Renate Handrock

Effects of selective angiotensin II receptor blockade on sympathetic nerve activity in primary hypertensive subjects.

Objective The role of the renin–angiotensin system in the regulation of sympathetic nervous activity in human hypertension was evaluated in patients with moderate primary hypertension. For that purpose, the effects of selective angiotensin II (ANG II) receptor blockade by valsartan on sympathetic outflow to the muscle vascular bed and hemodynamic parameters were examined. Results were compared with the effects of the peripherally acting calcium antagonist amlodipine. Design Eighteen hypertensive but otherwise healthy subjects were examined in a double-blind, placebo-controlled, cross-over protocol receiving either valsartan or amlodipine or placebo for 7 days in a randomized sequence. Treatment periods were separated by washout periods of 2 weeks. Methods At the seventh day of treatment, blood pressure, heart rate, muscle sympathetic nerve activity (MSNA), norepinephrine, renin and angiotensin were measured during resting conditions. Additionally, parameters were measured after administration of negative pressure of −15 mmHg to the lower part of the body and after a cold pressor test. Results Both antihypertensive drugs significantly decreased oscillometrically measured systolic blood pressure and diastolic blood pressure without any difference in effect. While valsartan did not affect the heart rate at rest, amlodipine increased it significantly. Likewise, MSNA was significantly enhanced by amlodipine but not by valsartan. Only ANG II receptor blockade increased renin and angiotensin levels. Conclusions Selective ANG II receptor blockade not only decreases blood pressure, but also shifts the baroreflex set-point for the initiation of counter-regulatory reflex responses of heart rate and blood pressure towards normal blood pressure levels. Thus, data suggest that ANG II plays a pathogenetic role in the elevation of the baroreflex set point in primary hypertensive subjects.

Valsartan in combination with lisinopril versus the respective high dose monotherapies in hypertensive patients with microalbuminuria: The VALERIA trial

Objectives Microalbuminuria is known as an independent predictor for stroke, myocardial infarction, and death. The purpose of the VALERIA trial was a comparison of the efficacy and safety of combination therapy of valsartan and lisinopril with valsartan and lisinopril high-dose monotherapy in patients with hypertension and microalbuminuria. Methods This was a randomized, double-blind, interventional, parallel-group study. After a washout/placebo- run-in phase of 3 weeks, 133 patients were randomized to treatment (1: 1:1) with either lisinopril 40 mg, valsartan 320 mg, or a combination of valsartan/lisinopril 320/20 mg for 30 weeks. Results At baseline, the urine albumin creatinine ratio was similar for the three treatment groups (geometric means, lisinopril 9.6 mg/mmol, valsartan 9.1 mg/mmol, and valsartan/lisinopril 9.5 mg/mmol). After 30 weeks of treatment, the geometric mean urine albumin creatinine ratio had decreased in all three groups by 41, 51, and 62% to 5.7 mg/mmol (lisinopril), 4.5 mg/mmol (valsartan), and 3.6 mg/mmol (valsartan/lisinopril). The decrease for valsartan/lisinopril was statistically significantly greater compared with lisinopril [adjusted ratio 60%, confidence interval (38–94%), P = 0.029]. Normalization of microalbuminuria was greatest with valsartan and valsartan/lisinopril (lisinopril 17%, valsartan 31%, and valsartan/lisinopril 38% of patients) and was statistically significant for lisinopril in contrast with valsartan/lisinopril (P = 0.034). Differences in blood pressure reduction between the groups were not statistically significant. All treatments were safe and well tolerated. Conclusion The combination of valsartan and lisinopril provided a significantly better reduction of urine albumin creatinine ratio and more than doubled the rate of patients with normalized urine albumin creatinine ratio compared with lisinopril alone. All treatments were safe and well tolerated.

