Diuretics and Cerebrovascular Outcomes––Beyond Traditional Endpoints

All major antihypertensive drug classes lower the incidence of stroke. The functional consequences of a stroke may vary from severe neurological deficits to complete functional recovery, but this clinical heterogeneity has not always been accounted for in traditional clinical trials of antihypertensive treatment regimens. Furthermore, the relative merits of different blood pressure–lowering drug classes as tools for primary and secondary stroke prevention remains an issue of debate. Therefore, it is pleasing that in this issue of the Journal, Tziomalos and colleagues present data that take into account stroke severity both at diagnosis and at follow-up in relation to different pre-stroke antihypertensive treatment strategies. Using observational data, the authors explored the associations between pre-stroke antihypertensive treatment regimens, stroke severity at admission, and functional outcome at discharge from the stroke ward. They studied 482 consecutive patients who were hospitalized with acute ischemic stroke at their facility, approximately 80% of which had a previous diagnosis of hypertension. Main outcome variables in their study were National Institutes of Health Stroke Scale (NIHSS) score at admission and modified Rankin score at discharge. Their main finding was that patients with a pre-stroke antihypertensive treatment regimen that included a diuretic had significantly lower NIHSS score at admission than patients who did not use a diuretic. No other antihypertensive drug class (including bblockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers) was associated with stroke severity at admission. Furthermore, patients with good functional outcome at hospital discharge were more likely than patients with poor functional outcome to have been treated with a diuretic previously. The authors defined severe stroke as scoring 16 or higher on the NIHSS at admission. It has previously been demonstrated that stroke patients who present with NIHSS score ≥16 have a high probability of death or severe disability at follow-up. Therefore, any drug that is associated with a reduced risk of having severe stroke according to this definition is likely to also be associated with a lower risk for poor functional outcome. Accordingly, the most relevant finding of this study was the association between pre-stroke use of diuretics and less severe stroke symptoms at admission. The finding that diuretic treatment was associated with less severe stroke at admission and with better functional outcome at discharge might not be entirely unexpected in light of previously reported data. Indeed, the results presented by Tziomalos and colleagues are in line with recently published data from a considerably smaller Taiwanese cohort, in which diuretic use was also associated with less severe stroke symptoms at presentation and with lower modified Rankin scale scores at follow-up. Furthermore, subgroup analyses of the randomized Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial revealed that in stroke survivors, randomization to combined antihypertensive therapy with the diuretic indapamide and the angiotensin-converting enzyme inhibitor perindopril reduced the risk of having a subsequent stroke compared with randomization to placebo, whereas perindopril monotherapy (ie, without diuretics) did not. Although it is likely that the difference in outcome between patients treated with or without the diuretic indapamide in the PROGRESS trial was the result of the extra blood pressure reduction, rather than by adding a diuretic per se, the results clearly demonstrated the clinical utility of using diuretics for secondary prevention of strokes. Observational studies serve as an important complement to randomized trials. It is important, however, to interpret observational data within the context of the methodological limitations that necessarily apply to noninterventional studies. In particular, observational data may contain some degree of confounding. The traditional definition of confounding refers to lack of comparability between an exposed and a nonexposed group, due to the uneven distribution of a factor, which, in itself, is related to the endpoint but which is not an intermediate step on the postulated causal pathway between exposure and outcome. Consider, for instance, our previously reported finding that prehospitalization use of diuretics was associated with a significantly increased risk of 1-year mortality following hospitalization for acute chest pain. A plausible explanation of this finding is that the presence of either congestive heart failure or renal failure, both of which were likely to have been more prevalent among diuretic users, confounded the apparent relationship between use of diuretics and 1-year mortality. In other words, use of diuretics did not cause an increased mortality risk in our cohort, but rather acted as a marker for underlying diseases, which was associated with a poor outcome. Although Tziomalos and colleagues have performed adjusted analyses in an attempt to adjust statistically for potential confounders, it would also have been interesting to see a description of the demographic and clinical Address for correspondence: Magnus Wijkman, MD, PhD, Vrinnevisjukhuset, 601 82, Norrk€ oping, Sweden E-mail: magnus.wijkman@liu.se