(2005) 19, 491 496 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh ORIGINAL ARTICLE High-dose monotherapy vs low-dose combination therapy of calcium channel blockers and angiotensin receptor blockers in mild to moderate hypertension EA Andreadis, GI Tsourous, GE Marakomichelakis, PM Katsanou, ME Fotia, CV Vassilopoulos and EJ Diamantopoulos 4th Department of Internal Medicine, Evangelismos State General Hospital, Athens, Greece The objectives of the study were to compare long-acting dihydropyridine calcium channel blockers (CCBs) with angiotensin II receptor blockers (ARBs) according to the ambulatory blood pressure monitoring (ABPM) profile in stage 1 and 2 newly diagnosed hypertensives and also to evaluate the efficacy of high-dose monotherapy vs low-dose combination therapy of the two drug categories among the subjects with inadequate blood pressure (BP) control after conventional low-dose monotherapy. We obtained 24-h ABPM readings from 302 subjects with newly diagnosed stage 1 or 2 essential hypertension. The study protocol consisted of initial drug treatment with a low dose of either CCBs or ARBs. Hypertensives who did not achieve BP control were randomized to high-dose monotherapy of either category of drug or low-dose combination therapy. CCBs and ARBs in low-dose monotherapy achieved BP control in 53.8 and 55.3% of the cases, respectively. However, subjects under treatment with CCBs experienced side effects more often and required that treatment be discontinued. Hypertensives who failed to control their BP with low-dose monotherapy did significantly better with low-dose combination treatment (61.6%) than with high-dose CCBs (42.8%) or ARBs (40.5%) monotherapy (Po0.05). In terms of ABPM, lowdose combination therapy exhibited better 24-h BP profile according to trough-to-peak ratio, hypertensive burden and BP variability. In conclusion, low-dose ARBs and CCBs have a comparable effect in subjects with grade 1 and 2 arterial hypertension. In hypertensives who are not controlled by low-dose monotherapy, lowdose combination therapy proves be more efficacious than high-dose monotherapy. (2005) 19, 491 496. doi:10.1038/sj.jhh.1001843 Published online 10 March 2005 Keywords: ambulatory blood pressure; calcium channel blockers; angiotensin receptor blockers Introduction Several prospective clinical trials and populationbased studies have demonstrated that the incidence of cardiovascular events is predicted by blood pressure (BP) as measured in the office or with ambulatory methods, even after adjustment has been made for a number of risk factors. 1,2 In some of these studies, ambulatory blood pressure monitoring (ABPM) predicted cardiovascular events even after fixing for conventional BP measurements. 2,3 ABPM is an accurate method of evaluating the BP reduction in treated hypertensives, due to the absence of the Correspondence: Professor EJ Diamantopoulos, 10 Oitis Street, 154 52 Paleo Psychiko, Athens, Greece. E-mail: Dpathologiki@evaggelismos-hosp.gr Received 17 September 2004; revised 7 December 2004; accepted 10 January 2005; published online 10 March 2005 white coat and placebo effect, with higher reproducibility over time. 4 Calcium channel blockers (CCBs) effectively lower systolic and diastolic BP and their use as monotherapy or in combination with other drugs is one of the most potent therapeutic options. 5 Angiotensin II receptor blockers (ARBs) belong to a relatively new class of antihypertensive drugs. ARBs are becoming increasingly popular as they are effective and well tolerated. 5 In subjects with stage 1 hypertension, the initiation of drug treatment with a low dose of either CCBs or ARBs is an established therapy. However, comparative data among the two classes of antihypertensive agents concerning the 24-h BP variability and burden reduction are lacking. Furthermore, optimal treatment strategies in hypertensives who failed to achieve BP control with low-dose monotherapy are not established. This prospective study has been conducted in order to evaluate the clinical efficacy, specifically
