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Evaluation of the Differences in the Effects of Antihypertensive Drugs on Blood Pressure Variability by 24-Hour Ambulatory Blood Pressure Monitoring in Chronic Cerebrovascular Disease
Evaluation of the Differences in the Effects of Antihypertensive Drugs on Blood Pressure Variability by 24-Hour Ambulatory Blood Pressure Monitoring in Chronic Cerebrovascular Disease Ryoji Nishioka, MD,*† Shunsuke Kinoshita, MD,* Michio Shiibashi, PhD,‡ Tomokazu Shimazu, MD,* Yoshihiko Nakazato, MD,* Toshimasa Yamamoto, MD,* Naotoshi Tamura, MD,* and Nobuo Araki, MD, PhD*
Background: It has been suggested that antihypertensive drug therapy is attributable to the lower blood pressure variability, we investigated the effects of 4 classes of antihypertensives on the blood pressure variability; in addition, we also compared the effects among 4 calcium channel blockers. Methods: We measured the 24-hour blood pressure variability in 309 patients with a history of cerebrovascular disease treated with angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, b blocker, or calcium channel blocker. Results: The daytime blood pressure variability treated with b blockers (14.3 6 3.1) was higher than that treated with an angiotensin receptor blockers (11.5 6 3.1) or calcium channel blockers (12.6 6 3.4) in patients with cerebrovascular disease (P , .05). In the analysis of the patient distribution of blood pressure variability, patients receiving b blockers occurred more frequently in the higher blood pressure variability (P 5.0023). Treatment with angiotensin receptor blockers and cilnidipine, which blocks N-type calcium channels, was shown to be more frequently associated with the lower blood pressure variability (P 5 .0202 and .0467). The mean blood pressure of patients grouped by distribution of blood pressure variability was found to be independent to blood pressure variability, for any of the antihypertensive drugs or calcium channel blockers examined. Conclusions: From the results, it is suggested that angiotensin receptor blocker and calcium channel blockers rather than b blockers may be more favorable for blood pressure management in patients with cerebrovascular disease. Among the calcium channel blockers, cilnidipine may be more favorable than other calcium channel blockers. Key Words: Hypertension—b-blocker—blood pressure variability— cerebrovascular disease(CVD)—cilnidipine—antihypertensive drugs. Ó 2015 by National Stroke Association
The risk of cardiovascular events in hypertension is correlated with the systolic and diastolic blood pressure (BP) levels, and major guidelines in the world for hypertension have presented targeted BP levels for antihyper-
tensive treatment taking into consideration with other cardiovascular risks.1,2 On the other hand, BP variability has been suggested to be an independent risk factor for cardiovascular diseases.
From the *Department of Neurology, School of Medicine, Faculty of Medicine, Saitama Medical University, Saitama; †School of Physical Therapy, Faculty of Health and Medical Care, Saitama Medical University, Saitama; and ‡Information Technology Center, Faculty of Medicine, Saitama Medical University, Saitama, Japan. Received February 28, 2015; revision received April 15, 2015; accepted April 16, 2015. R.N. and S.K. are equal first authors.
No potential conflicts of interest are disclosed. Address correspondence to Nobuo Araki, MD, PhD, Neurology, School of Medicine, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.023
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-7
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R. NISHIOKA ET AL.
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In these reports, it has been suggested that a high variability of BP recorded by ambulatory BP monitoring (ABPM) may be associated with a relatively higher cardiovascular risk,3 cardiac hypertrophy,4 and leukoaraiosis.5 In addition to ABPM, analyses of data obtained by long-term home BP6 and long-term office BP measurement7 have also suggested the elevated cardiovascular risk associated with high variability of BP. Many randomized controlled trials and meta-analyses have shown the efficacy of antihypertensive drugs for the prevention of stroke; however, it has been pointed out that there are differences in the effect on BP variability among the drug classes.8 In their study, it has been suggested that the reduced risk of stroke associated with calcium channel blocker (CCB) therapy is attributable not only to the antihypertensive efficacy but also to the lower BP variability of CCB. Among the antihypertensive drugs used, CCBs are often prescribed for antihypertensive treatment in CVD patients, and many kinds of CCB drugs are available for clinical use. CCBs have been subdivided according to their selectivity for Ca21 channel subtypes and possible differences in the efficacy in relation to specific complications of hypertension have been suggested.9 In this study, we measured the 24-hour BP variability in patients with a history of cerebrovascular disease (CVD), by ABPM and investigated the effects of 4 classes of antihypertensive drugs, CCBs, b-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs).
antihypertensive medication group; systolic BP of 140 mm Hg or more or diastolic BP of 90 mm Hg or more), ABPM was performed at least 3 months after the start of treatment. Of the CVD patients receiving CCBs, 39 patients received 5-10 mg of cilnidipine, 50 patients received 5-7.5 mg of amlodipine, 14 patients received 20-40 mg of nifedipine, and 50 patients received 20-40 mg of nicardipine. The data obtained from these patients were analyzed to compare the effects among the CCBs.
