Heart Rate as a Predictor of Stroke in High-risk, Hypertensive Patients with Previous Stroke or Transient Ischemic Attack Else Charlotte Sandset, MD, PhD,* Eivind Berge, MD, PhD,† €rn Holzhauer, MSc,k Sverre E. Kjeldsen, MD, PhD,†‡x Stevo Julius, MD, ScD,x Bjo Lars-Henrik Krarup, MD, PhD,{ and Tsushung A. Hua, PhD#

Background: Risk factors for first stroke are well established, but less is known about risk factors for recurrent stroke. In the present analysis, we aimed to assess the effect of heart rate and other possible predictors of stroke in a hypertensive population with previous stroke or transient ischemic attack (TIA). Methods: The Valsartan Antihypertensive Long-Term Use Evaluation trial was a multicentre, doublemasked, randomized controlled, parallel group trial comparing the effects of an angiotensin receptor blocker (valsartan) and a calcium channel blocker (amlodipine) in patients with hypertension and high cardiovascular risk. We used Cox proportional hazard models to investigate the effect of baseline variables on the risk of stroke. Quadratic terms of the continuous variables were entered in the models to test for linearity. Results: Of 15,245 patients included in the trial, 3014 had a previous stroke or TIA at baseline and were included in the present analysis. Stroke recurrence occurred in 239 patients (7.9%) during a median of 4.5 years of follow-up. Resting heart rate (per 10 beats per minute; hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.18-6.58) and diabetes mellitus at baseline (HR, 1.47; 95% CI, 1.03-2.10) were significantly associated with an increased risk of stroke recurrence in the multivariable analysis. Conclusions: In high-risk, hypertensive patients with previous stroke or TIA, resting heart rate was the strongest predictor of recurrent stroke. Key Words: Stroke—predictors—recurrence—hypertension—heart rate. Ó 2014 by National Stroke Association

Introduction Predictors of first stroke are well established; however, there is still uncertainty regarding predictors of recurrent stroke. The absolute risk of recurrent stroke varies widely

From the *Department of Neurology, Oslo University Hospital, Oslo, Norway; †Department of Cardiology, Oslo University Hospital, Oslo, Norway; ‡Faculty of Medicine, University of Oslo, Oslo, Norway; xDivision of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan; kNovartis Pharma, Basel, Switzerland; {Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark; and #Novartis Pharma, East Hanover, NJ. Received May 11, 2014; accepted July 7, 2014. The sponsor of the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial was Novartis Pharma AG. The trial was designed interactively between an advisory board (later the VALUE Executive Committee) and the sponsor. The sponsor managed operational execution, storage of data, and performed the analyses. The Executive Committee has full access to the

in the literature, ranging from 2% to 4% during the first month and from 12% to 42% within 5 years.1-6 Some cardiovascular risk factors have been identified, such as atrial fibrillation, previous myocardial infarction,

data, is responsible for the data analysis, and has full control over the right to publish. S.J. has served as consultant and received grants from Novartis and other major pharmaceutical companies. S.E.K. has received lecture honoraria from AstraZenca, Bayer, Medtronic, Merck Sharp & Dome, and Takeda, honoraria for consulting from Bayer, Medtronic, Takeda, and Serodus, and research support from AZ and Pronova. T.A.H. and B.H. are Novartis employees and hold stocks in the company. E.C.S., E.B., and L.-H.K. have no relevant disclosures. Address correspondence to Else Charlotte Sandset, MD, PhD, Department of Neurology, Oslo University Hospital, P. O. Box 4956 Nydalen, NO-0424 Oslo, Norway. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.009

Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2014: pp 1-5

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diabetes mellitus, and older age, yet traditional risk factors such as, for example, hypertension have not been consistently shown to predict recurrence.1,3,7–10 The strongest predictor of stroke recurrence is probably the disease itself, which may overwhelm other traditional risk factors. In other words, patients with a previous stroke are at a particularly high risk of stroke, and it is therefore of importance to identify other, modifiable risk factors in this group.11 Several epidemiologic and clinical studies have recently identified resting heart rate as a strong predictor of hypertension and cardiovascular disease,12-15 and interventions to lower heart rate have been shown to reduce the risk of cardiovascular events in patients with chronic heart failure.16 In stroke, a relationship between resting heart rate, cognitive decline, and poor functional outcome was identified in a population with ischemic stroke within the last 120 days,17 and in experimental studies, decreasing heart rate with the selective I(f)-channel inhibitor ivabradine has been associated with reduction of infarct size.18 The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial was an investigator-designed, multicentre, double-masked, randomized controlled, parallel group trial comparing the effect of the angiotensin receptor blocker valsartan and the calcium channel blocker amlodipine on cardiovascular events in patients with hypertension and high risk of cardiovascular disease.19,20 In a previous article, Julius et al12 found an association between high heart rate and an increased risk of stroke, myocardial infarction, heart failure, sudden death, and all-cause death in the entire VALUE population. In the present analysis, we specifically aimed to investigate whether heart rate predicted recurrent stroke in 3014 VALUE patients with previous stroke or transient ischemic attack (TIA) and to identify other predictors of recurrent stroke in this subgroup.

Materials and Methods The VALUE trial included 15,245 patients with hypertension (treated or untreated), aged 50 years or older, and with predefined combinations of cardiovascular risk factors and cardiovascular disease. Previously untreated patients were included if found to have a mean sitting systolic blood pressure between 160 and 210 mm Hg (inclusive) and a diastolic blood pressure less than 115 mm Hg or a mean sitting diastolic blood pressure between 95 and 115 mm Hg (inclusive) and a mean systolic blood pressure up to 210 mm Hg. There were no upper or lower blood pressure limits for patients already undergoing antihypertensive treatment. There was no difference between the 2 drug regimens in the primary composite end point of cardiac morbidity and mortality.20,21 The design and results of the trial have previously been presented in detail elsewhere.20-23

Table 1. Baseline characteristics in patients with previous stroke or transient ischemic attack Baseline characteristics

N 5 3014

Age, y Female Caucasian Body mass index, kg/m2 Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Heart rate, beats per min Fasting glucose, mmol/L Total cholesterol, mmol/L Diabetes mellitus Smokers Left ventricular hypertrophy with strain History of atrial fibrillation Treatment with diuretics Treatment with beta blockers Randomized to treatment with valsartan

67.3 (8.3) 1157 (38.4) 2593 (86.0) 28.1 (5.0) 153.9 (19.3) 87.7 (11.3) 69.2 (13.3) 6.4 (2.3) 5.6 (1.1) 657 (21.8) 572 (19.0) 535 (17.6) 107 (3.6) 1135 (37.7) 815 (27.2) 1513 (50.2)

Data presented are n (%) unless otherwise specified.

We selected patients with a history of stroke or TIA. Stroke or TIA had to be verified by a persistent hemiparesis, computer tomography, cerebral angiography, Doppler ultrasound, positron emission tomography scan, or had to be documented in hospital records.22,24 All events of stroke or TIA reported during the course of the trial were reviewed by an independent end point committee blinded to treatment allocation. Adjudication was done according to the protocol criteria where stroke was defined according to the World Health Organization definition.25 Heart rate was assessed from electrocardiogram (ECG) recordings obtained at baseline. Echocardiography was not a part of the trial protocol, and left ventricular hypertrophy was calculated using traditional and validated ECG measures, either with the Cornell product26,27 or the Sokolow– Lyon criteria or the Sokolow–Lyon criteria with strain.28 The ECG recordings were managed by an independent clinical research organization (Premier Research Worldwide, Peterborough, Cambridgeshire, United Kingdom) and were analyzed at 1 of 2 central reading centers.12 Both univariable and multivariable Cox proportional hazard models were used to identify baseline demographic factors, baseline laboratory variables, and previous antihypertensive medication significantly predicting recurrent stroke. Both linear and quadratic terms of continuous variables were entered into the models to investigate the possibility of a curved relationship between the predictor variable and recurrent stroke. A P value less than or equal to .05 was used to signify statistical significance, using 2-sided testing. Statistical analyses were done with SAS, version 8.2 (SAS Institute, Cary, NC).