492 the 24-h BP variability and burden reduction of high-dose monotherapy with CCBs or ARBs vs low-dose combination treatment in subjects with inadequate BP control after conventional low-dose monotherapy. Methods Study population The study population was recruited from individuals who attended the Blood Pressure Clinic of our Department during the period 2002 2003 and originated from the ethnically homogeneous Greek population living in the greater Athens area. Office measurements of systolic and diastolic BP were performed manually with a calibrated mercury sphygmomanometer. The diagnosis and staging of arterial hypertension was based on the mean value of three consecutive office BP measurements that were taken between 11:00 and 13:00, 1 week apart according to the criteria of JNC 6, before randomization. 6 The prerequisite for inclusion was stage 1 and 2 hypertension diagnosed within the past 6 months, without antihypertensive medication. In order to be eligible, hypertensives had to be free of cardiovascular events. All subjects gave written informed consent. Criteria for exclusion were secondary hypertension, any coexisting disease that might seriously reduce life expectancy, use of experimental drugs, pregnancy and the refusal to undergo follow-up visits and ABPM. Hypertension was confirmed after 1 month of lifestyle modification. A total of 302 participants, 156 males (51.7%) and 146 females (48.3%), with a mean age of 54.10711.43 years (range 38 75 years) were enrolled in the study. At the screening visit, the medical history of each participant was recorded. A thorough clinical examination was performed for each patient, followed by laboratory investigations. Study protocol The participants were randomized to receive either low-dose long-acting dihydropyridine CCBs (Group A) or ARBs (Group B). The drugs of each class and the initial dose used are shown in Table 1. They Table 1 Long-acting dihydropyridine calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs) used in the study CCBs (low/high dose) Felodipine (5/10 mg) Amlodipine (5/10 mg) Lacidipine (2/4 mg) ATII (low/high dose) Irbesartan (150/300 mg) Candesartan (8/16 mg) Losartan (50/100 mg) Telmisartan (40/80 mg) Valsartan (40/80 mg) were chosen consecutively in the presented order in a 1:1 relation, except for patients with diabetes mellitus who were all included in group B, taking into consideration current recommendations. 7 All subjects were re-evaluated 6 weeks after the initiation of the drug treatment (follow-up 1). BP control was based on office BP measurements and adequate control was considered as BP below 140/90 mmhg for the systolic and diastolic BP, respectively. Hypertensives with inadequate BP control were randomly assigned to receive either higher doses of the initial therapy (by doubling the doses) or a combination of low doses of the initial therapy plus a drug from the other class (Table 1). The second reevaluation of the study cohort was performed after an additional 6-week period (follow-up 2). Side effects of drug treatment were recorded according to a standard questionnaire during both re-evaluation periods. Individuals with intolerance to the selected regimen were crossed over to the other class of drugs, but the analysis was performed according to the intention-to-treat model. Ambulatory blood pressure monitoring ABPM was performed the day before the initiation of drug treatment and in 12-week follow-up periods. ABPM was carried out with electronic devices (Diasys 2000) that have been validated and recommended for clinical use, meeting the criteria of the Association for the Advancement of Medical Instrumentation. 8 They were preset to measure BP at 15-min intervals during daytime (07:00 to 23:00) and at 30-min intervals during night time (23:00 to 07:00). The patients were sent home with instructions to hold their arm immobile at the time of measurements; to keep a diary of daily activities and quality of night rest; and to return to the hospital 24 h later. The monitoring was always carried out on a working day and during the normal intake of the selected antihypertensive treatment. The participants had no access to the ambulatory BP values. ABPM readings with systolic BP o70 or 4260 mmhg and/or diastolic BP o40 or 4150 mmhg were not taken into account. Home readings that were 450% higher than the next highest home BP reading were considered as irrelevant and were also discarded. In the second follow-up, each subject took the medication before the initiation of the ABPM. In the analysis of the ABPM recordings, we evaluated the mean 24-h systolic and diastolic BP, the mean daytime and night time systolic and diastolic BP and the trough-to-peak systolic and diastolic BP. Peak BP changes were calculated by considering the interval between the 2nd and 8th hour after drug intake (ie when the peak effect was expected to occur) and by averaging, within this time window, the values for: (1) the hour in which the BP fall was maximal and (2) the adjacent hour in