Data Analysis BP and PR were expressed as mean 6 standard deviation, and the coefficient of variation (CV: CV 5 100 3 standard deviation/mean) was calculated to determine the short-term variability of the BP and PR. Differences were analyzed using the Tukey–Kramer multiple comparison test. BP variability as the association of cardiovascular mortality was shown by quintile analysis in the previous study,3 so the subjects of all antihypertensive medications or CCBs medications were divided equally into 5 subgroups according to the distribution of the BP variability to analyze the BP variability characteristic of each antihypertensive medication. Trend analysis was conducted using simple linear regression by assigning an ordinal number (from 1 to 5) to each subgroups. P values smaller than .05 were considered significant.
Results Methods Patients and BP Measurement Of the outpatients who visited our department, a total of 309 patients, with a history of CVD and treated by one antihypertensive drug, were enrolled in this study. Informed consent was obtained from all patients before participation in this study. Data analysis was approved by Institutional Review Board of Saitama Medical University Hospital (No.14-063). The patients with CVD included in this study were those with chronic stroke, at least 1 month after the onset. The diagnosis of stroke was confirmed by magnetic resonance imaging or computed tomography using the criteria of stroke by the classification of CVDs III reported by National Institute of Neurological Disorders and Stroke.10 ABPM was performed using a portable automated BP/heart rate monitor (TM-2421, A&D, Tokyo). The potable monitor was programmed to record the BP and pulse rate (PR) every 15 minutes for 24 hours and attached to the patients. Individual data stored on the portable monitor were retrieved and analyzed using software (TM-2021). The mean measured values from ‘‘wake to sleep’’ (daytime) and ‘‘during sleep’’ (sleep time) were used as the measured values in each time zone. For the patients judged as needing antihypertensive treatment (morning
The patients’ background characteristics of the 4 study groups were similar (Table 1). The characteristics of the patients treated with 4 CCBs (cilnidipine, amlodipine, nifedipine, and nicardipine) were picked up from 169 CCB-treated patients (Table 2). As there were no heart disease patients only in nifedipine group, the ratio of hypercholesterolemia, heart disease, and cholesterol-lowering drugs were significantly different among the 4 groups by the chi-square statistic (P , .01, P , .01, P , .05; Table 2).
BP Variability in CVD Patients Administered Antihypertensive Drugs The all-day average systolic BP was higher in the ACEI group than in the ARB group. As for the BP variability, the all-day and daytime systolic BP variability was higher in the BB group than in the ARB group. In addition, the daytime systolic BP variability was also higher in the BB group than in the CCB group (Table 3). All patients administered antihypertensive drugs were grouped into quintiles according to the daytime systolic BP variability, and the frequency distributions by drug class are shown in Figure 1. Also, in this analysis, contrasting frequency distributions were obtained for patients under BB and ARB treatment, indicating that a
EVALUATION OF THE EFFECTS OF ANTIHYPERTENSIVE DRUGS ON BP VARIABILITY IN CHRONIC CVD
3
Table 1. Patients characteristics Enrolled all patients Characteristics
CCB
BB
ARB
ACEI
Number Age, y Male (%) Body weight (kg) BMI (kg/m2) Smoking (%) Hypercholesterolemia (%) Heart disease (%) Antiplatelet drugs (%) Cholesterol-lowering drugs (%)
169 66.9 6 9.5 73.4 59.8 6 10.1 24.0 6 3.0 27.8 30.9 27.2 86.1 26.6
53 65.5 6 10.0 69.8 54.5 6 11.1 23.0 6 2.4 30.2 27.8 22.2 94.4 20.7
52 69.1 6 10.7 67.3 60.9 6 12.1 23.8 6 3.0 28.8 26.9 34.6 51.9 11.5
35 68.8 6 9.5 65.7 57.2 6 11.8 23.5 6 4.0 11.4 52.9 41.2 77.3 31.4
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b blocker; BMI, body mass index; CCB, calcium channel blocker.
was significantly lower in the cilnidipine and amlodipine group as compared with that in the nifedipine group (Tukey–Kramer method). Patients administered CCBs were grouped into quintiles according to the daytime systolic BP variability, and frequency distributions of patients administered these 4 CCBs in each quintile are shown in Figure 2. A higher proportion of patients administered cilnidipine showed low BP variability (P 5 .0467), whereas no relationship were noted in the patients administered the other 3 CCBs.
larger proportion of patients showed high BP variability in the BB group (P 5 .0023) and larger proportion of patients showed low BP variability in the ARB group (P 5 .0202). On the other hand, no strong trends were found for the CCB and ACEI groups.
