Kouichi Tamura, MD, PhD, FACP, FAHA, Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan E-mail:email@example.com
Aliskiren is a direct renin inhibitor that exerts its effect at the rate-limiting step of the renin-angiotensin system. This study was performed to examine the beneficial effects of aliskiren-based antihypertensive therapy on the ambulatory blood pressure (BP) profile, central hemodybamics, and arterial stiffness in untreated Japanese patients with mild to moderate hypertension. Twenty-one Japanese nondiabetic patients with untreated mild to moderate essential hypertension were initially given aliskiren once daily at 150 mg, and the dose was titrated up to 300 mg as needed. After 12 weeks of aliskiren-based therapy, the clinic, ambulatory, and central BP values as well as brachial-ankle pulse wave velocity (baPWV) were all significantly decreased compared with baseline (clinic systolic BP, 151±11 mm Hg vs 132±11 mm Hg; clinic diastolic BP, 91±13 mm Hg vs 82±9 mm Hg; 24-hour systolic BP, 144±12 mm Hg vs 133±11 mm Hg; 24-hour diastolic BP, 88±8 mm Hg vs 81±9 mm Hg; central BP, 162±16 mm Hg vs 148±14 mm Hg; baPWV, 1625±245 cm/s vs 1495±199 cm/s; P<.05). These results show that aliskiren, as a first-line regimen, improves the ambulatory BP profile and may have protective vascular effects in Japanese nondiabetic patients with untreated mild to moderate essential hypertension.
Hypertension is highly prevalent worldwide and is one of the major risk factors for cardiovascular and renal diseases. In Japan, the first-line antihypertensive drugs are calcium channel blockers (CCBs), angiotensin II (Ang II) type 1 receptor (AT1R) blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, diuretics, and β-blockers (including α-/β-blockers), according to the 2009 Japanese Society of Hypertension Guidelines for the Management of Hypertension.1
Experimental and clinical evidence has indicated that activation of the renin-angiotensin system (RAS) is involved in the pathogenesis of hypertension and the related target organ damage, and multiple studies have proven the usefulness of RAS blockade induced by ACE inhibitor and ARB for the management of hypertension. Both ACE inhibitor and ARB function downstream of the rate-limiting step in the RAS cascade, which involves the renin-catalyzed conversion of angiotensinogen to angiotensin I (Ang I). This leads to the promotion of renin release and to an increase in plasma renin activity (PRA) via the intrarenal short feedback loop due to lack of AT1R-mediated suppression of renin production in the juxtaglomerular cells of kidney. Renin inhibition is a means for blocking the RAS. Aliskiren is a direct renin inhibitor that acts at the rate-limiting step of the RAS cascade, inhibiting the formation of Ang I from angiotensinogen. Therefore, unlike either ACE inhibitors or ARBs, aliskiren does not induce a compensatory increase in PRA, but rather, reduces it.2,3
Recent evidence has shown that ambulatory as well as clinic BP profiles are important for a proper estimation of BP control. In particular, ambulatory BP monitoring has allowed a more accurate diagnosis of hypertension and a determination of the circadian rhythm of BP under different pathophysiologic conditions.4,5 The central hemodynamics (ie, the central systolic BP [cSBP], augmentation index [AI]) and pulse wave velocity (PWV), a marker of large artery stiffness, do not always correlate with the peripheral brachial BP value, but do reflect the pressure load in the major organs. Several previous studies demonstrated that these variables (cSBP, AI, and PWV) are more closely related to organ damage than brachial BP.6–9 Previous meta-analyses also showed that the cSBP, AI, and PWV are independent risk factors for cardiovascular disease, and that these variables may reflect the different characteristics of the pathophysiologic abnormalities related to arterial stiffness.10 Thus, this study aimed to examine the beneficial effects of aliskiren-based antihypertensive therapy on ambulatory BP profile, central hemodybamics, and PWV in nondiabetic Japanese patients with untreated mild to moderate essential hypertension.