which the BP fall was more evident, compared with the corresponding pretreatment values. Trough BP changes were calculated by averaging the difference between pretreatment and during treatment BP values, which were recorded during the last 2 h of the monitoring period. 9 Furthermore, we calculated the hypertensive burden (BP load) as the percentage of abnormal BP readings (4135/85 mmhg, during a 24-h period, 4135/85 mmhg, during the daytime period and 4120/75 mmhg during the night time period). Also, we focused on BP variability every 30 min (short-term variability). Systolic BP variability was estimated according to the formula: standard deviation of 24-h systolic BP/mean 24-h systolic BP (coefficient of variation). Similarly, the diastolic BP variability was calculated. Statistical analysis The study variables compared were: the office BP readings in the first and the second re-evaluation visit (follow-up 1 and 2), obtained as described above, and the mean of the 24-h, daytime and night time ABPM of systolic and diastolic BP, also recorded in 12 weeks. The distribution of baseline characteristics in the groups A and B were compared with the use of Yate s corrected w 2 test or Fisher s exact test for proportions and the one or pairedsamples t-test or Mann Whitney U-test for continuous variables. Variability comparison was tested by Leven s test for the equality of variances. The statistical analysis was performed according to the intention to treat principle. All statistical analyses were performed using SPSS Inc. software, version 11.0.1 (Chicago, IL, USA, 2001). Results The mean systolic BP in the initial evaluation was 153.1717.4 mmhg (in men, 150.9716.8 mmhg and in women, 155.5717.7 mmhg), while the mean diastolic was 97.278.8 mmhg (in men, 98.078.8 mmhg and in women, 96.478.7 mmhg). Women appeared to have a higher systolic BP in comparison to men (P ¼ 0.021, mean difference 4.61, 95% CI 0.71 8.52). A total of 143 (47.35%) participants were randomized to group A and 159 (52.65%) to group B. According to the baseline characteristics, the two groups were similar in age, sex, body mass index (BMI), smoking status, diabetes mellitus and levels of serum cholesterol, triglycerides, HDL and LDL cholesterol, systolic and diastolic BP (Table 2). In the first follow-up, 165 participants (54.6%), 87 (55.8%) men and 78 (53.4%) women, had their BP controlled. The two categories of drugs had a similar effect on BP control (77 out of 143 subjects in group A, 53.8%; 88 out of 159 in group B, 55.3%; P ¼ 0.8). The mean systolic BP fall in group A was 19.6717.3 mmhg and in group B, 16.2716.5 mmhg Table 2 Demographic characteristics of the studied population according to drug randomization (low-dose monotherapy with CCBs for group A and ARBs for group B) Demographics Group A (n ¼ 143) Group B (n ¼ 159) Age (years) 55.4710.7 52.9712.0 0.7 Sex (M/F) 74/69 82/77 0.9 BMI (kg/m 2 ) 28.675.0 28.474.0 0.6 Diabetes mellitus 15 (10.5%) 19 (11.9%) 0.4 Smoking 26 (18.1%) 31 (19.4%) 0.5 Total cholesterol (mg/dl) 227.5741.5 225.5743.3 0.4 Triglycerides (mg/dl) 125.5755.6 127.4760.5 0.3 HDL-cholesterol (mg/dl) 53.6714.0 53.3714.2 0.4 LDL-cholesterol (mg/dl) 146.5737.3 144.9738.1 0.9 Systolic blood pressure 151.76714.2 154.34714.7 0.4 (mmhg) Diastolic blood pressure (mmhg) 96.8178.34 97.5678.69 0.3 (P ¼ 0.7). The mean diastolic BP fall in group A was 10.879.6 mmhg and in group B, 8.679.4 mmhg (P ¼ 0.7). BP control did not differ between men and women in group B (63.8 vs 71.6%, respectively, P ¼ 0.6). However, in group A, CCBs tended to be more effective in men than in women (65.2 vs 49.2% respectively, Po0.05). In all, 10 (6.7%) group A