BP Variability in Patients Treated with CCBs The effects on the BP variability were compared among 4 drugs, amlodipine, nifedipine, and nicardipine, which are representative L-type CCBs used for BP management in CVD, and cilnidipine, which has inhibitory effects on both L-type and N-type Ca channels. The BP variability was the lowest in the group treated with cilnidipine in daytime (CV of daytime systolic BP; amlodipine 5 12.3 6 3.4, nifedipine 5 12.6 6 3.0, nicardipine 5 13.0 6 3.8, cilnidipine 5 12.0 6 3.0, CV of daytime diastolic BP; amlodipine 5 12.9 6 3.3, nifedipine 5 16.7 6 4.5, nicardipine 5 14.0 6 4.6, cilnidipine 5 12.4 6 1.7), and in particular, diastolic BP variability
Relationship between BP Variability and Mean BP CVD patients were grouped into quintiles according to the BP variability, and the relationship between the BP variability and the daytime mean systolic BP was investigated for each antihypertensive drug treatment group (Fig 3, A). No relationship between the BP variability and the mean BP was found for any drug class. Likewise, patients treated with CCBs were grouped into quintiles
Table 2. Patients characteristics (CCB) 4 CCBs treatments (patients picked up from Table 1) Characteristics
Cilnidipine
Amlodipine
Nifedipine
Nicardipine
Number Age, y Male (%) Body weight (kg) BMI (kg/m2) Smoking (%) Hypercholesterolemia (%), P , .01 Heart disease (%), P , .01 Antiplatelet drugs (%) Cholesterol-lowering drugs (%), P , .05
39 68.9 6 8.6 64.1 61.0 6 10.1 25.1 6 2.9 20.5 28.2 38.5 85.7 25.6
50 69.0 6 9.5 65.8 59.7 6 10.7 23.7 6 3.3 22.0 32.0 40.0 85.2 22.0
14 66.6 6 9.5 92.9 58.9 6 9.7 23.3 6 2.0 50.0 .0 .0 80.0 .0
50 63.9 6 8.8 88.0 60.6 6 8.6 24.0 6 2.9 22.0 78.0 10.0 92.3 36.0
Abbreviations: BMI, body mass index; CCB, calcium channel blocker.
R. NISHIOKA ET AL.
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Table 3. Blood pressure variability in CVD (all antihypertensives) Systolic BP
CV of systolic BP
Antihypertensive drug
All-day (mm Hg)
All-day
Daytime
Sleep time
ACEI ARB BB CCB
143.2 6 15.3* 134.3 6 16.4* 137.6 6 16.3 138.2 6 12.5 Diastolic BP All-day (mm Hg)
14.5 6 4.3 12.7 6 3.8* 15.0 6 3.8* 13.8 6 3.5
11.0 6 4.0 9.9 6 3.0 10.8 6 3.0 9.9 6 2.9
All-day
13.1 6 4.3 11.5 6 3.1* 14.3 6 3.1* 12.6 6 3.4* CV of diastolic BP Daytime
82.3 6 9.7 82.9 6 11.7 79.6 6 9.1 81.7 6 9.0
15.6 6 4.2 14.3 6 3.5 15.9 6 3.0 15.1 6 3.6
13.9 6 4.9 12.5 6 3.2 14.3 6 3.6 13.5 6 3.7
13.3 6 4.6 11.7 6 3.5 13.1 6 4.6 12.2 6 4.0
ACEI ARB BB CCB
Sleep time
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b blocker; BP, blood pressure; CCB, calcium channel blocker; CV, coefficient of variation; CVD, cerebrovascular disease. *P , .05 by Tukey–Kramer.
according to the BP variability; however, no relationship was found between the BP variability and the mean BP for any of the 4 CCBs (Fig 3, B).
Discussion In this study, we analyzed short-term (24-hour) BP variability of CVD patients using ABPM and demonstrated differences in the BP variability among antihypertensive drug classes. Of the antihypertensive drugs investigated, higher systolic BP variability in the daytime was observed in the BB group than in the CCB or ARB group. In addition, frequency analysis in quintiles of BP variability revealed higher proportions of patients receiving BBs in the higher quintiles. These results were consistent with the following reports: It was reported from the AngloScandinavian Cardiac Outcomes Trial - Blood Pressure
Lowering Arm (ASCOT-BPLA) study, based on a comparative analysis of BP variability measured by ABPM, that the BP variability was higher in the group treated with atenolol than in the group treated with amlodipine.8 Analysis of BP variability by office measurements in multiple outpatient visits also revealed that the variability was higher in the patients treated with atenolol than in the patients treated with amlodipine; this study also revealed that the BP variability was more strongly related to the risk of stroke than the systolic/diastolic BP levels. Therefore, because of the higher BP variability observed in the patients receiving BBs, it is suggested that it might be characteristic in BB class agents and that caution should be exercised in the administration of BBs in CVD patients requiring antihypertensive treatment. On the other hand, the results for the patients treated with ARBs obtained in this study were inconsistent with
Figure 1. Daytime systolic blood pressure (BP) variability histogram in cerebrovascular disease (CVD) patients treated with antihypertensive drugs. All coefficients of variation (CVs) of systolic BP were sequentially divided into quintile and frequencies in each CV range were plotted for 4 drug classes, that is, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), b blocker (BB), and calcium channel blocker (CCB). 1: CV ,9.66, 2: 9.66 ,CV , 11.30, 3: 11.30 ,CV , 13.13, 4: 13.13 ,CV , 15.34, 5: 15.34 ,CV.
