Prevalence and covariates of uncontrolled hypertension in ischemic stroke survivors: the Norwegian stroke in the young study

Abstract

Purpose: Hypertension is the most important modifiable risk factor for stroke. Few data are available on control of hypertension in younger ischemic stroke survivors.

Material and methods: We assessed clinic and ambulatory blood pressure (BP) measurements in 320 patients aged 15–60 years (mean 48 ± 10) included in the Norwegian Stroke in the Young Study during 3-months follow-up after the index stroke. Controlled hypertension was defined as ambulatory BP <130/80 mmHg. Carotid-femoral pulse wave velocity (PWV) was measured by applanation tonometry. Carotid plaque was considered present if focal intima-media thickness >1.5 mm.

Results: At hospital discharge, 58% of the patients were treated for hypertension. Another 9% of the total study population was diagnosed with new-onset hypertension during follow-up. At the 3-months follow-up visit, 56% of patients with treated hypertension were uncontrolled. Patients with uncontrolled treated hypertension were older, had higher body mass index (BMI) and PWV, and were more likely to have diabetes and carotid plaques compared to patients with normotension (p < .01). Compared to controlled treated hypertension, patients with uncontrolled treated hypertension had higher prevalence of carotid plaque (p < .01). In a multivariate logistic regression, uncontrolled treated hypertension was associated with higher PWV and BMI, and presence of carotid plaque, independent of the more intensified use of antihypertensive treatment (all p < .05).

Conclusion: Uncontrolled hypertension was highly prevalent in ischemic stroke survivors <60 years and associated with co-presence of obesity and functional and structural arterial damage. Our results highlight the unmet potential and challenge of optimization of hypertension diagnosis and management in order to prevent recurrent vascular events in ischemic stroke survivors.

Keywords:

• Ischemic stroke
• uncontrolled hypertension
• pulse wave velocity
• arterial damage
• carotid intima-media thickness

Introduction

Ischemic stroke is one of the most frequent causes of death and disability worldwide [1], and hypertension is highly prevalent in ischemic stroke patients [2]. Young stroke survivors have a high risk of recurrent stroke and other cardiovascular events which lead to higher mortality, greater disability and increased healthcare costs in this patient group [3]. Therefore, recognition and control of underlying cardiovascular risk factors, most importantly hypertension, is a main tool for improving prognosis in ischemic stroke survivors [4]. Since both diagnosis and management of hypertension at the time of acute ischemic stroke may be difficult as blood pressure (BP) tend to be labile following acute stroke [2,5], a systematic follow-up of BP after discharge is essential. The current study explored the prevalence and covariates of uncontrolled treated hypertension 3 months after the incident ischemic stroke among patients <60 years of age enrolled in the Norwegian Stroke in the Young Study (NOR-SYS).

Materials and methods

Study population and design

NOR-SYS is a prospective research program conducted at the Department of Neurology, Haukeland University Hospital, Bergen, Norway [6]. The rationale, study design, inclusion and exclusion criteria of NOR-SYS have previously been published in details [6]. In brief, between September 2010 and August 2015, 385 patients aged 15–60 years (mean 48 ± 10) with a documented acute ischemic stroke were recruited. The acute ischemic stroke was primarily verified by cerebral magnetic resonance imaging, but 1.5% was verified by cerebral computed tomography alone. Among these, 320 patients (83%) with technically adequate ambulatory BP recording and carotid-femoral pulse wave velocity (PWV) measurement performed during out-patient visits were included in the present analysis (Figure 1). Serious sequelae after the ischemic stroke, death and repeated failure to attend the out-patient visits were the main reasons for drop-out during follow-up, leading to missing PWV and ambulatory BP monitoring in 65 patients. Ischemic stroke subtypes were classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria into large artery atherosclerosis, cardioembolic infarct, small-vessel occlusion, stroke of other determined etiology, or stroke of undetermined etiology [7]. The study was approved by the Regional Committee for Medical Research Ethics of Western Norway, and conducted in accordance with the Declaration of Helsinki. All patients or their legal representatives signed a written informed consent.