subjects developed leg oedema due to the administration of CCBs and three (2.1%) required discontinuation of treatment. In group B, only minor side effects were reported by eight (5.0%) hypertensives, but no treatment discontinuation was necessary. From the 137 subjects who were not controlled by low-dose monotherapy, 35 (25.5%) received highdose CCBs (group A1), 42 (30.6%) received highdose ARBs (group B1) and 60 (43.7%) received a combination of low-dose therapy (group C). In subjects who were not controlled, randomization was carried out according to the concept of 1:1, except for those who could tolerate dose increment without side effects. There was no significant difference in the systolic and diastolic BP levels among the three groups (for group A1, B1 and C: systolic BP, 158.3716.9 vs 153.8715.9 vs 162.4717.6 mmhg, P ¼ 0.1 and diastolic BP, 98.377.9 vs 99.077.2 vs 102.1710.0 mmhg, P ¼ 0.1, respectively). The mean reduction of systolic BP in the three groups was 9.8715.2, 8.7715.9 and 12.7716.2 mmhg, and of diastolic BP, 6.877.2, 6.977.2 and 6.779.3 mmhg for groups A1, B1 and C, respectively. The reduction in systolic BP was significantly higher in group C than in groups A1 and B1 (Po0.05). After the initiation of the dosage increment or drug combination, an additional 22.8% of the total cohort was controlled. In group A1, 42.8% (15/35) of the subjects achieved adequate BP control, while in group B1, 40.5% (17/42) and in group C, 61.6% (37/60) achieved adequate BP control. BP control was significantly better in group C compared to groups A1 and B1 (Po0.05, for both comparisons). Drug withdrawal or treatment mod- P 493
494 ification was significantly higher among subjects of group A1 than those of groups B1 and C due to their intolerance to high doses of CCBs. Specifically, 11.4% (4/35) of group A1 hypertensives required treatment modification in comparison to only 4.8% (2/42) of group B1 and 6.7% (4/60) of group C (Po0.05). Analysis of ABPM in terms of blood pressure control and reduction Hypertensives who achieved BP control with lowdose monotherapy exhibited significant BP reductions in terms of mean 24-h systolic and diastolic, mean daytime systolic and diastolic, and mean night time systolic and diastolic BP. The mean BP reduction was comparable between the two groups (Table 3). In both groups, there was a significant burden reduction in systolic and diastolic BP during the 24-h, the daytime and the night time periods. Similarly, the mean burden reduction was comparable between the two groups, except for the night time diastolic BP burden reduction, where the CCBs were inferior to the ARBs (Table 4). High-dose monotherapy and combination therapy Subjects requiring high-dose monotherapy with ARBs or CCBs achieved a similar reduction in systolic and diastolic BP, during the daytime, the night time and the 24-h periods. Those receiving low-dose combination therapy had greater systolic Table 3 Ambulatory blood pressure reduction after low-dose monotherapy with CCBs (group A) or ARBs (group B) Ambulatory BP reduction Mean7s.d. Group A Group B P Mean 24-h SBP 7.26710.00 8.77710.16 0.7 Mean 24-h DBP 4.7376.22 5.2277.52 0.6 Mean daytime SBP a 10.07716.29 9.24711.21 0.4 Mean daytime DBP b 4.8777.38 5.4278.10 0.3 Mean night time SBP 5.94712.10 6.81714.45 0.7 Mean night time DBP 3.6476.93 4.5778.15 0.6 a SBP: systolic blood pressure. b DBP: diastolic blood pressure. Table 4 Mean 24-h hypertensive burden reduction in subjects treated with CCBs (group A) or ARBs (group B) Burden reduction Mean7s.d. Group A Group B P Mean 24-h SBP burden 15.75722.90 14.04717.39 0.3 Mean 24-h DBP burden 15.39721.23 16.18723.10 0.4 Mean daytime SBP burden 18.37725.58 16.00721.20 0.6 Mean daytime DBP burden 17.17724.72 17.61726.28 0.4 Mean night time SBP burden 10.48728.51 10.73728.33 0.7 Mean night time DBP burden 6.97730.19 18.55727.25 0.01 and diastolic BP reduction, as well as burden reduction in comparison to those receiving highdose monotherapy. These differences reached the level of statistical significance for the diastolic BP (P ¼ 0.04), while they showed a clear trend for the systolic BP (P ¼ 0.07) (Table 5). According to BP variability, the combination therapy was characterized by lower variability in