EVALUATION OF THE EFFECTS OF ANTIHYPERTENSIVE DRUGS ON BP VARIABILITY IN CHRONIC CVD
5
Figure 2. Daytime systolic blood pressure variability histogram in cerebrovascular disease (CVD) patients treated with calcium channel blockers. All coefficients of variation (CVs) of systolic blood pressure were divided into quintile and frequencies in each CV range were plotted for 4 drugs. 1: CV ,9.50, 2: 9.50 ,CV , 11.00, 3: 11.00 , CV, 12.83, 4: 12.83 , CV , 15.19, 5: 15.19, CV. Abbreviation: CCB, calcium channel blocker.
a previous report.11 The reasons are speculated to be as follows: first, short-term mean BP variability within individuals obtained by ABPM was analyzed in this study, whereas Webb et al analyzed the BP variability among patients receiving different drug classes because of meth-
A
Figure 3. Mean of daytime systolic blood pressure grouped in each coefficient of variation (CV) range. (A) All antihypertensive drugs. (B) Calcium channel blockers. (A) 1: CV ,9.66, 2: 9.66 , CV , 11.30, 3: 11.30 , CV , 13.13, 4: 13.13 , CV , 15.34, 5: 15.34 , CV; (B) 1: CV ,9.50, 2: 9.50 , CV , 11.00, 3: 11.00 , CV , 12.83, 4: 12.83 , CV , 15.19, 5: 15.19, CV. Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b blocker; CCB, calcium channel blocker.
B
odological limitations in the meta-analysis. Therefore, the result of that analysis is considered to be obtained under the hypothesis that BP variability among drug classes reflects individual variation more strongly than interindividual variations. Second, no differences were found in
R. NISHIOKA ET AL.
6
the achieved mean BP level among the patients treated with an ARB, CCB, and BB in this study, whereas in the report by Webb et al, the analysis was performed after statistically removing BP determinants because of differences in the BP. Because of the previously mentioned differences between the studies, it is necessary for data on individual BP variations in subjects treated with ARBs to be accumulated from a larger study population and evaluated in the future. Concerning the risk of stroke, according to a recent randomized controlled trial, CCBs are not necessarily superior to ARBs.12 Furthermore, some placebo-controlled studies have reported the possibility of a reduction in the risk of stroke by ARBs.13-15 Compliance with dihydropyridine CCB therapy, the target molecules of which are vascular smooth muscle L-type Ca channels, has been improved by prolonging the half-life periods in the blood through synthesis of derivative compounds and through the improved controlled-release technology. Furthermore, in recent years, cilnidipine that also blocks the N-type Ca channels present in the peripheral sympathetic nerves in addition to the L-type Ca channels has been introduced for use as antihypertensive drug.9 Because the choice of CCBs available for antihypertensive management has widened, the effects of individual CCB drugs on the BP variability were also investigated in this study. Among the CCBs, which, as described previously, were found to be associated with a low BP variability as compared with the other antihypertensive drug classes examined, cilnidipine was associated with a particularly low BP variability. The underlying mechanism is speculated to be as follows: cilnidipine inhibits peripheral sympathetic nerve activity to inhibit noradrenaline secretion and also exerts a vasodilatory effect via its action on the vascular smooth muscle16,17; through these effects, cilnidipine reduces the cerebrovascular resistance, thereby inhibiting decrease of the cerebral blood flow18 and also vascular remodeling.19 It has been reported that the low BP variability obtained with CCB therapy is not dependent on the half-life of the drugs.9 From the above, it is suggested that among the CCBs, cilnidipine may be particularly effective for reducing the risk of recurrent CVD. BP levels, affected by antihypertensive drug treatment and BP variability have been reported as independent risk factors of stroke.7 In this investigation, no relationship was observed between the degree of reduction of the BP and the effect on the BP variability for any of the drugs. Taking this finding into consideration, the differences in the stroke risk reduction among the drugs may be caused by differences in the effects of each drug on the BP variability (perhaps involved in reduction of the residual risk after stroke risk reduction by BP lowering) as a determinant factor. In particular, relatively sudden cerebrovascular BP reduction, which may be associated with short-term BP variability, assessed in this study by ABPM, may further reduce the perfusion pressure in
small vessel areas in the presence of impaired BP autoregulation, inducing cerebral ischemia.20 Therefore, it is considered that drugs associated with lower BP variability would be more effective for reducing the risk of stroke among those with identical effects in reducing the BP levels. Acknowledgment: The authors deeply thank the late professor Kunio Shimazu for his special contribution on this study.