Figure 1. Flow chart of the prevalence of hypertension and BP control in the study population.

Clinic and ambulatory blood pressure measurements

Brachial BP was measured in triplicate after 5 min of rest in the sitting position with 1-min intervals by the same investigator using regularly calibrated aneroid sphygmomanometers and small, medium or large cuff-size, as appropriate in the individual patient [8]. The average of the last two measurements was taken as the clinic BP. Clinic BP measurements and aortic stiffness measurements were performed on the same day one month after the index stroke.

Twenty-four hours ambulatory BP measurements were performed with a validated device (Diasys Integra II device, Novacor, Cedex, France) 3 months after the index stroke to avoid any influence of the recent stroke on the circadian BP rhythm [5,9]. The cuff was mounted on the arm not affected by the stroke, and the patients were instructed to relax their arms when inflations were initiated. The device was preset to automatically measure BP and heart rate at 30-min intervals during night-time (between 11:00 p.m. and 07:00 a.m.) and 15-min intervals during daytime for a period of 24-hours, giving a total of about 78 measurements over the 24-hour period. If <70% of the BP recordings were valid, the ambulatory BP recording was repeated.

Hypertension was considered present if any of the following was found in the individual patient: history of hypertension, use of antihypertensive treatment, persistently elevated BP during the hospitalization, or elevated ambulatory BP at the 3-months follow-up. Patients were divided in four groups: normotension, untreated hypertension, treated controlled hypertension and treated uncontrolled hypertension (Figure 1). Uncontrolled treated hypertension was considered present if 24-hours ambulatory BP ≥130/80 mmHg at the 3-months follow-up visit in treated hypertensive patients.

Assessment of arterial damage

Pulse wave velocity

Central arterial stiffness was derived from carotid-femoral PWV, measured by the same investigator with a SphygmoCor^® device (AtCor Medical, Sydney, West Ryde, Australia) in accordance with the guidelines [10]. Pressure pulse waveforms were obtained with a tonometer from the right common carotid artery and right femoral artery sites, as previously described [11]. PWV was calculated as the distance in meters between the carotid and femoral recording sites, divided by transit time in seconds, and adjusted for mean BP [11]. High for age PWV was defined as PWV higher than age-adjusted normal range, identified by the reference normogram based upon the Anglo-Cardiff collaborative trial [12]. PWV ≥10 m/sec was considered as a marker of target arterial damage [8].

Carotid ultrasound

Carotid intima media thickness (IMT) was measured by ultrasound with a 9-3 mHz multi-linear array transducer Philips (iU22^®; Philips Medical System, Bothell, WA, USA) during the hospital stay, as previously described [6]. Mean carotid IMT was measured at the far wall of the common carotid artery at four pre-defined angles on each side of the neck. Image analysis was performed at a work station, using Philips QLAB^® (Philips Medical Systems, Bothell, WA, USA). Increased carotid IMT was considered present if mean carotid IMT >0.90 mm [8]. Carotid artery plaque was defined as a focal maximum IMT >1.5 mm [13].

Metabolic risk factors

A standardized questionnaire was used to record self-reported information on cardiovascular risk factors and any use of drug therapy. The information was quality assured against hospital medical record information. BMI was calculated from body weight in kilograms divided by height in meters squared, and obesity was considered present if BMI ≥30 kg/m². Venous blood samples were drawn for analysis of fasting serum lipids and glucose. Hypercholesterolemia was defined as presence of total serum cholesterol >5 mmol/l and/or low-density lipoprotein (LDL) cholesterol >3 mmol/l [14]. Low high-density lipoprotein (HDL) cholesterol was defined as <1 mmol/l in men and <1.3 mmol/l in women [14]. Diabetes mellitus was considered present in patients with history of diabetes, use of anti-diabetic treatment, or fasting blood glucose ≥7 mmol/l [15]. Metabolic syndrome was defined according to modified American Heart Association/National Heart, Lung, and Blood Institute criteria [16].

