Original Article

Journal of Human Hypertension (2012) 26, 656–663; doi:10.1038/jhh.2011.91; published online 13 October 2011

There is a Retraction (9 October 2014) associated with this article.

There is a Corrigendum (13 October 2011) associated with this article.

Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: a subanalysis of the VART

H Takano1, H Hasegawa1, H Narumi1, S Shindo1, H Mizuma1, Y Kuwabara1, Y Kobayashi1 and I Komuro2 on behalf of the VART investigators

  1. 1Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
  2. 2Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

Correspondence: Dr H Takano, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: htakano-cib@umin.ac.jp

Received 27 May 2011; Revised 6 September 2011; Accepted 12 September 2011
Advance online publication 13 October 2011

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Abstract

The Valsartan Amlodipine Randomized Trial (VART) was performed to compare the beneficial effects of valsartan and amlodipine on cardiovascular events in Japanese hypertensive patients. In this subanalysis of the VART, we assessed the relationship between home blood pressure (HBP) levels and cardiovascular events in the enrolled patients. We enrolled 1021 patients with mild-to-moderate hypertension in the VART. The participants were allocated randomly to either the valsartan group or the amlodipine group. The primary end point was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. A total of 621 patients (valsartan group: 305 and amlodipine group: 316) completed the measurements of HBP (morning and evening) throughout the trial. Both the agents evenly and significantly lowered morning HBP and evening HBP throughout the trial. There was no significant difference in the primary end point between the two groups. However, we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group. There were no significant differences in HBP levels and the main outcome of the cardiovascular events between the valsartan and amlodipine groups. However, in the valsartan group, significant improvements in left ventricular hypertrophy and microalbuminuria were observed.

Keywords:

angiotensin II receptor blocker; calcium channel blocker; home blood pressure; left ventricular hypertrophy

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Introduction

Hypertension is the most common disease in Japan and is a leading cause of morbidity and mortality. Therefore, intensive management of blood pressure (BP) is important for prevention of cardiovascular events in patients with hypertension. Antihypertensive agents, which inhibit the renin–angiotensin system, have been known to have beneficial effects on cardiovascular and renal functions that extend beyond their reduction of BP. Many clinical randomized trials have shown the beneficial effects of angiotensin II receptor blockers (ARBs) on cardiovascular morbidity and mortality in patients with hypertension, heart failure, stroke or end-stage renal disease.1, 2, 3 ARBs and calcium channel blockers have effective BP-lowering effects and are widely used around the world. Although it is important to investigate the differences in the effects of ARBs and calcium channel blockers on cardiovascular events in the clinical setting, few trials have been performed in Japan.4, 5 Because of the differential response to the therapeutic agents and the variation in event rates of cardiovascular disease between Asian and Western populations,6 the data from the trials performed in other countries are not necessarily applicable to Japanese patients.

In the Valsartan Amlodipine Randomized Trial (VART),7 we compared the beneficial effects of ARB valsartan and calcium channel blocker amlodipine on cardiovascular events in Japanese patients with mild-to-moderate hypertension. Office BP levels were well controlled and remained similar in the valsartan group and the amlodipine group. There was no significant difference between the two groups in the primary end point, which was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. However, in the valsartan group, significant improvements in left ventricular hypertrophy (LVH) and microalbuminuria were observed.7

It has been shown that home BP (HBP) is superior to office BP in the prediction of HT-related cardiovascular complications.8, 9, 10, 11, 12 Especially, high morning HBP is closely correlated with organ damage and future cardiovascular events.13, 14, 15 Self-monitoring of BP at home is now popular in Japan and the Japanese guidelines for the management of hypertension appreciate its usefulness.16 In the present study, we examined whether there were any differences in HBP and cardiovascular protection between the valsartan group and the amlodipine group in Japanese hypertensive patients who participated in the VART.