comparison to both high-dose treated groups (Figure 1). The mean trough-to-peak ratio for systolic BP was significantly higher for combination therapy (0.950) in comparison to high-dose treatment with CCBs (0.936, Po0.05) and high-dose treatment with ARBs (0.935, Po0.05). Discussion This study provides a direct comparison of the antihypertensive efficacy of CCBs and ARBs in terms of BP control and ambulatory BP profile. Both drug categories have a similar effect in achieving target BP and burden reduction when they are prescribed as low-dose monotherapy in subjects with stage 1 and 2 hypertension. The primary reason for selecting an antihypertensive drug is efficacy. Controversial reports about the efficacy of ARBs may explain why fewer than 10% of individuals around the world are prescribed ARBs, despite the advantages provided by superior compliance. 10 Several small studies, however, have compared ARBs to commonly used antihypertensive agents, such as atenolol, lisinopril and amlodipine. 11,12 In each of these studies, the antihypertensive efficacy of ARBs was at least comparable or superior to that of the other antihypertensive agents. These studies used only one ARB and thus the results cannot be interpreted as categorical efficacy. Only the studies DBPC and PROBE used more than one ARB. In a meta-analysis of these trials, telmisartan, losartan and valsartan, in various dosages, exhibited similar BP reduction to amlodipine in a dosage of 5 mg per day. 13,14 In the present study, less than half of the subjects with mild to moderate arterial hypertension were not controlled by low-dose monotherapy of either category of drugs (CCBs or ARBs). In the literature, it has not been completely clarified whether these patients should receive incremental doses of the initial monotherapy or should be managed by lowdose combination therapy. 14 It has been shown that low-dose combination therapy is associated with better compliance and possibly greater BP reduction. In our study, low-dose combination therapy of ARBs and CCBs, as categorical agents, achieved better BP control in comparison to high doses of both CCBs or ARBs, irrespective of the initial drug choice in patients not controlled by low-dose monotherapy. Specifically, low-dose combination therapy led to BP control in approximately 60% of subjects treated with low-dose monotherapy, while
Table 5 Ambulatory blood pressure reduction in subjects receiving high-dose monotherapy (group A1 and B1) vs low-dose combination therapy (group C) 495 Group A1 (n ¼ 35) B1 (n ¼ 42) C (n ¼ 60) P Initial BP (mmhg7s.d.) Systolic 158.3716.9 153.8715.8 162.4717.6 0.11 Diastolic 98.377.9 99.0577.2 102.1710.0 0.12 Daytime systolic reduction 9.374.4 11.073.8 14.678.7 0.08 Daytime systolic burden reduction 7.377.9 9.278.2 13.178.2 0.08 Night time systolic reduction 0.870.05 1.770.7 4.172.4 0.08 Night time systolic burden reduction 0.870.65 0.875.34 7.176.6 0.07 Daytime diastolic reduction 0.571.6 1.470.5 9.276.2 0.04 Daytime diastolic burden reduction 0.0070.14 2.271.9 13.274.3 0.04 Night time diastolic reduction 0.571.3 3.177.9 4.870.5 0.04 Night time diastolic burden reduction 0.271.3 0.971.3 10.574.1 0.01 24-h systolic reduction 2.271.3 2.171.5 8.875.3 0.07 24-h systolic burden reduction 3.870.6 9.973.5 16.173.7 0.06 24-h diastolic reduction 0.271.2 2.771.9 9.076.0 0.05 24-h diastolic burden reduction 0.0071.44 2.973.9 13.375.6 0.02 24-h systolic pressure variability 0.1270.03 0.1670.03 0.1470.03 0.05 24-h diastolic pressure variability 0.1470.03 0.1870.04 0.1870.15 0.07 150 148 CCBs ARBs Combination Blood pressure (mmhg) variability 146 144 142 140 138 136 134 0.935 0.950 0.936 132 130 8am 10am 12pm 2pm 4pm 6pm 8pm 10pm 12am 2am 4am 6am Figure 1 Comparison of 24-h BP variability between subjects treated with low-dose combination therapy or high-dose monotherapy with CCBs or ARBs. Low-dose combination therapy is characterized by a significantly smoother BP variation and higher trough-to-peak ratio (0.950) during the 24-h period. Time the results of high-dose CCBs or ARBs were approximately 40%. Moreover, this finding was associated with an increased trough-to-peak ratio of low-dose combination therapy on ABPM recordings and also with a lower variability of BP. The