Statistics

The IBM SPSS statistical program version 23 (IBM, Armonk, New York, USA) was used for statistical analyses. Data are presented as mean ± standard deviation for continuous variables and as percentages for categorical variables. Comparison between groups were done by analysis of variance with Scheffe’s post hoc test for continuous variables and a general linear model with Sidak’s post hoc test for categorical variables. Covariates of uncontrolled treated hypertension were identified in logistic regression models, reported as odds ratio (OR) and 95% confidence interval (CI). Covariates of uncontrolled treated hypertension were identified in univariable binary logistic regression models, reported as odds ratio (OR) and 95% confidence interval (CI). Significant covariates of uncontrolled treated hypertension in univariate analyses were included in the multivariate logistic regression model, using an enter method. Statistical significance was considered present if p value <.05 in all analyses.

Results

Prevalence of hypertension

The overall prevalence of hypertension in the NOR-SYS population was 67%. In the total study population, 37% had a history of hypertension before the index stroke, and another 30% had hypertension diagnosed after inclusion in the NOR-SYS research program (Figure 1). Among patients with newly detected hypertension, 70% were diagnosed due to persistently elevated BP during hospitalization and 30% from elevated clinic and/or ambulatory BP during follow-up (Figure 1). All patients with previously known or newly detected hypertension during the hospitalization (systolic BP persistently >160 mmHg) for the index stroke were discharged with antihypertensive treatment [8]. The antihypertensive treatment included angiotensin receptor blockers in 75%, β-blockers in 23%, calcium antagonists in 23%, diuretics in 39% and angiotensin-converting enzyme inhibitors in 7%. Patients diagnosed with hypertension during these out-patient visits were prescribed antihypertensive medication and are not included in the current assessment of controlled treated hypertension.

The prevalence of hypertension differed significantly between stroke subtypes based upon the TOAST classification (p < .01) (Figure 2). Also, the prevalence of uncontrolled hypertension was higher in patients with older-onset stroke causes including 50% in large artery atherosclerosis and 60% in small-vessel occlusion, though these numbers were not matched for age (Figure 2).

Figure 2. The prevalence of hypertension and uncontrolled treated hypertension in ischemic stroke subtypes. *p < .01 vs cardioembolic infarct, †p < .01 vs stroke of other determined etiology. Dark columns show the prevalence of hypertension in ischemic stroke subtypes, and grey columns demonstrate the prevalence of uncontrolled hypertension in ischemic stroke subtypes.

Uncontrolled treated hypertension

Among patients discharged with antihypertensive treatment (n = 186), uncontrolled hypertension was found in 56% (n = 104) at the 3-month visit. In the total study population, patients with uncontrolled BP were characterized by older age and higher prevalence of obesity, diabetes and metabolic syndrome (p < .01) (Table 1). They also had higher PWV, carotid IMT and a higher prevalence of carotid plaque (all p < .01) (Table 2). Compared to the controlled treated hypertensive group, uncontrolled treated hypertensive patients had on average 17 mmHg higher systolic and 13 mmHg higher diastolic BP (Table 2). Uncontrolled treated hypertensive patients also had significantly higher prevalence of carotid plaque (p < .01) (Table 2).

Table 1. Baseline characteristics of study population according to blood pressure control.