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Subjects and methods

Study population

The study population of the VART has been previously reported in detail.7 Briefly, subjects aged greater than or equal to30 years who were newly diagnosed with hypertension (systolic BP greater than or equal to140mmHg or diastolic BP greater than or equal to90mmHg in a sitting position at clinic) or were already treated with antihypertensive agents were included. The exclusion criteria were secondary hypertension, serious valvular disease or congenital heart disease requiring operative treatment, hypertrophic or dilated cardiomyopathy, percutaneous transluminal coronary angioplasty or coronary artery bypass graft within 6 months previous to the study, occurrence of stroke within 3 months previous to the study and serious renal dysfunction (serum creatinine >3mg per 100ml). We enrolled 1021 patients with mild-to-moderate hypertension between July 2002 and February 2006. The VART was closed on March 2009.

Study design

The detailed protocol of the VART was described in our recent publication.7 The VART was a multicenter, prospective, randomized, open-labeled, blinded-endpoint design comparing two antihypertensive treatment strategies involving 92 medical facilities in Japan. The participants were assigned randomly to either the valsartan group or the amlodipine group with the minimization method after obtaining informed consent. The office BP of each patient was measured in a sitting position with a validated mercury sphygmomanometer at a clinic. The mean of three measurements was calculated and recorded. We aimed to control office BP to <140/90mmHg in both the treatment groups. The patients were instructed to measure HBP twice (morning and evening) a day with a validated oscillometric device (HEM-741C; Omron Healthcare, Kyoto, Japan) throughout the trial. Morning BP was measured within 1h after waking, after urination, and before taking breakfast and antihypertensive agents. Evening BP was measured before going to bed. The morning and evening BP were measured in the sitting position on each occasion and the averages of HBP values in the 7 days before the visit were used for data analysis. The first dose of valsartan or amlodipine was 80 or 5mg day−1, respectively. When the patient's BP did not reach the office BP target, the doses were increased to 160 or 10mg day−1, respectively. α-Blockers, β-blockers or diuretics could be added when necessary as described previously.7

Outcome measurements

The primary end point was a composite of all-cause death, sudden death, cerebrovascular events (new occurrence or recurrence of a stroke, or transient ischemic attack), cardiac events (new occurrence or recurrence of acute myocardial infarction or angina pectoris, or new occurrence or exacerbation of heart failure), vascular events (dissecting aneurysm of aorta or hospitalization due to arteriosclerotic occlusion of the peripheral artery) and renal events (doubling of serum creatinine or end-stage renal disease) as described previously.7 The secondary end points were effects on LVH, renal function and incidence of new-onset diabetes. After the enrollment, routine laboratory tests were done every 6 months. Urinary albumin to creatinine ratio (UACR) was also measured every 12 months. Echocardiography was performed to examine the change in left ventricular mass index (LVMI) every 12 months. Left ventricular mass was measured on the M-mode-guided echocardiogram, according to the formula introduced by Devereux et al: 0.80 × {1.04 × [(septal thickness+left ventricular internal diameter × posterior wall thickness)3–(left ventricular internal diameter)3]}+0.6g and LVMI was calculated with correction of body surface area. New-onset diabetes was diagnosed if treatment with hypoglycemic agents was initiated and/or the plasma hemoglobin A1c level exceeded 6.1% during the trial.

Statistical analysis

We estimated hazard ratios and 95% confidence intervals (CIs) to compare the treatment groups. Hazard ratios were calculated and adjusted for age, gender, smoking, diabetes and hypercholesterolemia with Cox's proportional hazard model. Statistical analysis of events rates over time was presented as Kaplan–Meier plots according to the treatment arms. Differences in the frequency of adverse events were analyzed with the chi-square test. The changes from baseline in LVMI and UACR were analyzed with the paired t-test. All the statistical tests were two-sided with an α level of 0.05%.

