Benefits of statins in stroke vary based on cerebrovascular history

Issue: April 2009

ByEric Gupta, PharmD, BCPS, CLS, FCPhA

Ischemic stroke has a similar pathophysiology to coronary artery disease, where elevated amounts of LDL play a key role in atherosclerosis development.

The most effective way to lower LDL is with statins. However, the relationship between LDL, the use of statins and cerebrovascular disease is not as clear as the relationship between statins and LDL with CAD.

A closer evaluation of the relationship between statins and stroke reveals four patient populations in the literature: Patients with prior CAD but not cerebrovascular disease, a mix of patients with or without CAD (~50% had CAD) but no cerebrovascular disease, patients with neither CAD nor cerebrovascular disease, and patients without CAD but with cerebrovascular disease.

Comparing trials

The table complementing this column summarizes data from 12 prospective, large statin trials. Five (TNT, LIPID, CARE, PROVE-IT and 4S) included patients with a history of CAD but no prior cerebrovascular disease. The risk of stroke was reduced from 19% to 31% in four of these trials while one (PROVE-IT) failed to demonstrate any stroke risk reduction from statin therapy. However, the incidence of stroke was only 1% in this study.

Eric Gupta, PharmD, BCPS, CLS
Eric Gupta

The number needed to treat to prevent a stroke varied significantly and was inversely related to the degree of LDL reduction. Thus, more intensive statin therapy may be warranted in patients with stroke, which is currently recommended in patients with CAD.

Two statin trials (PROSPER and HPS) contained a mix of patients with and without CAD but no prior cerebrovascular disease. PROSPER demonstrated an increase in stroke in the statin treatment arm but these results may have been confounded by the enrollment of elderly patients (aged 70 to 82), given that advanced age is a risk factor for stroke. In HPS a 25% reduction in stroke was observed.

For patients with no prior CAD or cerebrovascular disease, four trials — WOSCOPS, CARDS, ASCOT-LLA and JUPITER — demonstrated a reduction in stroke from 11% to 48%. Although the relative risk reduction of 48% in the JUPITER study is impressive, the incidence of stroke was low (<0.5%) in both treatment groups, resulting in a very large number needed to treat. The greatest benefit from statins was observed in CARDS, which enrolled patients with diabetes, and in JUPITER, in which LDL reduction was greatest.

Only SPARCL enrolled patients with no prior CAD but with prior cerebrovascular disease. In this trial, the mean reduction in LDL was 43% and the risk of cerebrovascular disease decreased by 16%. Patients in this trial were enrolled within six months of their index cerebrovascular disease event, perhaps explaining the higher incidence of cerebrovascular disease outcomes in the trial and low number needed to treat (n=53) observed in SPARCL.

Statins are effective in reducing stroke, and these effects vary based on prior history of cerebrovascular disease. Patients suffering a recent cerebrovascular event derive the greatest benefit from statins for secondary prevention.

Stroke Outcomes in Statin Trials

Study	Citation	N=	Duration (Years)	Prior CAD	Prior Stroke/CVA	LDL % Δ
TNT	N Engl J Med. 2005;352:1425-1435	10,001	4.9	Y	N (5%)	↓24%
LIPID	N Engl J Med. 1998;339:1349-1357	9,014	6.1	Y	N (4%)	↓25%
CARE	N Engl J Med. 1996;335:1001-1009	4,159	5	Y	N	↓28%
PROVE-IT	N Engl J Med. 2004;350:1495-1504	4,162	2	Y	N	↓32%
4S	Lancet. 1994;344:1383-9	4,444	5.4	Y	N	↓36%
PROSPER	Lancet. 2002;360:1623-1630	5,804	3.2	Mixed	N (11%)	↓34%
HPS	Lancet. 2002;360:7-22	20,356	5	Mixed	N (12%)	↓38%
WOSOCOPS	N Engl J Med. 1995;333:1301-1307	6,595	4.9	N	N	↓26%
CARDS	Lancet. 2004;364:685-696	2,838	3.9	N	N	↓33%
ASCOT-LLA	Lancet. 2003;361:1149-1158	19,342	3.3	N	N (10%)	↓35%
JUPITER	N Engl J Med. 2008;359:2195-2207	17,802	1.9	N	N	↓50%
SPARCL	N Engl J Med. 2006;355:549-559	4,731	4.9	N	Y	↓43%

CVA = cerebrovascular accident.

Stroke Outcomes in Statin Trials

Study	Statin	Incidence Stroke/CVA (%)	Comparator	Incidence Stroke/CVA (%)	RRR (%)	P value	NNT
TNT	Atorvastatin, 80 mg	2.3	Atorvastatin, 10 mg	3.1	25	0.02	125
LIPID	Pravastatin, 40 mg	3.7	Placebo	4.5	19	0.048	125
CARE	Pravastatin, 40 mg	2.6	Placebo	3.8	31	0.03	83
PROVE-IT	Atorvastatin, 80 mg	1.0	Pravastatin, 40 mg	1.0	-9	-	∞
4S	Simvastatin, 20 mg-40 mg	2.7	Placebo	4.3	30	0.024	63
PROSPER	Pravastatin, 40 mg	4.7	Placebo	4.5	-3	0.81	-
HPS	Simvastatin, 40 mg	4.3	Placebo	5.7	25	0.01	71
WOSOCOPS	Pravastatin, 40 mg	1.6	Placebo	1.6	11	0.57	∞
CARDS	Atorvastatin, 10 mg	1.5	Placebo	2.5	48	0.016	100
ASCOT-LLA	Atorvastatin, 10 mg	1.7	Placebo	2.4	27	0.024	143
JUPITER	Rosuvastatin, 40 mg	0.18	Placebo	0.34	48	0.002	625
SPARCL	Atorvastatin, 80 mg	11.2	Placebo	13.1	16	0.03	53