Angiotensin receptor blockers (ARBs) are gaining a great market in most countries. The major current hypertension guidelines (1–3) recommend ARBs as first-line drugs for the treatment of hypertension; however, it is assumed that patients with lower renin hypertension respond less to monotherapy with a blocker of the renin–angiotensin system (RAS), such as an ARB, than those with higher renin hypertension.
Monotherapy with an RAS blocker may not be suitable for uncomplicated patients with low-renin hypertension, who are free from congestive heart failure, chronic kidney disease or diabetes mellitus. A growing body of evidence has shown that the effectiveness of antihypertensive medications is derived primarily from the blood pressure-lowering effect itself rather than the characteristic actions of various classes of antihypertensive drugs.1, 2, 3 To date, several investigators have studied the association of pretreatment plasma renin activity (PRA) levels with ambulatory blood pressure (ABP) responses to ARBs in essential hypertension.4, 5, 6 Recently, we showed that ABP reductions by telmisartan were significantly smaller in hypertensive patients with lower PRA levels than in those with higher PRA levels.4 However, it is uncertain whether the same is true of all ARBs. Among ARBs, valsartan has been suggested to be effective in lowering the blood pressure in both Whites and Blacks,7 although Blacks often show low-renin status. Thus, we conducted this study to investigate whether pretreatment PRA levels predicted an ABP response to valsartan in newly diagnosed patients with essential hypertension.
We prospectively studied 16 Japanese hypertensive patients whose initial systolic blood pressure was ⩾140 mm Hg and/or diastolic blood pressure was ⩾90 mm Hg (seven women and nine men, mean age: 53±10 (±s.d.) years, mean body mass index: 24.7±3.8 kg m−2). All patients had been the outpatients of Dokkyo University Hospital. They had been newly diagnosed with essential hypertension and had not received any antihypertensive medication. They were found not to have secondary forms of hypertension by comprehensive examinations.2, 3 We recruited consecutive patients. All patients had normal renal and liver function. No patient had a past history of coronary artery disease, stroke, congestive heart failure, diabetes mellitus or malignancy. No pregnant women were included. Informed consent was obtained from all subjects. This study was approved by the Research Ethics Committee of our institute.
After a 4-week drug-free period, valsartan was administered orally once daily at an initial dose of 40 mg for 4 weeks. If the office blood pressure remained high (systolic blood pressure ⩾140 mm Hg and/or diastolic blood pressure ⩾90 mm Hg), the dose was increased to 80 mg once daily for another 4 weeks. In this study, a placebo was not administered in the drug-free period. Patients were instructed to maintain their usual diet, including sodium intake, throughout the study.
Office blood pressure was measured twice every 4 weeks by a cardiologist (JM) with a mercury sphygmomanometer in the sitting position using the right arm with an appropriate cuff size and after the patient had been sitting quietly for at least 5 min. The values of two measurements were averaged. The 24 h ABP was measured every 30 min using a cuff-oscillometric device (TM-2421 or TM-2431; A&D Co. Ltd, Tokyo, Japan). The first measurement was performed at the end of the 4-week drug-free period and the second measurement at the end of the 8-week treatment period with valsartan. Daytime and nighttime ABPs were defined as the mean values in the awake period between 0700 hours and 2130 hours and in the sleeping period between 2200 hours and 0630 hours, respectively.
During the drug-free period, overnight-fasting blood samples to measure PRA levels were obtained after the patients had rested in the supine position for at least 30 min. PRA was measured with a conventional radioimmunoassay method (plasma renin activity kit; SRL Co., Ltd, Tokyo, Japan). To avoid cryoactivation, plasma was not chilled before the renin assay. Plasma was processed at room temperature and stored completely frozen. Frozen samples were thawed rapidly to room temperature and not chilled until they were at pH 6.8
Data are expressed as the means±s.d. The Shapiro–Wilks W-test was applied to verify the distribution normality. Skewed data were transformed into naturally logarithmic values. A paired t-test, unpaired t-test, the χ2-test, and simple and multiple regression analyses were used where appropriate. Patients were divided into two groups of lower PRA levels (<0.33 ng per ml per h) and higher PRA levels (⩾0.33 ng per ml per h). This cut-off value for renin status was based on the lower limit of the normal range in supine position in the radioimmunoassay method used in this study. Values of P<0.05 were considered significant.
Plasma renin activity levels before treatment ranged from 0.1 to 3.5 ng per ml per h. Although the distribution of untransformed PRA levels was not normally distributed (W=0.75, P<0.01), log-transformation of PRA levels created an approximately normal distribution (W=0.97, P=0.77). According to untransformed PRA levels, five patients were found as having lower PRA levels (<0.33 ng per ml per h), and the other 11 patients as having higher PRA levels (⩾0.33 ng per ml per h). The mean daily dose of valsartan was 70.0±17.9 mg at the end of the study period.
There were no differences in sex distribution, body mass index, and 24-h daytime and nighttime ambulatory systolic and diastolic blood pressures and pulse rate before treatment between patients with lower PRA levels and those with higher PRA levels.