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Results

Baseline characteristics

A total of 1021 patients were enrolled in the VART. Of these, 621 patients (valsartan group: 305 and amlodipine group: 316) completed measurements of HBP in the morning and evening throughout the trial. Table 1 shows the baseline characteristics of the patients. There were no significant differences in the baseline characteristics such as age, gender, body mass index, coronary artery disease, diabetes mellitus, dyslipidemia, LVH, antihypertensive treatment before enrollment and the other clinical parameters between the two groups. Table 2 demonstrates medication at the baseline. There were no significant differences in medication at the baseline between the two groups.



Follow-up and adherence to the treatment

The mean follow-up period was 3.4 years. During the follow-up of the trial, the percentages of the patients who received the allocated drugs were over 99% in both groups. At the end of the trial, the percentages of the patients who received only valsartan or amlodipine were 69% in the valsartan-based regimen and 81% in the amlodipine-based regimen (Table 3). Other additional treatments in both groups were mainly diuretics, β-blockers and α-blockers. The average number of antihypertensive drugs taken during the study was slightly higher in the valsartan group than in the amlodipine group. Few adverse events were recognized in both groups as reported previously.


Blood pressure

Office BP levels were well controlled in the two groups and there were no significant differences in the office BP levels between the two groups throughout the trial as described previously. Figure 1 shows that HBP was reduced substantially in both treatment groups. The mean morning HBP was 149±20/89±12mmHg at baseline and 135±14/81±10mmHg after 3 years in the valsartan group (Figure 1a). The mean evening HBP was 141±18/84±14mmHg at baseline and 129±14/76±12mmHg after 3 years in the valsartan group (Figure 1b). The mean morning HBP was 149±21/90±13mmHg at baseline and 134±13/81±9mmHg after 3 years in the amlodipine group (Figure 1a). The mean evening HBP was 141±18/83±13mmHg at baseline and 129±12/76±13mmHg after 3 years in the amlodipine group (Figure 1b). The target office BP (both systolic BP <140mmHg and diastolic BP <90mmHg) was achieved in 200 (66%) patients in the valsartan group and 222 (70%) patients in the amlodipine group. The target HBP (both systolic BP <135mmHg and diastolic BP <85mmHg, which are the BP levels used to diagnose home hypertension in the JSH 2009 guideline) was achieved in 177 (58%) patients in the valsartan group and 196 (62%) patients in the amlodipine group.

Figure 1.
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Changes in the HBP (SBP (systolic BP) and DBP (diastolic BP)) in the morning (a) and in the evening (b). SBP and DBP during the follow-up period of the trial. Data are expressed as mean±s.d. P=NS.

Full figure and legend (24K)

Primary end point

The number of patients who reached a primary end point during the follow-up period was quite small in the present subanalysis. The primary events occurred in 11 (3.6%) patients in the valsartan group and 13 (4.1%) patients in the amlodipine group. There was no significant difference in the primary composite end point between the two groups (hazard ratio: 0.88; 95% CI: 0.40–1.93; P=0.743) (Figure 2). Table 4 shows the comparisons of the primary end point for both the groups. The first event for each category was counted. There were no significant differences in the rates of each primary end point category between the two groups. Stroke, which was the most frequent event, occurred in 8 patients (2.6%) in the valsartan group and 7 patients (2.2%) in the amlodipine group.

Figure 2.
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Kaplan–Meier curves for the primary composite end point.

Full figure and legend (32K)


Secondary end points

The secondary end points were effects on LVH, renal function and incidence of new-onset diabetes. We measured the changes from baseline in LVMI by echocardiography to evaluate LVH. At 12 and 24 months, we observed similar changes in LVMI in both the valsartan group and the amlodipine group. However, we observed a significant reduction in LVMI at 36 months compared with baseline only in the valsartan group (valsartan group: 132±40 to 119±36gm−2, amlodipine group: 130±34 to 129±30gm−2) (Figure 3). There were significant reductions in UACR at 24 and 36 months compared with baseline only in the valsartan group (valsartan group: 56±197 to 23±36mg per g creatinine, amlodipine group: 37±74 to 59±164mg per g creatinine) (Figure 4). During the follow-up period, the incidence of new-onset diabetes was 5.4% in the valsartan group and 9.1% in the amlodipine group. There was a trend for fewer rates of new-onset diabetes in the valsartan group, but this did not reach statistical significance (P=0.093).