compliance to low-dose combination therapy was similar to the high-dose ARBs but significantly better to the high-dose CCBs. It appears that lowdose combination therapy is more effective in BP and burden-lowering in comparison to high-dose monotherapy. Furthermore, low-dose monotherapy has a favourable effect on BP variability in contrast to high-dose monotherapy. The physiologic mechanism that could explain the favourable results of low-dose combination therapy on BP reduction may be associated with the simultaneous blockade of two different pathways of BP control that are effective for both low and high renin hypertension. Moreover, the combination of two drugs with different pharmacodynamic and
496 pharmacokinetic properties seems to result in a better 24-h BP profile in terms of trough-to-peak ratio and BP variability, as indicated by the population of this study. The ultimate therapeutic significance of this strategy can be evaluated through its effect on the long-term prognosis of the hypertensive subjects, in terms of target organ damage and, consequently, cardiovascular morbidity and mortality. In the present work, we did not evaluate long-term prognosis, but since it has been established that better BP control results in decreasing cardiovascular risk, the use of low-dose combination therapy in subjects who are not controlled by low-dose monotherapy seems to be a promising therapeutic alternative. In conclusion, low-dose angiotensin II receptor blockers and calcium channel blockers have comparable antihypertensive effect in subjects with mild and moderate arterial hypertension. In hypertensives who are not controlled by low-dose monotherapy, low-dose combination therapy seems to be a more attractive therapeutic strategy than high-dose monotherapy in terms of BP control and 24-h BP profile. Acknowledgements This work was supported by AstraZeneca Pharmaceutical Co, Greece. References 1 Perloff D, Sokolow M, Cowan R. The prognostic value of ambulatory blood pressure. JAMA 1983; 249: 2792 2798. 2 Ohkubo T et al. Prediction of mortality by ambulatory blood pressure monitoring versus screening blood pressure measurements: a pilot study in Ohasama. J Hypertens 1997; 15: 357 364. 3 Staessen JA et al. Predicting cardiovascular risk using conventional versus ambulatory blood pressure in older patients with systolic hypertension. JAMA 1999; 282: 539 546. 4 Mancia G et al. Ambulatory blood pressure normality: results from the Pamela study. J Hypertens 1995; 13: 1377 1390. 5 World Health Organization/International Society of Hypertension. Guideline for the management of hypertension. J Hypertens 1999; 17: 151 183. 6 Joint National Committee. The Sixth Report of the Joint National Committee on detection, evaluation and treatment of high blood pressure (JNC 6). Arch Intern Med 1997; 157: 2413 2446. 7 Joint National Committee. The Seventh Report of the Joint National Committee on detection, evaluation and treatment of high blood pressure (JNC 7). Hypertension 2003; 42: 1206 1252. 8 Association for the Advancement of Medical Instrumentation. American national standards for electronic and automated sphygmomanometers. AAMI, Washington, DC, 1987. 9 Omboni S et al. Reproducibility and clinical value of the trough-to-peak ratio of the antihypertensive effect. Evidence from the Sample Study. Hypertension 1998; 32: 424 429. 10 Messerli FH. yyand losartan was no better than placebo. Editorial. J Hum Hypertens 1999; 13: 649 650. 11 Freytag F et al. Comparison of 26-week efficacy and tolerability of telmisartan and atenolol, in combination with hydrochlorothiazide as required, in the treatment of mild to moderate hypertension: randomized multicenter study. Clin Ther 2001; 23: 108 123. 12 Neutel JM et al. Comparison of telmisartan with lisinopril in patients with mild to moderate hypertension. Am J Ther 1999; 6: 161 166. 13 Hanson L, Hedner T, Dahlof B. Prospective randomized open blinded endpoint (PROBE) study. A novel design of intervention trials. Blood Press 1992; 1: 113 119. 14 Smith DH et al. Prospective, randomized, open-label, blined-endpoint (PROBE) designed trials yield the same results as double-blind, placebo controlled trials with respect to ABPM measurements. J Hypertens 2003; 21: 1291 1298.