	NT (n = 105)	Controlled treated HT (n = 82)	Uncontrolled treated HT (n = 104)	Untreated HT (n = 29)	ANOVA p value
Age (year)	44.5 ± 11.5	51.5 ± 9.0*	52.3 ± 6.8*	51.6 ± 8.4*	<.001
Male (%)	56	71	74	70	.027
Weight (kg)	75.5 ± 12.6	86.5 ± 13.5*	90.5 ± 19.2*	85.6 ± 14.6*	<.001
Waist circumference (cm)	87.6 ± 11.5	99.2 ± 11.3*	100.6 ± 14.8*	98.9 ± 11.5*	<.001
Body mass index (kg/m^2)	24.8 ± 3.1	27.8 ± 4.4*	29.3 ± 5.6*	27.6 ± 3.5**	<.001
Current or exsmokers (%)	48	54	51	57	.777
Obesity (%)	8	29*	44*	29	<.001
Diabetes (%)	4	15	21*	16	.003
Metabolic syndrome (%)	12	44*	47*	42*	<.001
Atrial fibrillation (%)	4	7	10	4	.112
Hypercholesterolemia (%)	61	66	54	63	.301
Total cholesterol (mmol/l)	5.3 ± 1.1	5.6 ± 1.3	5.2 ± 1.3	5.5 ± 1.2	.247
LDL cholesterol (mmol/l)	3.5 ± 1.0	3.8 ± 1.1	3.4 ± 1.2	3.7 ± 1.1	.161
HDL cholesterol (mmol/l)	1.6 ± 0.6	1.3 ± 0.4*	1.3 ± 0.4*	1.3 ± 0.6**	<.001
Triglycerides (mmol/l)	1.3 ± 0.9	1.7 ± 0.8**	1.8 ± 1.0*	2.1 ± 1.5*	.001
Serum creatinine (µmol/l)	71.1 ± 14.0	74.4 ± 14.6	82.0 ± 51.7	74.9 ± 15.2	.091
Fasting blood glucose (mmol/l)	5.2 ± 0.7	6.0 ± 1.4**	6.1 ± 1.8*	6.3 ± 3.0*	<.001
HbA1c (%)	5.3 ± 0.4	5.9 ± 0.9**	6.1 ± 1.2*	6.0 ± 1.5	<.001
Antihypertensive treatment at admission (%)	0	40	51	0	<.001
Antihypertensive treatment at follow-up (%)	0	100	100	0	<.001
No of antihypertensive drugs	0	1.6 ± 0.8	1.8 ± 1.0	0	<.001

ANOVA: analysis of variance; HbA_1c: hemoglobin A_1c; HT: hypertension; NT: normotension.

* p < .01.

** p < .05 versus NT.

Table 2. Ambulatory blood pressure (BP) measurements and arterial hemodynamics of the total study population according to BP control.

	NT (n = 105)	Controlled treated HT (n = 82)	Uncontrolled treated HT (n = 104)	Untreated HT (n = 29)	ANOVA p value
Clinic systolic BP (mmHg)	122 ± 13	137 ± 16*	143 ± 17*	130 ± 12	<.001
Clinic diastolic BP (mmHg)	76 ± 7	82 ± 9*	88 ± 9*†	82 ± 6**†	<.001
Clinic heart rate (bpm)	67 ± 10	72 ± 9**	73 ± 11*	70 ± 10	<.01
24 h systolic BP (mmHg)	110 ± 8	115 ± 8**	132 ± 13*†	126 ± 9*†‡	<.001
24 h diastolic BP (mmHg)	72 ± 5	74 ± 4	87 ± 8*†	83 ± 4*†‡	<.001
24h mean BP (mmHg)	85 ± 5	87 ± 5	102 ± 9*†	97 ± 4*†‡	<.001
Daytime systolic BP (mmHg)	113 ± 8	117 ± 9	135 ± 13*†	130 ± 10*†	<.001
Daytime diastolic BP (mmHg)	75 ± 5	75 ± 5	88 ± 8*†	86 ± 4*†	<.001
Night-time systolic BP (mmHg)	97 ± 9	105 ± 10*	122 ± 16*†	112 ± 10*†‡	<.001
Night-time diastolic BP (mmHg)	65 ± 5	68 ± 7**	79 ± 9*†	74 ± 6*†‡	<.001
Mean carotid IMT (mm)	0.7 ± 0.6	0.8 ± 0.2	0.9 ± 0.3**	0.9 ± 0.8	.016
Carotid plaque (%)	3	5	18*†	13	<.001
PWV (m/s)	6.8 ± 1.3	8.1 ± 1.7*	8.6 ± 2.1*	7.8 ± 1.8	<.001
High for age PWV (%)	3	16	27*	17	<.001
Any target arterial damage (%)	13	46*	60*	43**	<.001

ANOVA: analysis of variance; BP: blood pressure; HT: hypertension; IMT: intima media thickness; NT: normotension; PWV: pulse wave velocity.