References 1. Ogihara T, Kikuchi K, Matsuoka H, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res 2009;32:3-107. 2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-1252. 3. Kikuya M, Hozawa A, Ohkubo T, et al. Prognostic significance of blood pressure and heart rate variabilities: the Ohasama Study. Hypertension 2000;36:901-906. 4. Frattola A, Parati G, Cuspidi C, et al. Prognostic value of 24-hour blood pressure variability. J Hypertens 1993; 11:1133-1137. 5. Tartaro A, Budassi S, Pascali D, et al. Correlation between computed tomography findings of leukoaraiosis and 24-hour blood pressure variability in elderly subjects. J Stroke Cerebrovasc Dis 1999;8:66-70. 6. Ekbom T, Dahl€ of B, Hansson L, et al. The stroke preventive effect in elderly hypertensives cannot fully be explained by the reduction in office blood pressure–insights from the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Blood Press 1992;1:168-172. 7. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010; 375:895-905. 8. Rothwell PM, Howard SC, Dolan E, et al. Effects of beta blockers and calcium-channel blockers on withinindividual variability in blood pressure and risk of stroke. Lancet Neurol 2010;9:469-480. 9. Takahara A. Cilnidipine: a new generation Ca channel blocker with inhibitory action on sympathetic neurotransmitter release. Cardiovasc Ther 2009;27:124-139. 10. Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990;21:637-676. 11. Webb AJ, Fischer U, Mehta Z, et al. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010;375:906-915. 12. Schrader J, L€ uders S, Kulschewski A, et al. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005;36:1218-1226. 13. Schrader J, L€ uders S, Kulschewski A, et al. The ACCESS study: evaluation of acute candesartan cilexetil therapy in stroke survivors. Stroke 2003;34:1699-1703. 14. Papademetriou V, Farsang C, Elmfeldt D, et al. Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis
EVALUATION OF THE EFFECTS OF ANTIHYPERTENSIVE DRUGS ON BP VARIABILITY IN CHRONIC CVD in the Elderly (SCOPE). J Am Coll Cardiol 2004;44: 1175-1180. 15. ONTARGET InvestigatorsYusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559. 16. Takahara A, Dohmoto H, Hisa H, et al. Cilnidipine attenuates renal nerve stimulation-induced renal vasoconstriction and antinatriuresis in anesthetized dogs. Jpn J Pharmacol 1997;75:27-32. 17. Sakata K, Shirotani M, Yoshida H, et al. Effects of amlodipine and cilnidipine on cardiac sympathetic nervous system and neurohormonal status in essential hypertension. Hypertension 1999;33:1447-1452.
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18. Kato Y, Ohkubo T, Asano Y, et al. Effects of cilnidipine on NO production and ischemic change of hippocampal CA1 neurons during cerebral ischemia and reperfusion in mice. J Cereb Blood Flow Metab 2009;29(suppl): 237-239. 19. Kobayashi N, Mori Y, Mita S, et al. Effects of cilnidipine on nitric oxide and endothelin-1 expression and extracellular signal-regulated kinase in hypertensive rats. Eur J Pharmacol 2001;422:149-157. 20. Sorond FA, Khavari R, Serrador JM, et al. Regional cerebral autoregulation during orthostatic stress: age-related differences. J Gerontol A Biol Sci Med Sci 2005;60: 1484-1487.
Background: It has been suggested that antihypertensive drug therapy is attributable to the lower blood pressure variability, we investigated the effects of 4 classes of antihypertensives on the blood pressure variability; in addition, we also compared the effects among 4 calcium channel blockers. Methods: We measured the 24-hour blood pressure variability in 309 patients with a history of cerebrovascular disease treated with angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, b blocker, or calcium channel blocker. Results: The daytime blood pressure variability treated with b blockers (14.3 6 3.1) was higher than that treated with an angiotensin receptor blockers (11.5 6 3.1) or calcium channel blockers (12.6 6 3.4) in patients with cerebrovascular disease (P , .05). In the analysis of the patient distribution of blood pressure variability, patients receiving b blockers occurred more frequently in the higher blood pressure variability (P 5.0023). Treatment with angiotensin receptor blockers and cilnidipine, which blocks N-type calcium channels, was shown to be more frequently associated with the lower blood pressure variability (P 5 .0202 and .0467). The mean blood pressure of patients grouped by distribution of blood pressure variability was found to be independent to blood pressure variability, for any of the antihypertensive drugs or calcium channel blockers examined. Conclusions: From the results, it is suggested that angiotensin receptor blocker and calcium channel blockers rather than b blockers may be more favorable for blood pressure management in patients with cerebrovascular disease. Among the calcium channel blockers, cilnidipine may be more favorable than other calcium channel blockers. Key Words: Hypertension—b-blocker—blood pressure variability— cerebrovascular disease(CVD)—cilnidipine—antihypertensive drugs. Ó 2015 by National Stroke Association
The risk of cardiovascular events in hypertension is correlated with the systolic and diastolic blood pressure (BP) levels, and major guidelines in the world for hypertension have presented targeted BP levels for antihyper-
tensive treatment taking into consideration with other cardiovascular risks.1,2 On the other hand, BP variability has been suggested to be an independent risk factor for cardiovascular diseases.
From the *Department of Neurology, School of Medicine, Faculty of Medicine, Saitama Medical University, Saitama; †School of Physical Therapy, Faculty of Health and Medical Care, Saitama Medical University, Saitama; and ‡Information Technology Center, Faculty of Medicine, Saitama Medical University, Saitama, Japan. Received February 28, 2015; revision received April 15, 2015; accepted April 16, 2015. R.N. and S.K. are equal first authors.
No potential conflicts of interest are disclosed. Address correspondence to Nobuo Araki, MD, PhD, Neurology, School of Medicine, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.023
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-7
1
R. NISHIOKA ET AL.
2
In these reports, it has been suggested that a high variability of BP recorded by ambulatory BP monitoring (ABPM) may be associated with a relatively higher cardiovascular risk,3 cardiac hypertrophy,4 and leukoaraiosis.5 In addition to ABPM, analyses of data obtained by long-term home BP6 and long-term office BP measurement7 have also suggested the elevated cardiovascular risk associated with high variability of BP. Many randomized controlled trials and meta-analyses have shown the efficacy of antihypertensive drugs for the prevention of stroke; however, it has been pointed out that there are differences in the effect on BP variability among the drug classes.8 In their study, it has been suggested that the reduced risk of stroke associated with calcium channel blocker (CCB) therapy is attributable not only to the antihypertensive efficacy but also to the lower BP variability of CCB. Among the antihypertensive drugs used, CCBs are often prescribed for antihypertensive treatment in CVD patients, and many kinds of CCB drugs are available for clinical use. CCBs have been subdivided according to their selectivity for Ca21 channel subtypes and possible differences in the efficacy in relation to specific complications of hypertension have been suggested.9 In this study, we measured the 24-hour BP variability in patients with a history of cerebrovascular disease (CVD), by ABPM and investigated the effects of 4 classes of antihypertensive drugs, CCBs, b-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs).
