By Dara Jamieson, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Jamieson reports she is on the stroke adjudication committee for Bayer and is a consultant for Boehringer-Ingelheim.

Synopsis: Although lowering of systolic blood pressure (SBP) in chronically hypertensive individuals decreases the risk of ischemic and hemorrhagic stroke, decreased SBP in the 2 years immediately after a stroke may be associated with an increase in all causes of mortality.

Source: Okin PM, et al. Systolic blood pressure control and mortality after stroke in hypertensive patients Stroke 2015;46:2113-2118.

Patients with chronically elevated blood pressure (BP) are at increased risk of all-cause and cardiovascular death, with a particularly increased risk of ischemic and hemorrhagic stroke. Treatment to lower systolic BP (SBP) decreases stroke risk, without an apparent lower threshold down to 120 mmHg. However, lowered SBP ( 120 mmHg) in the 5 years after a stroke may be associated with increased mortality. Lower SBP over a shorter period of time after a stroke in chronically hypertensive patients could potentially increase mortality as well.

The authors performed a post-hoc analysis of data from the Losartan Intervention For Endpoint reduction (LIFE) study to determine the relationship between SBP and all-cause and cardiovascular mortality in the 541 out of 9193 hypertensive patients with electrocardiographic left ventricular hypertrophy, a marker of increased vascular risk, who had an incident stroke during the study. Mortality was examined as a function of the average on-treatment SBP, which was measured after strokes that occurred during the follow-up antihypertensive treatment. Blinded treatment was begun with daily losartan 50 mg or atenolol 50 mg and matching placebo of the other agent with a target BP of 140/90 mmHg or lower. Hydrochlorothiazide and other antihypertensive medications were added, if necessary, to achieve the target pressure. Patients with average on-treatment SBP < 144 mmHg (lowest tertile) and average on-treatment SBP > 157 mmHG (highest tertile) were compared to patients with average on-treatment SBP between 144 and 157 mmHg.

Of the 170 patients (31.4%) in the LIFE study who died during the 2.02 ± 1.65 years mean follow-up after their incident stroke, 135 (25.0%) deaths were from cardiovascular causes. Compared with SBP of 144 to 157 mmHg, SBP < 144 mmHg was associated with significantly higher all-cause mortality and SBP > 157 mmHg with significantly higher cardiovascular and all-cause mortality rates. However, in a multivariate Cox analyses, adjusting for other univariate predictors of post-stroke mortality in the population, an average SBP < 144 mmHg was a significant predictor of cardiovascular and all-cause mortality, whereas an average SBP > 157 mmHg was not associated with significantly increased adjusted risk of either all-cause or cardiovascular death compared with an average SBP of 144 to 157 mmHg. In a multivariate analysis restricted to deaths occurring more than 90 days after the initial stroke, average in-treatment SBP < 144 mmHg remained significantly associated with an increased risk of all-cause mortality, after adjusting for other potential predictors of death. An average SBP > 157 mmHg more than 90 days after the stroke was not associated with a significant increased risk of death. The effect of SBP on mortality did not show any significant interaction with sex, age, history of atrial fibrillation, or randomized anti-hypertensive treatment arm. The authors concluded that lower achieved SBP (< 144 mmHg) is associated with a significantly increased risk of cardiovascular and all-cause mortality after initial stroke in hypertensive patients during short-term (i.e., average 2 years) follow-up.

Commentary

It is a truth, universally acknowledged, that treatment of chronically elevated BP decreases the risk of acute ischemic and hemorrhagic stroke. So how can there be anything but a beneficial effect of chronically lowered BP in a patient who has had a stroke? Some SBP treatment studies, including this analysis of the LIFE study, indicate an association between lowered SBP and increased cardiovascular and all-cause mortality. Even after factoring out effects of cardiac disease with SBP and early deaths due to low SBP, as well as studying chronically hypertensive patients with increased risk, the authors analyzing the LIFE data still did not explain the conundrum of the risk of decreased stroke, but increased death, with lowered BP. However, the data, which appeared to show mortality benefit from treatment failure, were not adequately analyzed to evaluate cerebrovascular disease. The relationship of SBP levels to recurrent stroke was not assessed and recurrent strokes were not adjudicated. Epidemiological studies frequently lump disparate vascular diseases together, ignoring obvious pathophysiological differences between cerebrovascular disease due to ischemic or hemorrhagic stroke and cardiovascular disease. Further dissection of BP and mortality may help to individualize patient management. In the 541 stroke patients in the LIFE study, incident strokes were characterized as atherothrombotic (74.5%), embolic (15.5%), and hemorrhagic (10.0%). However, mortality and recurrent stroke type were not categorized based on incident stroke type. Patients with hemorrhagic stroke may benefit from stricter blood pressure control, especially with a history suggestive of cerebral amyloid angiopathy. While there was no subgroup effect associated with atrial fibrillation, strict blood pressure control may have less impact on an embolic, rather than on an atherosclerotic, stroke mechanism. More details are needed to interpret these results that appear to show benefit to lack of adherence to the study treatment protocol.

Self-laudatory speculation by a vascular neurologist includes the theory that lower stroke risk related to hypertension treatment, combined with improved patient survival after stroke, has tipped risk of BP lowering to non-cerebrovascular causes of mortality. Distinguishing between cerebrovascular vs cardiovascular death in the BP treatment trials could differentiate the effect of BP lowering on distinctly different vascular systems. The results of the LIFE study emphasize that vascular researchers need to acknowledge the differences between cerebrovascular disease and cardiovascular disease. Clinical trials must abandon their “one-size-fits-all” approach to vascular disease and do a better job of differentiating brain vascular disease from heart vascular disease.