Study Participants and Design
Patients with untreated hypertension from the outpatient clinic of the Department of Internal Medicine, Yokohama City University Hospital (Yokohama, Japan) were enrolled from January 2010 to April 2011. Hypertension was defined as an average clinic systolic BP (SBP) of at least 140 mm Hg or diastolic BP (DBP) of at least 90 mm Hg or both on two different occasions (with at least a 2-week interval) during the run-in period (4 weeks) in advance of entry. Inclusion criteria were age 20 years or older and older than 80 years, mild to moderate essential hypertension (<140 mm Hg clinic SBP <180 mm Hg or <90 mm Hg clinic DBP <110 mm Hg), and no treatment for at least 4 weeks before the first hospital visit. Exclusion criteria included patients who exhibited severe hypertension (clinic SBP ≥180 mm Hg and/or DBP ≥110 mm Hg), secondary hypertension, type 1 or type 2 diabetes mellitus, arrhythmia, clinically significant cardiovascular disease, cerebrovascular disease or neuropathy, renal dysfunction (estimated glomerular filtration <60 mL/min/1.73 m2), overt proteinuria (urinary protein to creatinine ratio ≥300 mg/g-creatinine), taking cyclosporine, or women who were nursing or pregnant.
Determination of the clinic BP, ambulatory BP, baPWV, and cSBP were performed at baseline and 12 weeks after the start of aliskiren-based antihypertensive treatment. Venous blood and urine samples for the hematological, biochemical, and renal parameters were drawn and collected the morning after an overnight fast at baseline and 12 weeks after treatment. This study was approved by the ethics committees of Yokohama City University Hospital, and written informed consent was obtained from every participant prior to the start of the study.
The patients were initially given 150 mg of aliskiren once daily in the morning and the dose was titrated up to 300 mg daily 4 weeks after the treatment to reach the BP target if necessary. In addition, an optional addition of concomitant medication (either a thiazide diuretic at low dose or a CCB) was used to achieve the target BP control 8 weeks after the treatment as needed.
Clinic BP and 24-Hour Ambulatory BP Monitoring
The clinic sitting BP was measured at trough levels (24±2 hours postdose) using a calibrated standard mercury sphygmomanometer and the recommended cuff sizes.11 Two measurements were taken at 1- to 2-minute intervals, and their average was used for the subsequent calculation.
Ambulatory BP and heart rate (HR) were monitored every 30 minutes with a fully automated device (TM-2425; A&D, Tokyo, Japan), essentially as described previously.12–18 Ambulatory BP monitoring was repeated in patients who had >20% (missing) of the values missing out of the expected number of readings, a >30% error rate for the total readings, or values that were missing for >2 consecutive hours. The following readings were omitted because of technical artifacts: SBP >250 mm Hg or <70 mm Hg, DBP >130 mm Hg or <30 mm Hg, pulse pressure >160 mm Hg or <20 mm Hg, a systolic difference >60 mm Hg, or a diastolic differences >30 mm Hg compared with the immediately preceding or subsequent values. The patients were instructed to fill out a diary to record the time of sleeping, rising, and other daytime activities. Therefore, the term “day” and “night” hours in the present study reflect the average period during which the patients were awake/upright and asleep/supine, respectively. Short-term BP variability, which is comprised of the coefficients of variation of the BP values obtained from ambulatory BP monitoring, is defined as the within-patient standard deviation (SD) of all of the systolic and diastolic readings at 30-minute intervals divided by the mean BP during the course of the measurement periods.14–16,19–21 HR variability, which is comprised of the HR coefficients of variation, is defined as the within-patient SD of all the HR values at 30-minute intervals divided by the mean HR.14–16,19–21
The cSBP and AI were measured using an HEM-9000AI (Omron Healthcare, Kyoto, Japan) with an automatic tonometry probe wrapped onto the wrist to record radial waveforms, which were calibrated against the contralateral arm cuff brachial BP taken immediately after tonometry. An algorithm based on a linear regression model was then applied to estimate the cSBP from the “late systolic shoulder” (pSBP2) of the radial pulse waveform, which has been shown to closely agree with the cSBP.22–25 This device uses the maxima of the “multidimensional derivatives” on the recorded pressure waveforms to detect the first and second inflection points corresponding to the early and late systolic (pSBP2) pressure readings.
