Secondary stroke prevention: challenges and solutions

Figures & data

Table 1 Summary of studies from different ethnic and racial groups that disclosed stroke subtype rates

Reference(s)	Country/study	Population composition	Stroke types	Ischemic stroke subtypes (%)
Prospective, population-based studies
White, Boden-Albala et al 2005	USA/NOMAS	64% Hispanic	77% IS		Hispanic		Black		White
Collaborators, Sacco et al 1998	Follow-up = 4 years	13% Black	17% ICH	CE	20		17		24
		22% White	6% SAH	LAA	15		17		9
				SVO	21		21		15
				Crypto	43		44		51
				Other	1		1		1
Morgenstern, Smith et al 2004	USA/BASIC project	48% White	83% IS		Mexican American		White
		53% Mexican	14% ICH	CE	16		26
Uchino, Risser et al 2004	Follow-up = 3 years	American	3% SAH	LAA	14		15
				SVO	21		17
				Crypto	22		22
				Other	2		1
Broderick, Brott et al 1998	USA/GCNKSS	18.5% Black	84% IS		Black		White
Schneider, Kissela et al 2004	Follow-up = 2–4 years	72.5% White	10% ICH	CE	15		22
			4% SAH	LAA	10		12
			2% undetermined	SVO	18		15
				Crypto	54		49
				Other	3		2
Ohira, Shahar et al 2006, 2011	USA/ARIC	25% Black	88% IS		Black		White
	Follow-up = 13 years	75% White	12% ICH	CE	18		19
				SVO	30		13
				Non-SVO	52		68
Petty, Brown et al 1999	USA/Rochester	95% White	Not available		Whites (95% of the sample)
	Follow-up = 4 years			CE	29
				LAA	16
				SVO	16
				Crypto	36
				Other	3
Hajat, Heuschmann et al 2010 Hajat, Dundas et al 2001	England/SLSS Follow-up = 7 years	71% White 20% Black (13% Caribbean and 7% African) 9% Other	80% IS 14% ICH 6% SAH	CE LAA SVO Crypto Other	Black 17 9 42 21 11		Other 17 11 35 30 7		White 31 10 22 25 12
Feigin, Carter et al 2006	New Zealand/ARCSS	66% White	73% ischemic		Maori/Pacific Islander		Asian/other		White
	Follow-up = 1 year	20% Maori/Pacific Islander	12% ICH	CE	36		18		29
			6% SAH	LAA	4		2		6
		14% Asian/other	9% undetermined	SVO	10		15		11
				Crypto	46		61		51
				Other	4		4		3
Turin, Kita et al 2010	Japan/TSR	100% Japanese	67% IS		Japanese
	Follow-up =16 years		22% ICH	CE	23
Kita, Turin et al 2007			10% SAH	SVO	54
			1% undetermined	Non-SVO	21
				Other	2
Cross-sectional, hospital-based studies
Gutierrez, Koch et al 2013	USA/JMH	53% Hispanic	83% IS		Hispanic	Black	Caribbean Black		White
	Sample size = 473	23% African	17% ICH	CE	38	22	23		44
		American		LAA	22	23	31		15
		13% Black		SVO	17	25	28		19
		Caribbean		Crypto	13	13	13		12
		11% White		Other	5	16	5		10
Sharma, Tsivgoulis et al 2012	Singapore	74.2% Chinese	Not available		Chinese		Malay		Indian
	Sample size = 481	16.6% Malay		CE	8		7		4
		9.2% Indian		LAA	12		18		25
				SVO	52		43		25
				Crypto	26		30		39
				Other	2		2		7
					Guayaquil	Santiago	Buenos aires		Bogota
							Whites	Natives
Saposnik and Del Brutto 2003	South America N = 912 (Meta-analysis of hospital-based samples)	Mix of mestizos, whites and natives	65% IS	CE	14	33	20	22	18
			34% ICH	LAA	7	33	11	13	19
			1% Other	SVO	43	14	48	36	19
				Crypto	30	15	16	21	29
				Other	6	5	5	8	6

Notes: Stroke subtypes vary across different populations. Demographic information may be helpful in guiding workup for stroke subtypes. The different proportions of stroke subtypes in each of the reported groups underscore the burden of certain risk factors in these populations and how it may lead to targeted strategies for secondary stroke prevention from a public health perspective. With kind permission from Springer Science+Business Media: Curr Cardiovasc Risk Rep, An epidemiological perspective on race/ethnicity and stroke, 9, 2015, 19, Sevush-Garcy J, Gutierrez J, Table 1.⁹³

Abbreviations: CE, cardioembolism; crypto, cryptogenic; ICH, intracranial hemorrhage; IS, ischemic stroke; LAA, large artery atherosclerosis; SAH, subarachnoid hemorrhage; SVO, small vessel occlusion.

