Rita Samuel

Valsartan: more than a decade of experience.

Valsartan is a nonpeptide angiotensin receptor antagonist that selectively blocks the binding of angiotensin II to the angiotensin II type 1 receptor. The efficacy, tolerability and safety of valsartan have been demonstrated in large-scale studies in hypertension, heart failure (HF) and post-myocardial infarction (MI). This review focuses on what was learned from the valsartan clinical research programme and other comparative trials published from 1997 to the present. Many studies have demonstrated the efficacy of valsartan in lowering blood pressure (BP) in a variety of patient populations (including elderly, women, children, obese patients, patients with diabetes mellitus, patients with chronic kidney disease [CKD], patients at high risk of cardiovascular [CV] disease, African Americans, Hispanic Americans and Asians) and in improving outcomes in CV disease and CKD. In hypertension, valsartan exhibits dose-dependent efficacy in reducing both systolic and diastolic BP over the once-daily dose range of 80-320 mg; doses as high as 640 mg/day have been studied and found to be efficacious and safe. BP control can be enhanced with a more consistent 24-hour BP-lowering profile by using single-pill, fixed-dose combination therapy with valsartan plus hydrochlorothiazide (HCTZ). The cardioprotective benefits of valsartan have been demonstrated in large-scale outcome trials and include significant reductions in CV morbidity and mortality in HF, following MI, and in patients with co-morbid hypertension and coronary artery disease and/or HF; reductions in HF hospitalizations; and reductions in the incidence of stroke. The magnitude of these effects is comparable with that demonstrated with angiotensin-converting enzyme (ACE) inhibitors; however, valsartan has a more favourable tolerability profile, with a significantly lower incidence of cough and only rare reports of angio-oedema, both class effects of ACE inhibitor use. Consistent with its angiotensin receptor-blocking effects, valsartan also reduces circulating levels of biochemical markers that are associated with angiotensin II-mediated endothelial dysfunction and CV risk (e.g. high-sensitivity C-reactive protein or oxidized low-density lipoprotein). Improvements in CKD with valsartan include statistically and clinically meaningful reductions in urinary albumin and protein excretion in patients with type 2 diabetes and in nondiabetic patients with CKD. In short-term studies, valsartan has improved or stabilized various indices of metabolic function in at-risk patients, including those with co-morbid hypertension, obesity and/or metabolic syndrome. Because of this, valsartan is being prospectively investigated for its ability to reduce the incidence of new-onset diabetes and provide cardioprotection in patients with impaired glucose tolerance. Valsartan and valsartan/HCTZ are well tolerated. In clinical trials, adverse events during valsartan treatment were similar to those occurring with placebo. The combination of valsartan/HCTZ was better tolerated than HCTZ alone. Valsartan is administered once daily for hypertension; doses are usually taken upon awakening. In patients with HF or MI, valsartan is administered twice daily.

Angiotensin receptor blocker/diuretic combination preserves insulin responses in obese hypertensives

Background Thiazide diuretics can impair glucose metabolism and increase new-onset diabetes. Adding an angiotensin receptor blocker to diuretics may protect against these metabolic effects; however, the mechanism of this protection is unclear. Method To explore potential mechanisms, a 16-week multicenter trial was conducted to ascertain the relative glucose metabolism effects of combined hydrochlorothiazide and angiotensin receptor blocker (valsartan) therapy compared with hydrochlorothiazide and calcium channel blocker (amlodipine) treatment in 412 centrally obese hypertensive individuals (BMI = 35 ± 7 kg/m2, seated BP = 159 ± 8/94 ± 8 mmHg, and mean age 56 years). Individuals were randomized to valsartan/hydrochlorothiazide, with force-titration to 320/25 mg or hydrochlorothiazide, with titration to hydrochlorothiazide 25 mg and amlodipine 10 mg, respectively. Changes from baseline to week 16 in fasting and 2-h postprandial glucose and insulin levels after an oral glucose load were measured. Results At week 16, clinic blood pressure reductions were similar (P > 0.05) in both groups. Fasting and 2-h glucose levels increased (P < 0.05) with the amlodipine combination but not with the valsartan combination. In concert with these glucose responses, postprandial insulin increases from baseline were substantially greater with valsartan than with amlodipine plus hydrochlorothiazide group (P = 0.001). The glucose responses were inversely related to insulin responses at the study conclusion. Conclusion The novel observation of this investigation was that the combination of valsartan and hydrochlorothiazide was associated with greater glucose-stimulated insulin secretory and lesser glycemic excursion responses than the amlodipine combination group. Thus, this data suggests that adding an angiotensin receptor blocker attenuates the negative effects of thiazides on pancreatic beta-cell glucose-induced insulin secretion.