The baPWV values were determined with a PP analyzer (model BP-203RPEII; Nihon Colin, Tokyo, Japan) as described previously.14,15 The baPWV values obtained by this method are reported to significantly correlate with the aortic PWV determined by the catheter method.26
Blood sampling was performed after the patients had spent 30 minutes at quiet rest in a semirecumbent position. PRA, plasma aldosterone, and plasma atrial natriuretic peptide were measured by radioimmunoassay. Other parameters were determined by routine methods in the Department of Clinical Chemistry, Yokohama City University School Hospital. We calculated the estimated glomerular filtration rate (eGFR) with an application of the revised equation for the Japanese population: eGFR (mL/min/1.73 m2)=194×serum creatinine−1.094×Age−0.287×0.739 (if female).27
The quantitative data are expressed as mean±SD. For the statistical analysis of the difference between baseline and 12 weeks of therapy, analysis of variance was compared by a paired comparison t test. A P value <.05 was considered statistically significant. Clinic BP and pulse rate were analyzed by one-way repeated measures analysis of variance. Analysis was performed with STATISTICA 6.0 (StatSoft, Inc, Tulsa, OK).
Twenty-one patients with untreated mild to moderate essential hypertension were enrolled. Four patients were discontinued from the study, so 17 patients completed the study. The reasons patients were lost to follow-up included referral to other hospitals (two patients) and protocol deviations (two patients). Table I shows the demographic and baseline characteristics of the participants. Mean age was 57±9 years, and there were 10 men and 7 women. Body mass index (BMI) was 24±2 kg/m2 and clinic SBP/DBP was 151±11/91±13 mm Hg, suggesting that the participants corresponded to marginally obese untreated hypertensive patients. No patients had any impairment of renal function, including reduced eGFR and albuminuria, and glucose and lipid metabolism. There were no detectable abnormalities on electrocardiography or chest x-ray. Thus, the participants were ultimately characterized as middle-aged, marginally obese, mild to moderate hypertensive patients without complications.
Aliskiren-based therapy was well tolerated in all of the patients without any significant adverse events and the average aliskiren dose was 212±74 mg daily after a period of 12 weeks of treatment. At the end of the study, 12 patients (71%) were taking aliskiren monotherapy (aliskiren 150 mg daily, n=10; 300 mg daily, n=2) and the remaining patients were taking combination therapy (aliskiren 300 mg daily/CCB, n=5; aliskiren/diuretic, n=0). The CCBs used were amlodipine (n=4, average dose 3.75 mg daily) and benidipine (n=1, 2 mg daily).
Effects of Aliskiren-Based Therapy on BP Profile
From baseline to week 4, aliskiren-based therapy significantly decreased the clinic SBP (151±11 vs 132±11, P<.001) and DBP (91±13 vs 82±9, P=.001) without any change in the clinic PRA (69±11 vs 70±8, not significant) (Figure 1). These decreases in the SBP and DBP by aliskiren were maintained at week 8 and week 12. At week 12, the ambulatory SBP/DBP during the 24-hour, daytime, and nighttime periods were significantly lowered without changes in the ambulatory HR during any of these periods (Table II). With respect to ambulatory short-term BP variability, nighttime diastolic short-term BP variability was slightly but significantly increased at week 12. The hourly ambulatory BP values at week 12 are shown in Figure 2 and indicate that the aliskiren-based therapy exerts a sustained reduction in the ambulatory SBP and DBP during 24 hours.