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Table 2. Predictors of recurrent stroke Univariable

Multivariable

Predictors

HR

95% CI

P value

HR

95% CI

P value

Age at screening (per 10 y) Age at screening (per 10 y)2 Female gender Race (Caucasian vs. non-Caucasian) BMI per 10 kg/m2 (BMI per 10 kg/m2)2 SBP per 10 mm Hg (SBP per 10 mm Hg)2 DPB per 10 mm Hg (DPB per 10 mm Hg)2 Heart rate per 10 bpm (Heart rate per 10 bpm)2 Fasting glucose (mmol/L) Fasting glucose (mmol/L)2 Total cholesterol (mmol/L) Total cholesterol (mmol/L)2 Diabetes before randomization Smoker LVH (with or without strain) Atrial fibrillation Treatment with diuretics Treatment with beta blockers Valsartan treatment

1.16 1.01 .94 1.14 .80 1.00 1.06 1.00 1.03 1.00 1.12 1.01 1.01 1.00 1.08 1.01 1.37 1.23 1.25 1.14 1.02 .85 .91

1.00-1.35 1.00-1.02 .73-1.23 .78-1.67 .61-1.05 1.00-1.00 .99-1.13 1.00-1.00 .92-1.15 1.00-1.01 1.03-1.23 1.00-1.01 .96-1.07 1.00-1.00 .97-1.21 1.00-1.02 1.03-1.82 .91-1.67 .92-1.71 .58-2.21 .79-1.33 .63-1.14 .70-1.17

.06 .04 .66 .50 .11 .13 .07 .07 .65 .65 .01 .03 .72 .91 .16 .18 .03 .18 .15 .71 .85 .27 .45

.20 1.14 .80 1.14 .88 1.00 .72 1.01 1.40 .98 2.78 .94 1.04 1.00 1.21 .99 1.47 1.26 1.24 .96 1.05 .98 .92

.03-1.33 .99-1.31 .60-1.05 .77-1.71 .18-4.22 1.00-1.00 .33-1.58 .99-1.04 .37-5.33 .91-1.06 1.18-6.58 .89-1.00 .79-1.37 .98-1.01 .54-2.72 .93-1.06 1.03-2.10 .91-1.75 .90-1.71 .48-1.92 .81-1.37 .72-1.33 .72-1.19

.10 .07 .11 .51 .87 .95 .41 .35 .62 .61 .02 .04 .80 .63 .64 .81 .03 .16 .19 .91 .71 .90 .54

Abbreviations: BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; HR, hazard ratio; LVH, left ventricular hypertrophy; SBP, systolic blood pressure.

Results Of the 15,245 patients included in the VALUE trial, 3014 patients (18.8%) had a history of stroke or TIA at baseline. Of these, 239 patients (7.9%) suffered a recurrent stroke during a median follow-up time of 4.5 years (interquartile range, 4.0-4.9 years). Baseline characteristics of the patients with previous stroke/TIA are presented in Table 1. The mean age was 67.3 (68.3) years, 38.4% were female, and most of the patients were Caucasian. The past medical history was as expected in a population with previous stroke or TIA, apart from atrial fibrillation, which was only present in 3.6% of the patients. Information on concomitant use of medication was collected throughout the trial. At baseline, 55.5% were taking aspirin, which increased to 73% during follow-up in the entire VALUE trial population. In the subgroup with stroke (n 5 3014), over 90% took aspirin, both at baseline and during follow-up. Serum creatinine was measured yearly in all participants. At baseline, mean creatinine was around 101 6 24 mmol/L in both the groups. During follow-up, mean creatinine rose to 108 6 45 mmol/L in the valsartan arm and to 103 6 48 mmol/L in the amlodipine arm, and, overall, only about 3% of the patients had values above the upper reference limit.

The results of the univariable and multivariable analyses are listed in Table 2. Diabetes mellitus and heart rate at baseline were significantly associated with an increased risk of recurrent stroke in both the univariable and multivariable analyses. In the univariable model, the associations between risk of recurrence and both age and systolic blood pressure were nearly significant, with P values of .06 and .07, respectively; however, this was not seen in the multivariable analysis. There was no association between atrial fibrillation or with beta blocker treatment and recurrent stroke. For heart rate the linear and quadratic terms were significant in both models, suggesting a curved relationship between heart rate and stroke (hazard ratio [HR], 2.78; 95% confidence interval, 1.18-6.58 and HR, .94; 95% confidence interval, .89-.99, respectively). Despite the fact that the HR for the quadratic term for heart rate was less than 1, there was a clear difference between the 2 highest and the 2 lowest heart rate quartiles, with a significantly increased risk of stroke in the higher 2 quartiles, as shown in Figure 1.