Improving Blood Pressure Control : Increase the Dose of Diuretic or Switch to a Fixed-Dose Angiotensin Receptor Blocker/Diuretic? The Valsartan Hydrochlorothiazide Diuretic for Initial Control and Titration to Achieve Optimal Therapeutic Effect (Val-DICTATE) Trial

To assess the strategy of increasing the dose of a diuretic compared with using an angiotensin receptor blocker in combination with a diuretic, the authors performed a multicenter, randomized, parallel group trial in hypertensive patients (baseline blood pressure [BP], 153/97 mm Hg) whose BP remained uncontrolled on initial low‐dose diuretic monotherapy (hydrochlorothiazide [HCTZ] 12.5 mg Hg). Patients with stage 1 and 2 hypertension were randomized to treatment with valsartan/HCTZ (160/12.5 mg) or to doubling of the HCTZ dose (25 mg). The primary end point was the percentage of patients whose clinic BP values were <140/90 mm Hg following 4 weeks of double‐blind therapy. A significantly higher proportion (P<.001) of hypertensive patients met BP control levels in the valsartan/HCTZ (160/12.5 mg) group compared with the HCTZ 25 mg group (37% vs 16%). Changes from baseline in BP were significantly greater (P<.001) for both systolic BP and diastolic BP in the combination therapy arm compared with the diuretic monotherapy arm (−12. 4/−7.5 mm Hg in valsartan/HCTZ 160/12.5 mg group vs −5.6/−2.1 mm Hg in HCTZ 25 mg group). Tolerability and adverse events were similar in the 2 treatment groups. This study suggests that in the management of hypertension, utilizing an angiotensin receptor blocker/diuretic combination was more effective in lowering BP and achieving BP goals when compared with increasing the dose of the diuretic.

Effects of force-titrated valsartan/hydrochlorothiazide versus amlodipine/hydrochlorothiazide on ambulatory blood pressure in patients with stage 2 hypertension: the EVALUATE study.

BackgroundPrevious studies using the combination of angiotensin-receptor blockers and hydrochlorothiazide (HCTZ) have shown superior ambulatory blood pressure (ABP) reduction in study participants with stage 2 hypertension compared with monotherapy. ObjectiveThis multicenter, double-blind, parallel group, forced-titration study of individuals with stage 2 hypertension, compared the efficacy of valsartan and amlodipine in combination with HCTZ on ABP reduction. MethodsAfter a 2-week washout period, participants (n=482) with mean office sitting systolic BP ≥160 mmHg and ≤200 mmHg were randomized to receive treatment with either valsartan 160 mg (n=241) or amlodipine 5 mg (n=241), force-titrated to a maximum dose of valsartan/HCTZ 320/25 mg or amlodipine/HCTZ 10/25 mg over 6 weeks and continued through week 10. The primary endpoint was change in mean 24-h ambulatory systolic BP from baseline to week 10. ResultsAt week 10, changes from baseline in mean office BP were significantly (P<0.0001) decreased by both valsartan/HCTZ (−34.2/−14.2 mmHg) and amlodipine/HCTZ (−34.1/−14.7 mmHg). Changes from baseline in mean 24-h ABP were significantly (P<0.0001) decreased by both valsartan/HCTZ (−21.1/−12.5 mmHg) and amlodipine/HCTZ (−18.1/−9.9 mmHg). However, treatment with valsartan/HCTZ provided significant additional systolic BP (−3.8 mmHg; P=0.0042) and diastolic BP (−2.7 mmHg; P=0.0002) reduction compared with the amlodipine/HCTZ group. The proportion of individuals reaching the office goal BP (<140/80 mmHg) were similar in the valsartan/HCTZ (55.3%) versus amlodipine/HCTZ (54.9%) group, ABP control rates for the recommended ABP goal (<130/80 mmHg) were greater (P=0.0170) in the valsartan/HCTZ group (54.3%) than the amlodipine/HCTZ group (42.7%). Both treatments were well tolerated. ConclusionOn the basis of ABP monitoring but not office measurements, the fixed-dose combination of valsartan/HCTZ is a significantly more effective treatment regimen than amlodipine/HCTZ, with similar tolerability.