Table II. Effects of Aliskiren-Based Therapy on Ambulatory BP Profile
Effects of Aliskiren-Based Therapy on Endocrine and Vascular Function
Concerning the endocrine function parameters, aliskiren significantly decreased PRA, with a change from baseline to week 12 of −0.4±0.3 ng/mL/h (P<.001) (Figure 3), which is consistent with previous studies.28 In addition, there was a trend toward a decrease in the plasma aldosterone concentration (PAC, a change from baseline to week 12 of −9.3±25.9 pg/mL, P=.1217) and plasma brain natriuretic peptide (BNP, a change from baseline to week 12 of −5.9±11.7 pg/mL, P=.1004). With respect to vascular function, aliskiren-based therapy for 12 weeks dramatically improved both cSBP (a change from baseline to week 12 of −14.3±9.8 mm Hg, P<.001) and baPWV (a change from baseline to week 12 of −130.0±119.7 cm/s, P<.001), although AI was not affected (a change from baseline to week 12 of −1.9%±6.8%, P=.286) (Figure 4).
At the end of the study, 12 patients (71%) were taking aliskiren monotherapy (aliskiren 150 mg daily, n=10; 300 mg daily, n=2), and aliskiren monotherapy significantly improved both cSBP (a change from baseline to week 12 of −12.6±10.7 mm Hg, P=.002) and baPWV (a change from baseline to week 12 of −121.0±136.0 cm/s, P=.010), although the AI was not affected (a change from baseline to week 12 of −2.6±7.2%, P=.250) (Figure 5).
The main finding of this study is that aliskiren-based antihypertensive therapy effectively lowers ambulatory BP throughout the 24-hour period in untreated non-diabetic Japanese patients with mild to moderate essential hypertension. In addition, the aliskiren-based therapy resulted in a significant improvement in vascular function. These therapeutic effects achieved with aliskiren merit further consideration.
With respect to the BP-lowering effects of aliskiren, while several previous studies showed that the reduced clinic BP-lowering responses to aliskiren tended to be more common in hypertensive patients with a low PRA at baseline, as is the case with other RAS inhibitors such as ARBs and ACE inhibitors,29,30 other studies reported that the antihypertensive effect of aliskiren was independent of the baseline PRA.28 Japanese hypertensive patients are reported to have a lower overall PRA than western hypertensive patients due to the high dietary salt intake in Japanese patients.31 In this study, although PRA was relatively low at baseline (0.7 ng/mL/h), the aliskiren-based therapy successfully caused substantial lowering of the clinic and ambulatory BP, not only for the 24-hour and daytime periods, but also for the nighttime period.
What might be the mechanism underlying the efficient BP-lowering effects of aliskiren in patients with relatively low renin profile? Previous animal studies demonstrated the critical role of the activation of the kidney AT1R in the pathogenesis of hypertension and its cardiovascular complications and suggested that the major mechanism of action of RAS inhibitors in hypertension was the attenuation of Ang II effects in the kidney.32,33 On the other hand, the (pro)renin receptor (PRR) is an emerging RAS component and is abundantly expressed in the kidney and cardiovascular system. PRR-bound renin and prorenin display enzymatic cleavage of angiotensinogen to Ang I, and the subsequently produced Ang II activates AT1R signaling at local tissue sites, including the kidney.34,35 Aliskiren was shown to be extensively distributed in kidney tissues and to efficiently inhibit the production of Ang II derived from PRR-bound renin and prorenin at the local tissue sites.36,37 Thus, it is possible that aliskiren exerts substantial BP-lowering effects through an effective blockade of kidney AT1R signaling, irrespective of the activity levels of circulating RAS, as reported recently.38 A recent study showed that, in the presence of a high sodium and low potassium diet, which suppresses renin release, circulating angiotensinogen concentrations are more closely related to aldosterone and BP than in patients receiving a low-sodium and high-potassium diet.39 Further studies are needed to examine the mechanistic basis of the aliskiren-mediated therapeutic effects on low renin hypertension.