In the group as a whole, valsartan significantly decreased the office blood pressure by 24±19mm Hg systolic (P<0.001) and 12±11 mm Hg diastolic (P<0.01). In addition, valsartan significantly decreased the 24 h ABP by 12±11 mm Hg systolic (P<0.01) and 8±6 mm Hg diastolic (P<0.001), the daytime ABP by 13±14 mm Hg systolic (P<0.01) and 9±7 mm Hg diastolic (P<0.001), and the nighttime ABP by 10±11 mm Hg systolic (P<0.01) and 6±8 mm Hg diastolic (P<0.01). Valsartan did not change the ambulatory pulse rate significantly in any time period.
Reduction in the office systolic blood pressure by valsartan was significantly smaller in the five patients with lower PRA levels than in the 11 patients with higher PRA levels by 25 mm Hg systolic (P<0.01). Reductions in 24-h systolic and diastolic ABPs were significantly smaller in five patients with lower PRA levels than in 11 patients with higher PRA levels by 17 mm Hg systolic (P<0.01) and 9 mm Hg diastolic (P<0.01). In addition, reductions in daytime systolic and diastolic ABPs were also significantly smaller in five patients with lower PRA levels than in 11 patients with higher PRA levels by 20 mm Hg systolic (P<0.01) and 10 mm Hg diastolic (P<0.01). In addition, reduction in nighttime systolic ABP was significantly smaller in five patients with lower PRA levels than in 11 patients with higher PRA levels by 12 mm Hg (P<0.05). These results were similar, even if patients were divided into two groups using the PRA cut-off value of 0.65 ng per ml per h proposed by Alderman et al.9 (lower renin, n=9; higher renin, n=7; data not shown).
In the group as a whole, changes in the office systolic blood pressure were significantly correlated with log PRA. Changes in 24-h systolic and diastolic ABPs were significantly correlated with log PRA (Figure 1). In addition, changes in daytime systolic and diastolic ABPs significantly correlated with log PRA and changes in the nighttime diastolic ABP significantly correlated with log PRA (Figure 1). As shown in Figure 1, 24-h systolic ABP increased after treatment with valsartan in two patients whose PRA levels were 0.1 and 0.3 ng per ml per h, and 24-h diastolic ABP also increased in two patients whose PRA levels were 0.1 and 0.2 ng per ml per h.
In multiple regression analysis, changes in the office systolic blood pressure significantly correlated with log PRA (β=−0.63, P<0.01), independently of office systolic blood pressure levels before treatment. In addition, changes in 24-h systolic and diastolic ABPs significantly correlated with log PRA (β=−0.50, P<0.01 and β=−0.65, P<0.01, respectively), independently of 24-h systolic and diastolic ABP levels before treatment; changes in daytime systolic and diastolic ABPs significantly correlated with log PRA (β=−0.53, P<0.01 and β=−0.62, P<0.05, respectively), independently of daytime systolic and diastolic ABP levels before treatment.
In this study, valsartan showed ABP-lowering effects dependent on PRA levels before treatment in patients with essential hypertension. Reductions in ABP by valsartan were significantly smaller in hypertensive patients with lower PRA levels than in those with higher PRA levels. These findings are well in agreement with our earlier observation regarding telmisartan,4 and earlier observations by other investigators regarding losartan5 and irbesartan.6 Therefore, measurements of pretreatment PRA levels are thought to be useful to predict the ABP-lowering effects of ARBs, irrespective of drugs, and should be performed routinely before the initiation of antihypertensive medication, especially in untreated and newly diagnosed patients with essential hypertension.
Basic and clinical researches and some clinical trials have shown that RAS blockers produce organ protection beyond that which can be explained by reductions in blood pressure; however, it has also been shown that the effectiveness of antihypertensive medications is derived primarily from the blood pressure-lowering effect per se rather than the characteristic actions of various classes of antihypertensive drugs.1, 2, 3 Therefore, monotherapy with a RAS blocker, such as an ARB or a renin inhibitor,5, 6, 10 may not be suitable for uncomplicated patients with low-renin hypertension who are free from congestive heart failure, diabetes mellitus or chronic kidney disease.
We should acknowledge our study limitations. First, we studied only a small number of patients, although blood pressure was evaluated by ABP monitoring. Second, in this study, the duration of angiotensin I generation step was 1.5 h, although it was desirable that this step lasted at least for 3 h.11 Finally, we investigated the association of pretreatment PRA levels with the ABP response to valsartan after only 8 weeks; therefore, it is uncertain whether the same is also true of a longer treatment period with valsartan; however, this results seem to provide valuable information to stress to clinicians that RAS blockers such as ARBs exert blood pressure-lowering effects dependent on the renin status.
Conflict of interest
The authors declare no financial conflict of interest.
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Minami, J., Ohno, E., Furukata, S. et al. Pretreatment levels of plasma renin activity predict ambulatory blood pressure response to valsartan in essential hypertension. J Hum Hypertens 23, 683–686 (2009). https://doi.org/10.1038/jhh.2009.31
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