* p < .01.

** p < .05 versus NT.

† p < .01 versus controlled HT.

‡ p < .01 versus uncontrolled.

The average number of antihypertensive drugs used was significantly higher among uncontrolled compared to controlled treated hypertensive groups (Table 1). Only 9.3% of treated hypertensive patients were using ≥3 antihypertensive drugs.

In univariate logistic regression analyses, uncontrolled hypertension was associated with higher age, BMI, PWV, triglycerides, glycosylated hemoglobin, higher number of anti-hypertensive drugs, lower serum HDL cholesterol, and with the presence of obesity, carotid plaque, metabolic syndrome and diabetes mellitus (all p < .05) (Table 3). In a multivariate logistic regression analysis, uncontrolled treated hypertension was associated with the presence of carotid artery plaque, higher PWV, and higher BMI independent of more intensified use of antihypertensive treatment (all p < .05) (Table 3).

Table 3. Covariables of uncontrolled treated hypertension in the total study population. Uni- and multivariable logistic regression analyses.

	Univariable		Multivariable
	OR (95% CI)	p-value	OR (95% CI)	p-value
Age >45 years	2.22 (1.27–3.89)	<.01	1.26 (0.64–2.51)	NS
Male gender	0.63 (0.39–1.03)	.064
Body mass index (kg/m^2)	1.14 (1.08–1.20)	<.001	1.09 (1.03–1.15)	<.01
Obesity	2.65 (1.59–4.4)	<.001
Pulse wave velocity (m/s)	1.39 (1.21–1.159)	<.001	1.20 (1.02–1.40)	<.05
Carotid artery plaque	5.00 (2.06–12.15)	<.001	3.70 (1.44–9.52)	<.01
Metabolic syndrome	2.06 (1.25–3.42)	<.01
Diabetes	2.34 (1.21–4.53)	<.05
Number of antihypertensive drugs	1.83 (1.46–2.30)	<.001	1.50 (1.16–1.92)	<.01
HDL cholesterol (mg/dl)	0.51 (0.31–0.84)	<.01
Triglycerides (mg/dl)	1.45 (1.14–1.86)	<.01
Fasting blood glucose (mg/dl)	1.26 (1.07–1.49)	<.01
HbA1c (%)	1.47 (1.08–2.01)	<.05

OR: odds ratio; CI: confidence interval; PWV: pulse wave velocity; HbA_1c: glycosylated hemoglobin.

Uncontrolled treated hypertension was numerically more common among patients with small-vessel occlusion stroke subtype (Figure 2). However, a significant difference in prevalence of uncontrolled treated hypertension was only found between the small-vessel occlusion and cardioembolic stroke (p < .05) (Figure 2).

Discussion

The data on uncontrolled hypertension among young and middle-aged stroke patients are limited, despite hypertension being the main modifiable stroke risk factor [4,17–19]. The key findings of our study are that uncontrolled treated hypertension was highly prevalent, and associated with presence of obesity and established arterial damage independent of more intensified use of antihypertensive drug treatment.

