Stroke in heart failure in sinus rhythm: the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial.
BACKGROUND
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses.


METHODS
We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions.


RESULTS
Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3-5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups.


CONCLUSIONS
The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.
University of Kent, Canterbury, UK.
Patrick M
PM
Pullicino
John L P
JL
Thompson
Ralph L
RL
Sacco
Alexandra R
AR
Sanford
Min
M
Qian
John R
JR
Teerlink
Haissam
H
Haddad
Monika
M
Diek
Ronald S
RS
Freudenberger
Arthur J
AJ
Labovitz
Marco R
MR
Di Tullio
Dirk J
DJ
Lok
Piotr
P
Ponikowski
Stefan D
SD
Anker
Susan
S
Graham
Douglas L
DL
Mann
J P
JP
Mohr
Shunichi
S
Homma
D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use*; D001925:Brain Damage, Chronic / Q000209:etiology; D002545:Brain Ischemia / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D020766:Intracranial Embolism / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012008:Recurrence; D012720:Severity of Illness Index; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D013318:Stroke Volume; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; D001241:Aspirin