Figure 3.
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Changes in LVMI. LVMI at 36 months was significantly decreased compared with baseline in the valsartan group. *P<0.05 compared with baseline.

Full figure and legend (13K)

Figure 4.
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Changes in UACR. UACR at 24 and 36 months were significantly decreased compared with baseline in the valsartan group. *P<0.05 compared with baseline.

Full figure and legend (14K)

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Discussion

Of the patients enrolled in the VART, 621 patients could complete the measurements of HBP in the morning and evening throughout the trial. In the present study, both morning BP and evening BP levels were well controlled and remained similar in the valsartan group and the amlodipine group throughout the trial. There was no significant difference in the primary end point between the two groups in agreement with the result in the VART. However, we observed significant changes in LVMI and UACR in the valsartan group but not in the amlodipine group in the subanalysis.

To date, many trials have been designed to evaluate the effects of antihypertensive agents on high-risk hypertensive patients. Although it is important to find the optimal treatment for high-risk hypertensive patients, it is also necessary to examine the appropriate treatment for low-risk patients with mild-to-moderate hypertension. The VART was designed to compare the ARB valsartan and the calcium channel blocker amlodipine in terms of the prevention of cardiovascular events in 1021 Japanese low-risk patients with mild-to-moderate hypertension.7 Office BP levels were well controlled and stayed equal in the valsartan group and the amlodipine group throughout the trial. Although there was no significant difference in the primary end point between the two groups, significant improvements of LVH, cardiac sympathetic nerve activity and UACR were observed in the valsartan group.7 The proportion of the patients with valsartan or amlodipine monotherapy was large, which allowed a valid comparison of valsartan and amlodipine. In the present subanalysis, we assessed the relationship between the HBP levels and the cardiovascular events in the patients who could measure HBP throughout the trial.

HBP measurement is beneficial in providing response to antihypertensive therapy, improving patient adherence to therapy and evaluating white-coat hypertension.12 Therefore, it is believed that HBP monitoring can improve hypertension-control better compared with office BP measurement. HBP measurement has been shown to be a better marker for predicting the cardiovascular events and target organ damage than office BP measurement in hypertensive patients.8, 9, 10, 11, 12 Especially, morning hypertension and morning BP surge have been reported to be a significant predictor of the cardiovascular events and target organ damage.13, 14, 15 A recent report suggested that the control of evening BP as well as morning BP is important in hypertensive patients with pre-diabetes and type 2 diabetes.17 In the VART, not only office BP but also HBP levels were well controlled in both the groups. It is possible that the appropriate management of hypertension resulted in a small number of primary end point events in the VART.

LVH is an independent cardiovascular risk factor in the general population, especially hypertensive patients, and is a powerful predictor of the cardiovascular morbidity and mortality. The Framingham heart study reported the relationship between an increase in left ventricular mass by echocardiography and the cardiovascular events.18, 19 A greater reduction in left ventricular mass has been associated with a lower incidence of the cardiovascular events in hypertensive patients.20, 21 Activation of the renin–angiotensin system and an increase in angiotensin II level induce hypertrophy of cardiomyocytes.22 Increased plasma angiotensin II level has been linked to the left ventricular mass independently of BP.23 Therefore, ARBs seem to be promising agents that could inhibit the progression of LVH. In the experimental studies, valsartan showed better effects on LVH than amlodipine through the reduction in reactive oxygen species.24 There are some reports suggesting that morning hypertension is a strong predictor of LVH as determined by ECG or echocardiography in hypertensive patients.13, 14, 15 Although morning BP levels were well controlled and remained similar in the two groups in the present study, a significant reduction in LVMI was observed in the valsartan group but not in the amlodipine group.

