placebo in Stroke/TIA Patients

- 0.4
- 60%

- 0.6
- 40%

- 0.8
- 20%

- 1
- 0%

- 1.2
- -20%

- 1.4
- -40%

- 1.6
- -60%

**RR and 95% CI**

**ASA ******** 100 mg**
**(2 Studies)**

**ASA ******** 900 mg**
**(7 Studies)**

**ASA 300 mg**
**(1 Study)**

**ALL**
**(10 Studies)**

- RR = 13%

- RR = 9%

- RR = 14%

- RR = 13%

- Low vs Med:	*P *= 0.75Low vs High:	*P *= 0.99Med vs High:	*P *= 0.71

- Relative Risk Reductions for VascularDeath, Stroke, MI from ASA Trials vs Placebo in Stroke/TIA Patients

## ACE TRIALAspirin Efficacy by DosePrevention of Vascular Events Following Carotid Endarterectomy

**Stroke or Death**
**at 3 Months**

**Stroke, MI, or Death at 3 Months**

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

- 9

- 10

**Low-Dose (N = 1395)**
**(81 or 325 mg)**

**High-Dose (N = 1409)**
**(650 or 1300 mg)**

**Event Rate (%)**

**5.7%**

**6.2%**

**7.1%**

**8.4%**

***P *****= 0.030**

***P *****= 0.120**

- Taylor DW, Thorpe KE, for the ACE Trial Study Group. Presented at The Challenge of Stroke;The Lancet Conference; October 15–16, 1998. Montreal, Quebec, Canada; 1998.

**ACE TRIAL**Aspirin Efficacy by Dose**Prevention of Vascular Events Following Carotid Endarterectomy**

## FDA RecommendsLow-Dose Aspirin

**FDA reviewed trials of aspirin vs placebo**
- The **“positive findings at lower dosages****are sufficient reason to lower the dosage****of aspirin...for subjects with TIA****and ischemic stroke.”**
- For **“ischemic stroke and TIA: 50 to 325 mg** [aspirin] once a day. Continue therapy indefinitely.”

- FDA, Federal Register. 1998.63:56802–56819.

## New Aspirin Dosing Guidelines for Secondary Stroke Prevention

- New Aspirin Dosing Guidelines for Secondary Stroke Prevention

**FDA **
- New professional labeling for aspirin recommends 50 to 325 mg/day
**American College of Chest Physicians **
- Aspirin at 50 to 325 mg/day as an initial choice
**American Heart Association**
- [50–325 mg/day proposed]

## Available Antiplatelet Agents

**Ticlopidine**
- Advantages
- Proven efficacy in patients having sufferedan ischemic stroke (compared with placebo)
- Proven efficacy in patients having suffered a TIAor minor stroke (compared with high-dose ASA)
- Disadvantages
- Risk of neutropenia
- Risk of thrombotic thrombocytopenic purpura (TTP)
- Require CBC monitoring
- Diarrhea/Rash

## Available Antiplatelet Agents (Cont’d)

**Clopidogrel**
- Advantages
- Proven efficacy compared with ASA in patients with stroke, MI, or PAD
- Well-tolerated
- Disadvantages
- Efficacy for TIA not proven
- Not more efficacious than ASA in the stroke and myocardial infarction subgroups

## Efficacy of Antiplatelet Agents in Patients With Cerebrovascular Disease

**Relative Risk Reduction vs Aspirin**

**7%**

**21%***

**9%**

**23%***

**22%***

**8%**

- 0

- 5

- 10

- 15

- 20

- 25

**Stroke**

**Stroke/MI/Vascular Death****†**

**Relative Risk****Reduction (%)**

**Clopidogrel (CAPRIE, N = 6431)**

**Ticlopidine (TASS, N = 3069)**

**ER-DP + ASA (ESPS-2, N = 3299)**

- Efficacy of Antiplatelet Agents in Patients With Cerebrovascular Disease

- * Statistically significant.
**†** Represents stroke/MI/Sudden Death for ESPS-2.

## ACCP Antiplatelet Guidelines

- “Every patient who has experienced a [non-cardioembolic] stroke or TIA...should receive an antiplatelet agent....”
- “Aspirin, clopidogrel...ticlopidine..., and the combinationof aspirin and dipyridamole are all acceptable options for initial therapy.”
- “Clopidogrel is recommended in favor of ticlopidine because it has a lower incidence of significant adverse effects.”
- “The combination of dipyridamole and aspirin b.i.d. may be more effective than clopidogrel and has a similarly favorable adverse effect profile.”

## Summary and Conclusions

- Antiplatelet agents are effective in the secondary prevention of non-fatal stroke and death
- Currently approved antiplatelet regimens providea modest reduction in risk
- More effective and safe treatment options for stroke prevention and its devastating consequences are needed

## Slide 21

## Risk Reductions

**Relative Risk:** 	Rate of events on drug A
- _	_Rate of events on drug B
**Odds Ratio:**	# of pts with event on drug A	# of pts with event on drug B
- _	_# of pts without event on drug A   	# of pts without event on drug B

**100 patients treated for 1 year: 5 strokes on drug A, 10 strokes on drug B**
**Relative Risk:**	5%_	__	_=	.50	Relative Risk 	= 	50%
- _	_10%				Reduction
- 					(1-relative risk)
**Odds Ratio:**	5	10    	= 	.47	Odds Reduction	=	53%
- _	_95	90			(1-odds ratio)

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