This study also shows that aliskiren exerted a beneficial effect on central hemodynamics (cSBP) and arterial stiffness (baPWV). Dihydropyridine CCBs, either as monotherapy or when used in combination with RAS blockers, have been reported to effectively reduce central BP to a greater extent than peripheral BP, as reported in the Conduit Artery Function Evaluation (CAFE) study.6,40 With respect to the possible beneficial effects of aliskiren on vascular function, accumulating experimental evidence has shown the beneficial effects of aliskiren on atherosclerosis and plaque stability. A previous study conducted leukocyte adhesion assays in vivo and in vitro using a novel real-time imaging system and showed that treatment with aliskiren significantly suppressed the leukocyte-endothelial interaction, a crucial step in vascular inflammation.41 In another previous study, treatment with aliskiren had protective effects on endothelial function via improvement in nitric oxide bioavailability and protected against atherosclerotic changes in Watanabe heritable hyperlipidemic rabbits.42 Other animal studies also revealed a prominent role for macrophage-derived renin in the development of atherosclerotic vascular changes43 and showed that renin inhibition by aliskiren resulted in striking reductions of pathological vascular change and atherosclerotic lesion size in genetically atherosclerosis-susceptible mice.43–45
Further, a previous clinical study showed that aliskiren improved the parameters of systemic vascular function, including arterial stiffness and endothelial function in diabetic patients,46 and, recently, a significantly greater reduction in central BP was observed with aliskiren/HCTZ combination therapy than amlodipine monotherapy.47 Given the well-known beneficial effects of CCBs on central hemodynamics as described above, it would be of interest if there were improvements in the vascular function parameters also on those patients who were treated with aliskiren only, without the addition of a CCB. The results of this study demonstrated that aliskiren exerted a beneficial effect on central hemodynamics (cSBP) and arterial stiffness (baPWV) not only in overall study patients (n=17) but also in patients taking aliskiren monotherapy (n=12).
Concerning the measurement of PWV, the most frequently studied index to date among a variety of PWV measures is carotid-femoral PWV (cfPWV), which is the gold standard and is most widely used in clinical practice.48 The cfPWV has been used in landmark studies of arterial stiffness conducted in Europe49,50 as well as in the Framingham Heart Study in the United States.51 On the other hand, an emerging measure of PWV that has been widely used in Japan and other East Asian countries in the past 10 years is baPWV.52 Although clinical evidence is still relatively limited, baPWV was an independent predictor for cardiovascular deaths and events in a small cohort of coronary heart disease patients,53 and baPWV and cfPWV were indices of arterial stiffness that exhibit similar extent of associations with cardiovascular disease risk factors and clinical events in the relatively large community-based research studies from 6 different institutions in Japan and 1 in the United States.54 Therefore, although this is a relatively short-term trial and it may be difficult to assess the beneficial effects of aliskiren on vascular remodeling beyond BP-lowering effects, the present results suggest potential vascular protective effects of aliskiren in untreated nondiabetic patients with mild to moderate hypertension.
The limitations of the present study include both the small number of patients and the study design. A prospective single-arm trial lacking a placebo control group does not allow for inferences to be made regarding cause and effect. Since the present study compared the parameters at baseline and after the aliskiren-based antihypertensive therapy, the influence of the timing of the therapy could not be fully excluded. Also, there was no mention of recording standards, ie, hours without smoking, meals, and caffeine. Furthermore, although the addition of aliskiren to the ARB losartan proved synergistic in lowering proteinuria in patients with diabetic nephropathy,55 an increase in adverse events and no apparent benefits among patients randomized to aliskiren in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE),56 which is a randomized, double-blind, placebo-controlled study in high-risk type 2 diabetic patients receiving aliskiren or placebo added to the preceding treatment including ACE inhibitor or ARB, has prompted an early termination of the study. Therefore, the long-term organ protective potential of aliskiren and its superiority over existing therapies remains to be elucidated. Further studies are also necessary to compare the beneficial effects of aliskiren-based therapy on target organ function with those of ACE inhibitor– or ARB-based therapy in hypertension.
These results suggest that aliskiren as a first-line regimen improves ambulatory BP profile as well as clinic BP and may afford protective vascular effects in patients with untreated mild to moderate essential hypertension and a relatively low renin profile.
This work was supported in part by grants from the Japanese Ministry of Education, Science, Sports and Culture, by Health and Labor Sciences Research grant and by grants from Salt Science Research Foundation (No. 1033, 1134), the Kidney Foundation, Japan (JKFB11-25), and Strategic Research Project of Yokohama City University. Pacific Edit reviewed the manuscript prior to submission. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.