Microalbuminuria has been recognized as a marker of early renal damage and an independent predictor of cardiovascular disease in diabetic and non-diabetic individuals.25, 26, 27 Microalbuminuria reflects microvascular damage not only in the glomeruli but also in the systemic vasculature. Increased UACR often indicates the presence of subclinical organ damage at the renal and cardiac levels. Reduction in urinary albumin induces a decrease in cardiovascular events in patients with hypertension and type 2 diabetes.28, 29 Epidemiological data show that a high level of UACR is associated with an increased cardiovascular mortality.30, 31, 32 In the subanalysis of the LIFE and the PREVEND, UACR was reported to be a predictor of all causes of mortality in the general population.26, 28 In the basic studies, inhibition of renin–angiotensin system has been shown to normalize estimated glomerular hydraulic pressure and glomerular permeability properties by the blocking of AII induced constriction of renal efferent arteriole, and to restore the charge-selectivity of the glomerular membrane.33, 34, 35, 36 Meanwhile, the renal protective effect of amlodipine is thought to be weak.37, 38, 39 It remains unclear whether morning BP level is a significant marker of microalbuminuria, the reduction in microalbuminuria by antihypertensive therapy is known to be correlated with the reduction in BP level.17 Although both office BP and HBP levels were well controlled and remained similar in the two groups in the present study, a significant decrease in UACR was observed in the valsartan group but not in the amlodipine group.

There were some studies that investigated the effect of valsartan and amlodipine in Japanese hypertensive patients as the VART study. In the KYOTO-HEART study,40 which investigated the effects of valsartan in Japanese hypertensive patients, the patients had also high cardiovascular risk (DM, 26%; dyslipidemia 70%; CAD, 23% and annual mortality, 0.54%). In the JIKEI-HEART study,41 which investigated the effects of valsartan in Japanese hypertensive patients, the patients had also high cardiovascular risk (DM, 20%; dyslipidemia, 53%; CAD, 33% and annual mortality, 0.58%). On the other hand, the patients in the VART had relatively low cardiovascular risk (DM, 7.3–9.0%; dyslipidemia, 26.7–28.4%; CAD, 3.3–3.5% and annual mortality, 0.14%). So, the VART study is quite a unique study in that the patients had low cardiovascular risk compared with other studies.

Because the low-risk patients with mild-to-moderate hypertension were enrolled in the VART, the proportion of the patients treated with valsartan or amlodipine monotherapy was large. This subanalysis has limitations. The number of the enrolled patients was small and the follow-up period was too short to demonstrate the statistical significance in the primary end point. In conclusion, both morning BP and evening BP levels were well controlled and remained similar in the valsartan group and the amlodipine group. However, valsartan showed beneficial effects on heart and kidney in Japanese hypertensive patients.

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Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

We thank all of the participants, physicians, medical staff and other contributors to the VART. Details of the members of the VART are as follows: Representative: Issei Komuro. Steering committee: Hiroyuki Takano, Yoichi Kuwabara, Satoshi Shindo, Keiko Nakayama, Miwa Fujita, Hiroya Narumi, Hiroshi Mizuma. Data and safety monitoring board: Toshiharu Himi (Kimitsu Chuo Hospital), Akira Aouda (Chiba Cardiovascular Center), Toru Takami (National Chiba Hospital). Event evaluation committee: Osahiro Takahashi (Chiba Aoba Municipal Hospital), Hiroyuki Niwayama (Funabashi Social Insurance Hospital), Yukinori Kohno (Chiba Social Insurance Hospital). Statistical analysis organization: Nobuo Shirahashi (Clinical Epidemiology, Osaka City University Graduate School).

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