antihypertensive medication group; systolic BP of 140 mm Hg or more or diastolic BP of 90 mm Hg or more), ABPM was performed at least 3 months after the start of treatment. Of the CVD patients receiving CCBs, 39 patients received 5-10 mg of cilnidipine, 50 patients received 5-7.5 mg of amlodipine, 14 patients received 20-40 mg of nifedipine, and 50 patients received 20-40 mg of nicardipine. The data obtained from these patients were analyzed to compare the effects among the CCBs.
Data Analysis BP and PR were expressed as mean 6 standard deviation, and the coefficient of variation (CV: CV 5 100 3 standard deviation/mean) was calculated to determine the short-term variability of the BP and PR. Differences were analyzed using the Tukey–Kramer multiple comparison test. BP variability as the association of cardiovascular mortality was shown by quintile analysis in the previous study,3 so the subjects of all antihypertensive medications or CCBs medications were divided equally into 5 subgroups according to the distribution of the BP variability to analyze the BP variability characteristic of each antihypertensive medication. Trend analysis was conducted using simple linear regression by assigning an ordinal number (from 1 to 5) to each subgroups. P values smaller than .05 were considered significant.
Results Methods Patients and BP Measurement Of the outpatients who visited our department, a total of 309 patients, with a history of CVD and treated by one antihypertensive drug, were enrolled in this study. Informed consent was obtained from all patients before participation in this study. Data analysis was approved by Institutional Review Board of Saitama Medical University Hospital (No.14-063). The patients with CVD included in this study were those with chronic stroke, at least 1 month after the onset. The diagnosis of stroke was confirmed by magnetic resonance imaging or computed tomography using the criteria of stroke by the classification of CVDs III reported by National Institute of Neurological Disorders and Stroke.10 ABPM was performed using a portable automated BP/heart rate monitor (TM-2421, A&D, Tokyo). The potable monitor was programmed to record the BP and pulse rate (PR) every 15 minutes for 24 hours and attached to the patients. Individual data stored on the portable monitor were retrieved and analyzed using software (TM-2021). The mean measured values from ‘‘wake to sleep’’ (daytime) and ‘‘during sleep’’ (sleep time) were used as the measured values in each time zone. For the patients judged as needing antihypertensive treatment (morning
The patients’ background characteristics of the 4 study groups were similar (Table 1). The characteristics of the patients treated with 4 CCBs (cilnidipine, amlodipine, nifedipine, and nicardipine) were picked up from 169 CCB-treated patients (Table 2). As there were no heart disease patients only in nifedipine group, the ratio of hypercholesterolemia, heart disease, and cholesterol-lowering drugs were significantly different among the 4 groups by the chi-square statistic (P , .01, P , .01, P , .05; Table 2).
BP Variability in CVD Patients Administered Antihypertensive Drugs The all-day average systolic BP was higher in the ACEI group than in the ARB group. As for the BP variability, the all-day and daytime systolic BP variability was higher in the BB group than in the ARB group. In addition, the daytime systolic BP variability was also higher in the BB group than in the CCB group (Table 3). All patients administered antihypertensive drugs were grouped into quintiles according to the daytime systolic BP variability, and the frequency distributions by drug class are shown in Figure 1. Also, in this analysis, contrasting frequency distributions were obtained for patients under BB and ARB treatment, indicating that a
EVALUATION OF THE EFFECTS OF ANTIHYPERTENSIVE DRUGS ON BP VARIABILITY IN CHRONIC CVD
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Table 1. Patients characteristics Enrolled all patients Characteristics
CCB
BB
ARB
ACEI
Number Age, y Male (%) Body weight (kg) BMI (kg/m2) Smoking (%) Hypercholesterolemia (%) Heart disease (%) Antiplatelet drugs (%) Cholesterol-lowering drugs (%)
169 66.9 6 9.5 73.4 59.8 6 10.1 24.0 6 3.0 27.8 30.9 27.2 86.1 26.6
53 65.5 6 10.0 69.8 54.5 6 11.1 23.0 6 2.4 30.2 27.8 22.2 94.4 20.7
52 69.1 6 10.7 67.3 60.9 6 12.1 23.8 6 3.0 28.8 26.9 34.6 51.9 11.5
35 68.8 6 9.5 65.7 57.2 6 11.8 23.5 6 4.0 11.4 52.9 41.2 77.3 31.4
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b blocker; BMI, body mass index; CCB, calcium channel blocker.
was significantly lower in the cilnidipine and amlodipine group as compared with that in the nifedipine group (Tukey–Kramer method). Patients administered CCBs were grouped into quintiles according to the daytime systolic BP variability, and frequency distributions of patients administered these 4 CCBs in each quintile are shown in Figure 2. A higher proportion of patients administered cilnidipine showed low BP variability (P 5 .0467), whereas no relationship were noted in the patients administered the other 3 CCBs.
larger proportion of patients showed high BP variability in the BB group (P 5 .0023) and larger proportion of patients showed low BP variability in the ARB group (P 5 .0202). On the other hand, no strong trends were found for the CCB and ACEI groups.