Combination angiotensin-receptor blocker (ARB)/calcium channel blocker with HCTZ vs the maximal recommended dose of an ARB with HCTZ in patients with stage 2 hypertension: the exforge as compared to losartan treatment in stage 2 systolic hypertension (EXALT) study.

J Clin Hypertens (Greenwich). 2011;13:588–597.

Treating systolic hypertension in the very elderly with valsartan-hydrochlorothiazide vs. either monotherapy: ValVET primary results.

J Clin Hypertens (Greenwich). 2011;13:722–730. ©2011 Wiley Periodicals, Inc.

The role of ambulatory blood pressure monitoring compared with clinic and home blood pressure measures in evaluating moderate versus intensive treatment of hypertension with amlodipine/valsartan for patients uncontrolled on angiotensin receptor blocker monotherapy

ObjectivesAmbulatory blood pressure monitoring (ABPM) has greater predictive value than office blood pressure (BP) with respect to hypertension-related target-organ damage and morbidity. ABPM in a subset of 80 patients from the Exforge Target Achievement trial (N=728) was used to compare the efficacy of intensive-treatment and moderate-treatment regimens of amlodipine/valsartan, and to determine whether treatment differences could be better assessed with ABPM than with office or home BP. Home BP was measured on the morning of clinic visits to minimize differences that timing might have on home versus office BP measures. MethodsA 12-week randomized, double-blind study in which hypertensive patients earlier uncontrolled (mean sitting systolic BP≥150 and <200 mmHg) on angiotensin receptor blocker monotherapy (other than valsartan) after 28 days or more (N=728) were randomized to amlodipine/valsartan treatment [10/320 mg (intensive) or 5/160 mg (moderate)]. Treatment-naive patients (in previous 28 days) or patients who failed on a nonangiotensin receptor blocker agent underwent a 28-day run-in period with a 20-mg or 40-mg dose of olmesartan, respectively. ResultsSignificantly greater 24-h ABP reductions from baseline to week 4 (primary time point) were observed with intensive versus moderate treatment (least-square mean systolic/diastolic BP reduction of −16.2/−10.1 vs. −9.5/−6.5 mmHg; P=0.0024/P=0.010 for least-square mean difference). Similarly, a significantly greater proportion of patients receiving an intensive treatment achieved ambulatory BP goal (<130/80 mmHg) at week 4 than did those receiving a moderate treatment (P=0.040). Treatment-group differences did not reach statistical significance for these end points when measured by office and home BP. ConclusionIn this first randomized trial evaluating the effects of intensive versus moderate dosing of the combination of amlodipine/valsartan, our data suggest that ABPM was a better method for assessing between-treatment differences than clinic or home BP recordings, although measurement of home BP as a single recording was a limitation of our trial.

Moderate versus intensive treatment of hypertension with amlodipine/valsartan for patients uncontrolled on angiotensin receptor blocker monotherapy

Objectives Many angiotensin receptor blocker (ARB) monotherapy patients need at least two agents to control blood pressure (BP). We investigated whether initiating intensive treatment with combination amlodipine/valsartan was superior to moderate treatment with amlodipine/valsartan in patients previously uncontrolled on ARB monotherapy. Methods In this 12-week study, patients aged at least 18 years on ARB (other than valsartan) for at least 28 days (with treatment-naïve patients or those not controlled on agents other than an ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic blood pressure (MSSBP; ≥150–<200 mmHg) were randomized to amlodipine/valsartan 5/320 mg (n = 369) or 5/160 mg (n = 359). At week 2, the dose was increased to 10/320 mg in the intensive arm. Hydrochlorothiazide 12.5 mg was added to both arms at week 4. Optional up-titration with hydrochlorothiazide 12.5 mg at week 8 was allowed if MSSBP was more than 140 mmHg. Results At baseline, mean office sitting BP was comparable in the intensive (163.9/95.5 mmHg) and moderate (163.3/95.0 mmHg) groups. Intensive treatment provided greater BP reductions versus moderate treatment (P < 0.05) from week 4 (−23.0/−10.4 versus −19.2/−8.7 mmHg; primary endpoint) to week 12 (−29.0/−14.8 versus −25.3/−12.3 mmHg). Adverse events were reported by a similar percentage of patients in both groups (36.3% intensive, 37.6% moderate); peripheral edema was more common with intensive versus moderate treatment (8.7 versus 4.5%; P = 0.025). Conclusions Initiating treatment with an intensive dose of amlodipine/valsartan provides significantly greater BP lowering versus moderate treatment in hypertensive patients unresponsive to ARB monotherapy. Both treatment regimens were generally well tolerated based on adverse event reports, but the lack of routine laboratory testing after screening limits conclusions on tolerability.