Discussion In patients with hypertension and previous stroke/ TIA, heart rate and diabetes mellitus were the strongest

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Figure 1. Baseline resting heart presented in quartiles and the risk of recurrent stroke. Abbreviation: bpm, beats per minute.

predictors of stroke, independent of blood pressure and other known risk factors. High resting heart rate has been associated with cardiovascular events and death in different populations,12–15,29,30 and in a previous analysis of the entire VALUE trial population, patients with the highest resting heart rate also had the highest risk of the composite primary end point, stroke, and death.12 Similarly, a post hoc analysis of the Prevention Regimen for Effectively Avoiding Second Stroke (PRoFESS) trial identified elevated heart rate as an independent predictor of death, whereas lower heart rate was associated with less cognitive decline and better functional outcome following stroke; yet an association between baseline resting heart rate and stroke recurrence was not seen.17 This difference can be difficult to explain, but differences between patient populations (stroke subtypes and time since first stroke) and treatments may contribute. Furthermore, PRoFESS did not adjust for trial treatment, and heart rate was analyzed as a categorical variable, whereas in our analysis, we used heart rate as a continuous variable, which may also have contributed a different result. Diabetes mellitus has also previously been identified as a predictor of recurrent stroke in several patient cohorts1,9,10,31 and the increased risk of stroke seems to be independent of blood glucose levels at the time of stroke.32 Other well-known predictors from the primary prevention setting, such as high blood pressure, high cholesterol levels and atrial fibrillation, were not identified in our analyses. An explanation for this could be that due the limited number of patients we only had a chance to identify very strong associations in our data. The VALUE trial population is a cardiovascular highrisk population, and this is the most likely explanation for the relatively high heart rate. The patients were randomized to either amlodipine or valsartan, with hydrochlorothiazide added in both arms, medications not known to alter heart rate. The use of beta blockers at baseline was rather limited and has been adjusted for in the analysis. The relationship between resting heart rate and recurrent stroke may be a marker of underlying

and undetected cardiovascular disease. Alternatively, it can represent increased sympathetic activity and/or adverse parasympathetic withdrawal, subclinical left ventricular dysfunction, or hypertension.33 In hypertensive patients, serum creatinine is also a potent predictor of cardiovascular death.34,35 A previous analysis of the entire VALUE trial population found no relationship between serum creatinine and glomerular filtration rate and the risk of stroke.36 It is, therefore, unlikely that renal dysfunction had any influence on our findings. In patients with chronic heart failure, lowering of heart rate with the selective I(f)-channel inhibitor ivabradine has been shown to reduce the risk of cardiovascular events,16 and in experimental studies, the same treatment reduced cerebral infarct size.17,18 In our study, treatment with beta blockers at enrollment was associated with a numerical, but statistically nonsignificant reduction of the risk of stroke (Table 2), but there are many alternative explanations for this finding, and our study cannot answer whether interventions to lower heart rate will reduce the risk of recurrent stroke. Our analysis has some limitations. First, patients with different heart rates are likely to be different in many respects, and although we have used appropriate statistical methods, we may not have been able to adjust for all confounding variables. Second, there is a possibility that our finding is a result of chance, because of the high number of predictor variables in the multivariable model. Finally, because of the crude nature of our data, we were not able to provide more detailed information about the risk of recurrent stroke. For example, the exact time and type of the previous stroke/TIA was not known, which means that we are not able to tell whether the associations that we have found are limited to a specific time after stroke or to specific types of stroke. The strengths of the study include the accurate and consistent measurement of heart rate, and the centralized, blinded adjudication of all end points by an independent end point committee, using strict protocol criteria for the diagnosis of stroke. We conclude that in a hypertensive patient population with previous stroke or TIA, resting heart rate was associated with recurrent stroke. Interventions to lower heart rate have been shown to reduce the risk of cardiovascular events,16 and this analysis of the VALUE trial, together with the analysis of the PRoFESS trial,17 suggests that a randomized controlled trial of heart rate control in stroke survivors may be warranted.

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Heart rate as a predictor of stroke in high-risk, hypertensive patients with previous stroke or transient ischemic attack.

Risk factors for first stroke are well established, but less is known about risk factors for recurrent stroke. In the present analysis, we aimed to as...
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