Ali Saad, MD

Sharma M, Pearce LA, Benavente OR, Anderson DC, Connolly SJ, Palacio S, et al. Predictors of Mortality in Patients With Lacunar Stroke in the Secondary Prevention of Small Subcortical Strokes Trial. Stroke. 2014

In this substudy of the SPS3 (The Secondary Prevention of Small Subcortical Strokes) trial, the authors looked for risk factors that predicted mortality and nonfatal bleeding. For those unfamiliar with the original study, SPS3 randomized patients with small subcortical strokes to ASA plus clopidogrel or placebo as well as two different levels of SBP control (130-149 vs <130).

Interestingly, they found patients had significantly greater mortality rates independent of the rate of fatal hemorrhages. some of the predictors found were unique to the dual antiplatelet group. Here are the numbers:

191 deaths over 10,758 patient years (1.78% annual mortality rate)
113 dual antiplatelet  vs 78 ASA only patients died (HR 1.5, 95% CI 1.1 to 2.0). This mortality rate was not affected by the BP arm assignment or by excluding a history of hypertension

The trial also had 161 major hemorrhages, 13 were fatal (9 of these were on dual antiplatelet). dual antiplatelet patients also had a higher rate of nonfatal major hemorrhages
dual: 1.9% (n=96), p<0.001
mono: 1% (n=52), p<0.001

dual: 4.2%/pt-yr vs. 1.8%, p=0.002
mono: 3.1% vs. 1.3%, p=0.03

7 predictors of mortality of patients in either dual antiplatelet or asa only groups:
Factor                                                                                            HR 1.6 (95% CI), p value
Diabetes                                                                                        2.0 (1.5, 2.7) < 0.001
Age, per 10 y increase                                                                  1.6 (1.3, 1.8) < 0.001
Body mass index per 10 kg/m2 decrease                                     1.8 (1.4, 2.4) < 0.001
History of hypertension                                                                 1.7 (1.1, 2.7) 0.02
Systolic blood pressure per 20 mmHg increase                           1.3 (1.1, 1.5) 0.003
Hemoglobin < 13 g/dL                                                                  1.6 (1.2, 2.1) 0.001
eGFR per 20 mL/min/1.73m2 decrease                                       1.3 (1.1, 1.5) 0.02

2 predictor of mortality unique to the dual antiplatelet group:
Factor                                                                                            HR 1.6 (95% CI)
Ischemic heart disease                                                                  2.7 (1.8, 4.1)
Normotenstive/prehypertensive                                                     2.5 (1.5, 4.0)

In other words, dual antiplatelet may lead to greater mortality in ways other than bleeding. Vascular mortality did not differ between the two antiplatelet groups so MI’s alone should not account for this difference. The 7 risk predictors of mortality in both groups aren’t surprising as they are all characteristics of “sicker” patients. However, we don’t have an explanation for the 2 predictors in the dual antiplatelet group. Meta-analysis with other dual antiplatelet trials showed this effect to be unique to the SPS-3 population. This data may caution practitioners when instituting dual therapy in similar populations. The authors suggest that this dual antiplatelet related mortality risk may be a unique feature of lacunar stroke populations as a similar trend was seen in CHARISMA.

This data is limited by the relatively small number of deaths in the total population and an older mean age.

If this data can be reproduced in other trials, it may cast serious doubt on the merits of dual antiplatelet therapy and influence the way future studies are designed. more to come with the completion of POINT. POINT patients are being treated with dual antiplatelet within 12 hours of incident stroke/TIA whereas SPS-3 patients were randomized at least 2 weeks out from their strokes. Perhaps the benefits of dual antiplatelet may end up outweighing the risks if started early.