Ambulatory blood pressure response to triple therapy with an angiotensin-receptor blocker (ARB), calcium-channel blocker (ccB), and HcTZ versus dual therapy with an ARB and HcTZ

Background Stage 2 hypertension often requires combination antihypertensive therapy. Ambulatory blood pressure monitoring (ABPM) is a useful tool for assessing antihypertensive drugs and their combinations. Objective To compare the effect of a moderate dose of angiotensin receptor blocker/calcium channel blocker (ARB/CCB) combined with a diuretic versus a maximal dose of ARB with a diuretic on 24-hour ambulatory blood pressure monitoring (ABPM) and other derived ambulatory blood pressure (ABP) parameters. Methods The EXforge As compared to Losartan Treatment ABPM substudy was a randomized, double-blind, parallel-group, active-control, forced-titration study of patients with Stage 2 hypertension that compared the efficacy of initial treatment with valsartan/amlodipine 160/5 mg (n = 48) or losartan 100 mg (n = 36). At week 3, hydrochlorothiazide (HCTZ) 25 mg was added in both treatment groups. ABP was measured at baseline and at week 6. Additionaly, 24-hour ABP, nighttime (10 pm to 6 am) and daytime (6 am to 10 pm) ABP, and ABP load (percentage of readings above 140/90 mmHg) were determined. Results Eighty-four patients (48 ARB/CCB/HCTZ, 36 ARB/HCTZ) had ABPM at baseline and at week 6. Reductions of systolic/diastolic ABP were greater in the ARB/CCB/ HCTZ group than in the ARB/HCTZ group for 24-hour mean ABP (−22.0/−13.3 versus −17.4/−8.1 mmHg), as well as nighttime ABP (−22.2/−13.3 versus −16.2/−7.4 mmHg), daytime ABP (−21.9/−13.0 versus −18.1/−8.6 mmHg), ABP in the last 4 hours of the dosing period (−21.5/−13.5 versus −17.0/−7.7 mmHg), and ABP load (21.7%/12.8% versus 30.8%/20.0%). Conclusion Initiating antihypertensive treatment with moderate doses of ARB/CCB with a diuretic is more effective in lowering nighttime and daytime ABP and reducing ABP load than a maximal dose of an ARB with a diuretic.

Moderate versus intensive treatment of hypertension using amlodipine/valsartan and with the addition of hydrochlorothiazide for patients uncontrolled on angiotensin receptor blocker monotherapy: Results in racial/ethnic subgroups

Combination therapy may reduce racial/ethnic differences in response to antihypertensives. In this post-hoc analysis, we evaluated treatment response by race/ethnicity among hypertensive adults enrolled in a 12-week, double-blind study in which patients previously uncontrolled (mean sitting systolic blood pressure [MSSBP] ≥150 and <200 mm Hg) on angiotensin receptor blocker (ARB) monotherapy (other than valsartan) for 28 days or more (n = 728) were randomized to amlodipine/valsartan 10/320 mg (intensive) or 5/160 mg (moderate). Treatment-naïve patients (in previous 28 days) or those who failed on a non-ARB first underwent a 28-day run-in period with olmesartan 20 mg or 40 mg, respectively. Hydrochlorothiazide (HCTZ) 12.5 mg was added to both arms at week 4; optional up-titration to 25 mg at week 8 (if MSSBP >140 mm Hg). Intensive treatment provided greater BP lowering versus moderate treatment throughout the study, regardless of race/ethnicity (474 white, 198 African American, 165 Hispanic individuals). Least-square mean reductions from baseline to week 4 in MSSBP (primary outcome) ranged from 20.4 to 23.5 mm Hg (intensive) versus 17.5 to 19.0 mm Hg (moderate), across racial/ethnic subgroups. Both regimens were well tolerated. Amlodipine/valsartan/HCTZ combination therapy was efficacious across racial/ethnic subgroups. Maximal efficacy was obtained with intensive treatment.