BP Variability in Patients Treated with CCBs The effects on the BP variability were compared among 4 drugs, amlodipine, nifedipine, and nicardipine, which are representative L-type CCBs used for BP management in CVD, and cilnidipine, which has inhibitory effects on both L-type and N-type Ca channels. The BP variability was the lowest in the group treated with cilnidipine in daytime (CV of daytime systolic BP; amlodipine 5 12.3 6 3.4, nifedipine 5 12.6 6 3.0, nicardipine 5 13.0 6 3.8, cilnidipine 5 12.0 6 3.0, CV of daytime diastolic BP; amlodipine 5 12.9 6 3.3, nifedipine 5 16.7 6 4.5, nicardipine 5 14.0 6 4.6, cilnidipine 5 12.4 6 1.7), and in particular, diastolic BP variability
Relationship between BP Variability and Mean BP CVD patients were grouped into quintiles according to the BP variability, and the relationship between the BP variability and the daytime mean systolic BP was investigated for each antihypertensive drug treatment group (Fig 3, A). No relationship between the BP variability and the mean BP was found for any drug class. Likewise, patients treated with CCBs were grouped into quintiles
Table 2. Patients characteristics (CCB) 4 CCBs treatments (patients picked up from Table 1) Characteristics
Cilnidipine
Amlodipine
Nifedipine
Nicardipine
Number Age, y Male (%) Body weight (kg) BMI (kg/m2) Smoking (%) Hypercholesterolemia (%), P , .01 Heart disease (%), P , .01 Antiplatelet drugs (%) Cholesterol-lowering drugs (%), P , .05
39 68.9 6 8.6 64.1 61.0 6 10.1 25.1 6 2.9 20.5 28.2 38.5 85.7 25.6
50 69.0 6 9.5 65.8 59.7 6 10.7 23.7 6 3.3 22.0 32.0 40.0 85.2 22.0
14 66.6 6 9.5 92.9 58.9 6 9.7 23.3 6 2.0 50.0 .0 .0 80.0 .0
50 63.9 6 8.8 88.0 60.6 6 8.6 24.0 6 2.9 22.0 78.0 10.0 92.3 36.0
Abbreviations: BMI, body mass index; CCB, calcium channel blocker.
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Table 3. Blood pressure variability in CVD (all antihypertensives) Systolic BP
CV of systolic BP
Antihypertensive drug
All-day (mm Hg)
All-day
Daytime
Sleep time
ACEI ARB BB CCB
143.2 6 15.3* 134.3 6 16.4* 137.6 6 16.3 138.2 6 12.5 Diastolic BP All-day (mm Hg)
14.5 6 4.3 12.7 6 3.8* 15.0 6 3.8* 13.8 6 3.5
11.0 6 4.0 9.9 6 3.0 10.8 6 3.0 9.9 6 2.9
All-day
13.1 6 4.3 11.5 6 3.1* 14.3 6 3.1* 12.6 6 3.4* CV of diastolic BP Daytime
82.3 6 9.7 82.9 6 11.7 79.6 6 9.1 81.7 6 9.0
15.6 6 4.2 14.3 6 3.5 15.9 6 3.0 15.1 6 3.6
13.9 6 4.9 12.5 6 3.2 14.3 6 3.6 13.5 6 3.7
13.3 6 4.6 11.7 6 3.5 13.1 6 4.6 12.2 6 4.0
ACEI ARB BB CCB
Sleep time
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b blocker; BP, blood pressure; CCB, calcium channel blocker; CV, coefficient of variation; CVD, cerebrovascular disease. *P , .05 by Tukey–Kramer.
according to the BP variability; however, no relationship was found between the BP variability and the mean BP for any of the 4 CCBs (Fig 3, B).
Discussion In this study, we analyzed short-term (24-hour) BP variability of CVD patients using ABPM and demonstrated differences in the BP variability among antihypertensive drug classes. Of the antihypertensive drugs investigated, higher systolic BP variability in the daytime was observed in the BB group than in the CCB or ARB group. In addition, frequency analysis in quintiles of BP variability revealed higher proportions of patients receiving BBs in the higher quintiles. These results were consistent with the following reports: It was reported from the AngloScandinavian Cardiac Outcomes Trial - Blood Pressure
Lowering Arm (ASCOT-BPLA) study, based on a comparative analysis of BP variability measured by ABPM, that the BP variability was higher in the group treated with atenolol than in the group treated with amlodipine.8 Analysis of BP variability by office measurements in multiple outpatient visits also revealed that the variability was higher in the patients treated with atenolol than in the patients treated with amlodipine; this study also revealed that the BP variability was more strongly related to the risk of stroke than the systolic/diastolic BP levels. Therefore, because of the higher BP variability observed in the patients receiving BBs, it is suggested that it might be characteristic in BB class agents and that caution should be exercised in the administration of BBs in CVD patients requiring antihypertensive treatment. On the other hand, the results for the patients treated with ARBs obtained in this study were inconsistent with
Figure 1. Daytime systolic blood pressure (BP) variability histogram in cerebrovascular disease (CVD) patients treated with antihypertensive drugs. All coefficients of variation (CVs) of systolic BP were sequentially divided into quintile and frequencies in each CV range were plotted for 4 drug classes, that is, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), b blocker (BB), and calcium channel blocker (CCB). 1: CV ,9.66, 2: 9.66 ,CV , 11.30, 3: 11.30 ,CV , 13.13, 4: 13.13 ,CV , 15.34, 5: 15.34 ,CV.