Figure 1 Stroke and extracranial carotid atherosclerosis.

Notes: A man in his 90s came to the hospital with sudden onset of right-sided weakness and difficulty finding words. On exam, he was found aphasic with mild right-sided hemiparesis. (A) A brain magnetic resonance image showed evidence of scattered infarcts over the left hemisphere and a small infarct in the territory of the right anterior cerebral artery. (B) The neck magnetic resonance angiograph showed a flow gap in the left extracranial proximal internal carotid artery (arrow). (C) The brain magnetic resonance angiograph showed the lack of the right proximal segment of the anterior cerebral artery, thus explaining the presence of bi-hemispheric infarcts attributable to left extracranial carotid stenosis through embolization of the anterior communicating artery. (D) A neck artery Doppler confirmed the degree of stenosis (>80%) and the patient underwent carotid endarterectomy and was discharged home after the initial neurological deficits resolved.

Figure 2 Stroke and intracranial atherosclerosis.

Notes: A woman in her 60s came to the hospital for left-sided weakness and headache. On exam, she was found to have mild left pronator drift and visuospatial neglect. (A) The brain magnetic resonance image showed evidence of a right parietal lobe cortical infarct and (B) the brain magnetic resonance angiograph showed evidence of diffuse luminal narrowing of her brain arteries (arrows), with some of these stenoses located proximal to the area of her infarction (small arrow), suggesting artery-to-artery embolism from intracranial large artery stenosis as the most likely stroke mechanism.

Figure 3 Small artery disease versus branch occlusive disease.

Notes: (A) An example of a small infarct in the left putamen and subcortical white matter (arrow), most likely due to the occlusion of a lenticulostriate artery branching of from the middle cerebral artery. (B) The brain magnetic resonance angiograph in this same patient showed no evidence of large artery stenosis in the proximal middle cerebral artery. (C) A patient with evidence of an infarct (arrow) involving the lenticular nucleus and the head of the caudate nucleus. (D) Contrary to the case presented in A, this patient shows evidence of a high-degree of stenosis in the middle cerebral artery in the brain computed tomography angiograph (large arrow), suggesting branch occlusive disease and “pure” small artery disease as the underling etiology of the infarct.

Table 2 Summary of some of the major studies comparing antiplatelets against each other or against placebo in stroke prevention

Secondary stroke prevention setting	Trial	Placebo	ASA	ASA+D	C	ASA+C	Results
Acute (0–2 weeks)	CAST^Citation95	+	+				12% RRR with ASA at 4 weeks with an ARR of 0.6% in early mortality and nonfatal stroke
	IST^Citation96	+	+				20% RRR with ASA at 2 weeks with an ARR of 0.9% in stroke recurrence
	CHANCE^Citation91		+			+	32% RRR with dual antiplatelets in stroke with an ARR of 3.5% over 3 months in stroke
Subacute (3–6 months)	UKA TIA^Citation100	+	+				18% RRR with ASA in composite outcome
	ESPS^Citation94	+		+			38% RRR with ASA+D in stroke recurrence with a yearly ARR of 2.5%
	EPS2^Citation99	+	+	+			18% RRR in ASA group compared to placebo
							37% RRR in ASA+D with a yearly ARR of 2.5% in stroke/death compared to placebo
	ESPIRIT^Citation101		+	+			20% RRR with ASA+D over ASA alone with a yearly ARR of 1% in composite outcome
	PROFESS^Citation35			+	+		No difference in stroke recurrence
	SPS3^Citation28		+			+	No benefit in stroke but increased risk of major hemorrhage with dual antiplatelets (2.1% vs 1.1% per year) and increased mortality (2.1% vs 1.5% per year)
	CAPRIE^Citation32		+		+		8.7% RRR of C over ASA in all groups with a yearly ARR of 0.5 in composite outcome (driven by PVD group)
Chronic (>3 months)	AICLA^Citation97	+	+	+			40% RRR in both groups as compared to placebo with a yearly ARR of 2% in stroke
	MATCH^Citation98				+	+	6.4% RRR with dual antiplatelets in composite outcome, countered by an increase in life-threatening bleeds (2% vs 1%)

Note: Although antiplatelets are frequently prescribed for preventing non-cardioembolic strokes, the relatively low risk reduction in all trials underscores the need to target other risk factors that may increase stroke recurrence. + signifies that the agent was studied in the trial.

