Expert Review: Thrombosis

Impact of resting heart rate on mortality, disability and cognitive decline in patients after ischaemic stroke

Background
Stroke is a disabling condition and constitutes the second most frequent cause of death leading to disability, cognitive impairment, and a huge economic burden on health care systems. Hypertension is regarded as one leading risk factor for stroke and reducing blood pressure has been shown to reduce morbidity and mortality due to stroke in large hypertension trials2,3. The heart rate has been demonstrated to be a risk indicator in hypertension4 and cardiovascular disease5 and a modifiable risk factor in heart failure6 as heart rate lowering with an If-channel inhibitor reduces events7.

Knowledge Gap
Although the effects of blood pressure on vascular outcomes, mortality, and functional outcomes after stroke are well characterized, no such information is available for the heart rate.

Aim of the Study
The aim of the study was to evaluate the association of the resting heart rate at baseline with cardiovascular outcomes and neurological outcomes among patients who recently experienced an ischaemic stroke or suffered a recurrent stroke.

Methods
This is a post-hoc analysis of the PROFESS trial, which assigned 20 332 patients from 695 centres in 35 countries to different antihypertensive and antiagregant treatment arms after they had had a non-cardioembolic ischaemic stroke. The trial had a two by two factorial design to compare for treatment regimens containing extended release dipyridamole plus aspirin compared with clopidogrel or telmisartan, compared with placebo.
Patients were grouped by quintiles of baseline heart rate and were evaluated for:
a) Primary outcome: recurrent stroke
b) Secondary outcomes:
-composite of recurrent stroke, myocardial infarction, or death from a vascular cause
-new or worsening heart failure and non-vascular death.
c) Additional pre-defined endpoints:
-disability after recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months
-cognitive function, assessed with the Mini-Mental State Examination (MMSE) score at 4 weeks after randomization and at the penultimate visit.

Results
The results could be summarized as follows:
a) Primary outcome: no significant relationship between baseline heart rate and recurrent stroke
b) Secondary outcomes:
There was no significant relationship of new myocardial infarction, or the composite secondary endpoint to baseline heart rate. However, patients in the two highest quintiles of heart rate (77–82 and .82 b.p.m.) were at higher risk for total death [hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.19–1.69; and HR 1.74, 95% CI 1.48– 2.06, p< 0.0001] compared with patients in the lowest quintile. Risk of vascular death (starting at heart rates from 71 to ≤76 b.p.m., HR 1.39, 95% CI 1.11–1.74, p< 0.0001) and non vascular death (from .82 b.p.m., HR 1.66, 95% CI 1.29–2.13, p=0.0016) was also strongly associated with higher baseline heart rate. Importantly, increased mortality risk persisted after adjusting for multiple confounders including baseline blood pressure. Noteworthy, in the group of patients with recurrent stroke, lower baseline heart rate was associated with better neurological outcomes as measured with the Barthel index and mRS score, and with less cognitive decline according to an MMSE score ≤ 24 points at 1 month and at the penultimate visit or a decline of ≥ 2 points between these two time periods. Conclusion A high baseline heart rate (>75lpm) is a risk indicator for mortality in patients with stroke. Myocardial infarction and recurrent stroke are not associated with baseline heart rate, but lower heart rates are associated with better functional neurological outcomes and less cognitive decline after the ischaemic stroke.

Clinical Impact:
It is not yet known whether therapeutic reduction of heart rate can improve cardiovascular prognosis. This analysis is hypothesis generating and sets the stage for the evaluation of potential pharmacological interventions to reduce the heart rate in patients after an ischaemic stroke. In light the benefit of ivabradine in heart failure patients6,7, randomized, controlled trials of this compound in stroke survivors as well as in hypertensive people with controlled blood pressure and residual heart rate elevation may be warranted.

Corresponding author from original paper
Michael Böhm. Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Kirrberger Str. 1, D 66424 Homburg/Saar, Germany
Tel: +49 68411623372, Fax: +49 68411623369
Email: michael.boehm@uks.eu

Citation: Eur Heart J 2012;33:2804–2812.

References:

1.-Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Diener HC, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton WA, et al. Lancet Neurol. 2008;7(10):875-84
2-Rashid P, Leonard-Bree J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 2003; 34:2741–2748.
3.- ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, Simons-Morton DG, Basile JN, Corson MA, Probstfield JL, Katz L, Peterson KA, Friedewald WT, Buse JB, Bigger JT, Gerstein HC, Ismail-Beigi F. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–1585
4.- Kolloch R, Legler UF, Champion A, Cooper-Dehoff RM, Handberg E, Zhou Q, Pepine CJ. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the International Verapamil SR/trandolapril Study (INVEST). Eur Heart J 2008;29:1327–1334.
5.- Reil JC, Custodis F, Swedberg K, Komajda M, Borer JS, Ford I, Tavazzi L, Laufs U, Böhm M. Heart rate reduction in cardiovascular therapy. Clin Res Cardiol 2011; 100:11–19.
6.- Böhm M, Swedberg K, Komajda M, Borer J, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; on behalf of the SHIFT investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 2010;376:886–894.
7.- Swedberg K, Komajda M, Bo¨hm M, Borer J, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; on behalf of the SHIFT investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–885.

Citation: Eur Heart J 2012;33:2804–2812.

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