The overall prevalence of hypertension in NOR-SYS was high compared to other studies of stroke patients with comparable age [4,18], but low compared to reports from studies in older ischemic stroke survivors [19,20]. While previous studies on BP control in ischemic stroke survivors have mostly been based upon clinic BP [19,20], the present study used combined clinic and ambulatory BP for optimal assessment of BP control. Ambulatory BP is also closer associated with hypertensive organ damage and a stronger predictor of CV morbidity and mortality than clinic BP [21]. Cífkova et al. demonstrated in 424 older ischemic stroke survivors that hypertension was the most prevalent risk factor, found in 91.5%, with nearly 50% having uncontrolled BP [19]. In another post hoc study of 3680 ischemic stroke survivors, the consistency of BP control using clinic BP measurements over a period of 2 years was assessed [22]. Less than one-third of patients achieved BP control ≥75% of the time [22]. Also, in 495 stroke survivors followed within the National Health and Nutrition Examination Survey from 1999 to 2004, the prevalence of hypertension was high, 75%, and 55.3% had uncontrolled hypertension, mostly due to uncontrolled systolic BP [23]. As demonstrated in the present study, 2/3 of patients with new-onset hypertension detected during follow-up were identified by ambulatory BP, pointing to the value of systematic use of ambulatory BP for optimization of secondary prophylaxis in ischemic stroke survivors. It is well known that achieving appropriate BP control is important for reducing the risk of recurrent vascular events in ischemic stroke survivors [2,8]. However, the optimal BP target in secondary prevention in ischemic stroke patients is still debated [2]. Although patients with uncontrolled treated hypertension in the present study used a higher number of antihypertensive drugs compared to the controlled patients, the average number of drugs was <2 in both groups, and less than 10% used 3 antihypertensive drugs or more. This highlights the potential of more systematic antihypertensive treatment in hypertensive ischemic stroke survivors, to reduce the high risk of recurrent vascular events [24].

The prevalence of hypertension in the present study was particularly high in small-vessel occlusion stroke subtype, found in 88% of the patients. The close association of hypertension with small-vessel disease, also characterized by lacunar infarcts, is well known [25]. As demonstrated, the proportion of BP control in this stroke subtype was also significantly lower compared to patients with other TOAST stroke subtypes.

Increased arterial stiffness is a predictor of cardiovascular morbidity and mortality in hypertensive patients [26]. We have previously shown that high for age arterial stiffness was common in the NOR-SYS population, and particularly associated with the presence of hypertension as well as a non-dipping BP pattern [11,27]. The present analysis adds to this by demonstrating that hypertensive arterial damage like higher arterial stiffness or carotid plaque was particularly associated with presence of uncontrolled treated hypertension. Of note, presence of carotid plaque was recommended as a better predictive marker of subclinical atherosclerosis than carotid IMT in current American College of Cardiology/American Heart Association recommendations for cardiovascular disease prevention [28].

Obesity is a major risk factor for preclinical and clinical cardiovascular disease, and often coexists with hypertension and diabetes [29]. Obesity is also a strong determinant of higher left ventricular (LV) mass [30], and reduces the cardiovascular benefit of antihypertensive treatment [31]. More recently, in the Campania Salute Network registry, it was demonstrated that, in treated hypertension, obesity had stronger association with presence of LV hypertrophy than of carotid atherosclerosis [32]. Still, in the present study, obesity was identified as an independent predictor of uncontrolled treated hypertension, in consistence with previous reports confirming obesity as a main cause of treatment-resistant hypertension and lack of LV hypertrophy regression [33].

A limitation of our study is that any causal relationship between the arterial stiff indices and uncontrolled hypertension could not be determined due to the cross-sectional study design.

In conclusion, our results suggest that in the real-life setting reflected in the prospective NOR-SYS registry, uncontrolled treated hypertension was highly prevalent in ischemic stroke survivors <60 years of age, and particularly associated with obesity and presence of functional and structural markers of arterial damage. The results also demonstrate the unmet potential of optimization of hypertension diagnosis and management and weight reduction to prevent recurrent cardiovascular events even in younger ischemic stroke survivors.

Acknowledgements

The authors thank the West-Norwegian Regional Health Authority for the financial support, and Simon Fougner Hartmanns Family Fund, Oslo, Norway, for donating the SphygmoCor device. We further thank Kristin Modalsli Sand M.D., Marina V. Kokorina M.D., and study nurses Liv Himle R.N., Linn Elin Rødal R.N. and Toril Synnøve Bjørgo R.N. for technical assistance with data collection, registration and patient management. Last, but not least we thank the participants of the NOR-SYS study for their important contributions.

Disclosure statement

The authors report no conflicts of interest.

This study is registered at ClinicalTrials.gov (NCT01597453)