Abbreviations: ARR, absolute risk reduction; ASA, aspirin; ASA+D, aspirin plus dipyridamole; C, clopidogrel; PVD, peripheral vascular disease; RRR, relative risk reduction; ASA+C, aspirin plus clopidogrel.

Table 3 Stroke mechanism and the estimated risk of stroke recurrence in the setting of prevention therapy

Stroke mechanism	Selected trials	Placebo/gold standard	Treatment	Outcome(s)	Results
Carotid stenosis	NASCET^Citation81	Best medical	CEA*	Stroke or death	ARR of 10% (6% vs 16%) with CEA vs best medical management at 1 year in patients with severe stenosis
	CREST^Citation14	CEA	CAS	Stroke, MI, death	Composite outcome for CAS (7.2%) is non-inferior to CEA (6.8%) at 4 years
intracranial artery stenosis	WASID^Citation13	Aspirin	Warfarin	Stroke or death	ARI of 2% (17% vs 15%) with warfarin compared to aspirin in patients with 50%–99% intracranial vessel stenosis
	SAMMPRIS^Citation90	Medical therapy	Angioplasty and stenting	Ischemic stroke	ARI of 8% (20% vs 12%) with angioplasty/stenting compared to best medical practice alone in stenosis >70%
Cardioembolic	EAFT^Citation102	Placebo/Aspirin	Warfarin	Stroke, death, MI, systemic embolism	ARR of 9% (8% vs 17%) with warfarin compared to placebo/aspirin
Atrial fibrillation	EAFT^Citation102	Placebo	Aspirin		ARR of 4% (15% vs 19%) with aspirin compared to placebo
	RE-LY^Citation51		Dabigatran		1.27% vs 1.6% per year favoring NOAC
	ROCKET AF^Citation53	Warfarin	Rivaroxaban	Stroke or systemic embolism	1.11% vs 1.71% per year favoring NOAC
	ARISTOTLE^Citation52		Apixaban		2.1% vs 2.4% per year favoring NOAC
	ENGAGE AF^Citation54		Edoxaban		1.18% vs 1.5% per year favoring NOAC
Heart failure	WARCEF^Citation16	Aspirin	Warfarin	Death or stroke	No difference (7.5% vs 7.9%) in event rate between warfarin and aspirin in patients with CHF and EF of <35%
Lacunar	SPS3^Citation23	Aspirin	Aspirin + clopidogrel	Stroke	No difference in yearly risk (2.7% vs 2.5%) of single vs dual-antiplatelet therapy in stroke incidence but increased risk of complications with dual-antiplatelet therapy
	CHANCE^Citation91	Aspirin	Aspirin + clopidogrel*	Stroke	ARR of 3.5% (8.2% vs 11.7%) with dual antiplatelets compared to a single antiplatelet agent, over 3 months

Notes: The stroke recurrence rates vary by stroke mechanism, thus the need to investigate for a plausible cause of stroke. The natural history of the disease is modified with various therapies as shown in this table. Large artery atherosclerosis, intra- and extracranial, confers one of the highest risks of stroke recurrence, thus the need to intensively look for it. Atrial fibrillation, sometimes elusive, may be identified with prolonged cardiac monitoring after the acute phase of stroke. Given the dramatic change in treatment if atrial fibrillation is found, ruling out this arrhythmia is one of the most important steps in deciding the adequate treatment for stroke prevention. “Stroke” refers to both ischemic and hemorrhagic unless otherwise specified.

* Unlike the SPS3 trial, dual-antiplatelet therapy in CHANCE was initiated within 24 hours of symptoms onset.

Abbreviations: ARI, absolute risk increase; ARR, absolute risk reduction; CAS, carotid artery stenting; CEA, carotid endarterectomy; CHF, chronic heart failure; EF, ejection fraction; MI, myocardial infarction; NOAC, novel oral anticoagulant; RRR, relative risk reduction.

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