EVALUATION OF THE EFFECTS OF ANTIHYPERTENSIVE DRUGS ON BP VARIABILITY IN CHRONIC CVD
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Figure 2. Daytime systolic blood pressure variability histogram in cerebrovascular disease (CVD) patients treated with calcium channel blockers. All coefficients of variation (CVs) of systolic blood pressure were divided into quintile and frequencies in each CV range were plotted for 4 drugs. 1: CV ,9.50, 2: 9.50 ,CV , 11.00, 3: 11.00 , CV, 12.83, 4: 12.83 , CV , 15.19, 5: 15.19, CV. Abbreviation: CCB, calcium channel blocker.
a previous report.11 The reasons are speculated to be as follows: first, short-term mean BP variability within individuals obtained by ABPM was analyzed in this study, whereas Webb et al analyzed the BP variability among patients receiving different drug classes because of meth-
A
Figure 3. Mean of daytime systolic blood pressure grouped in each coefficient of variation (CV) range. (A) All antihypertensive drugs. (B) Calcium channel blockers. (A) 1: CV ,9.66, 2: 9.66 , CV , 11.30, 3: 11.30 , CV , 13.13, 4: 13.13 , CV , 15.34, 5: 15.34 , CV; (B) 1: CV ,9.50, 2: 9.50 , CV , 11.00, 3: 11.00 , CV , 12.83, 4: 12.83 , CV , 15.19, 5: 15.19, CV. Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b blocker; CCB, calcium channel blocker.
B
odological limitations in the meta-analysis. Therefore, the result of that analysis is considered to be obtained under the hypothesis that BP variability among drug classes reflects individual variation more strongly than interindividual variations. Second, no differences were found in
R. NISHIOKA ET AL.
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the achieved mean BP level among the patients treated with an ARB, CCB, and BB in this study, whereas in the report by Webb et al, the analysis was performed after statistically removing BP determinants because of differences in the BP. Because of the previously mentioned differences between the studies, it is necessary for data on individual BP variations in subjects treated with ARBs to be accumulated from a larger study population and evaluated in the future. Concerning the risk of stroke, according to a recent randomized controlled trial, CCBs are not necessarily superior to ARBs.12 Furthermore, some placebo-controlled studies have reported the possibility of a reduction in the risk of stroke by ARBs.13-15 Compliance with dihydropyridine CCB therapy, the target molecules of which are vascular smooth muscle L-type Ca channels, has been improved by prolonging the half-life periods in the blood through synthesis of derivative compounds and through the improved controlled-release technology. Furthermore, in recent years, cilnidipine that also blocks the N-type Ca channels present in the peripheral sympathetic nerves in addition to the L-type Ca channels has been introduced for use as antihypertensive drug.9 Because the choice of CCBs available for antihypertensive management has widened, the effects of individual CCB drugs on the BP variability were also investigated in this study. Among the CCBs, which, as described previously, were found to be associated with a low BP variability as compared with the other antihypertensive drug classes examined, cilnidipine was associated with a particularly low BP variability. The underlying mechanism is speculated to be as follows: cilnidipine inhibits peripheral sympathetic nerve activity to inhibit noradrenaline secretion and also exerts a vasodilatory effect via its action on the vascular smooth muscle16,17; through these effects, cilnidipine reduces the cerebrovascular resistance, thereby inhibiting decrease of the cerebral blood flow18 and also vascular remodeling.19 It has been reported that the low BP variability obtained with CCB therapy is not dependent on the half-life of the drugs.9 From the above, it is suggested that among the CCBs, cilnidipine may be particularly effective for reducing the risk of recurrent CVD. BP levels, affected by antihypertensive drug treatment and BP variability have been reported as independent risk factors of stroke.7 In this investigation, no relationship was observed between the degree of reduction of the BP and the effect on the BP variability for any of the drugs. Taking this finding into consideration, the differences in the stroke risk reduction among the drugs may be caused by differences in the effects of each drug on the BP variability (perhaps involved in reduction of the residual risk after stroke risk reduction by BP lowering) as a determinant factor. In particular, relatively sudden cerebrovascular BP reduction, which may be associated with short-term BP variability, assessed in this study by ABPM, may further reduce the perfusion pressure in
small vessel areas in the presence of impaired BP autoregulation, inducing cerebral ischemia.20 Therefore, it is considered that drugs associated with lower BP variability would be more effective for reducing the risk of stroke among those with identical effects in reducing the BP levels. Acknowledgment: The authors deeply thank the late professor Kunio Shimazu for his special contribution on this study.
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