Effective and safe reduction of blood pressure with the combination of amlodipine 5 mg and valsartan 160 mg in hypertensive patients not controlled by calcium channel blocker monotherapy

IntroductionThe addition of an angiotensin II receptor blocker to calcium channel blocker-based antihypertensive therapy may be associated with enhanced efficacy and reduced risk of adverse events.MethodsThis 8-week, open-label, single-arm trial evaluated the efficacy and tolerability of the combination of amlodipine and valsartan in patients not responding adequately to treatment with amlodipine or felodipine alone. Patients aged ≥18 years with moderate essential hypertension (defined as mean sitting systolic blood pressure [MSSBP] ≥160 and <180 mmHg) were treated for 4 weeks with once-daily amlodipine 5 mg or felodipine 5 mg. At week 4, patients not adequately responding were treated for an additional 4 weeks with once-daily amlodipine 5 mg plus valsartan 160 mg. Of 214 patients treated for 4 weeks with amlodipine 5 mg or felodipine 5 mg, 181 failed to achieve MSSBP <140 mmHg. These non-responders were treated for an additional 4 weeks with amlodipine 5 mg and valsartan 160 mg.ResultsA clinically and statistically significant additional reduction in MSSBP of 13.1 mmHg (95% confidence interval [CI]: 11.4, 14.7; P<0.0001) and a mean sitting diastolic blood pressure of 5.3 mmHg (95% CI: 4.3, 6.3; P<0.0001) were observed. Of patients treated with amlodipine 5 mg and valsartan 160 mg, 51.1% achieved target blood pressure levels (<140/90 mmHg) after 4 weeks. Adverse event rates were low in both treatment phases, and most were mild or moderate in severity.ConclusionThe combination of amlodipine/valsartan was effective and well tolerated.

Antihypertensive Effects of Valsartan/Hydrochlorothiazide Combination in Essential Hypertension

Fixed-dose combination therapy has received increased interest since publication of JNC-VI report and WHO/ISH guidelines 1999. We compared in a randomized, double-blind study the efficacy and tolerability of valsartan 80 mg combined with hydrochlorothiazide (HCTZ) 12.5 mg to monotherapy with either HCTZ 12.5 mg or 25 mg in patients with essential hypertension inadequately controlled by previous HCTZ 12.5 mg monotherapy. Two hundred and seventeen patients whose blood pressure (BP) control remained poor (95 mmHg h sitting diastolic BP <115 mmHg) after a 4-week single-blind period with HCTZ 12.5 mg were randomized to receive either combination therapy with valsartan 80 mg plus HCTZ 12.5 mg (V/HCTZ) or monotherapy with HCTZ 12.5 mg or HCTZ 25 mg for 8 weeks. Reduction of sitting trough diastolic BP between baseline and week 8 as well as tolerability was evaluated. Reduction in trough diastolic BP was most pronounced in the V/HCTZ group (–11.3 mmHg) and significantly greater than in the HCTZ 12.5 mg group (–2.9 mmHg, p <0.001) and the HCTZ 25 mg group (–5.7 mmHg, p <0.001). Tolerability of study medication was comparable between all three groups. In conclusion, switching to V/HCTZ combination therapy provides an additional lowering of BP compared to dosage increase of the thiazide in patients with BP insufficiently controlled by HCTZ 12.5 mg monotherapy.

Impact of supportive measures on drug adherence in patients with essential hypertension treated with valsartan: the randomized, open-label, parallel group study VALIDATE.

Objective The majority of treated hypertensive patients do not achieve target blood pressure (BP) levels of less than 140/90 mmHg. One key reason is inadequate adherence with the prescribed drug regimen. Dosing regimens are either not executed as prescribed (noncompliance) or patients stop taking the medication (nonpersistence). It has been demonstrated that adherence with angiotensin receptor antagonists such as valsartan is high due to the tolerability profile of this drug class. The present study was designed to evaluate whether drug adherence could further be improved by the use of supportive measures. Design and methods Twenty-eight centers were randomized to provide pharmacological treatment with or without a set of supportive measures (e.g. structured physician–patient interaction, printed information about hypertension, reminder stickers, 24 h timer, and home BP measurement device). Two hundred and two patients with grade 1 hypertension (BP at baseline 149.8 ± 6.2/93.9 ± 4.4 mmHg) who were either newly diagnosed or who had not been treated for at least 1 year were included in this trial. All patients entered the 34-week treatment phase with valsartan 160 mg daily. Titration to valsartan 160 mg/hydrochlorothiazide 12.5 mg was allowed if necessary. Drug adherence was assessed by electronic monitors (Medication Event Monitoring System). Results Patients treated with a valsartan-based therapy receiving supportive measures as compared with the standard care group demonstrated an initially higher level of adherence with a maximum absolute difference of 7.8% (P = 0.041). This difference did not persist over the observation period but faded with time. In parallel, execution of the dosing regimen (compliance) was also improved in the intervention group during the early months of treatment but this effect also disappeared by the end of the observation period. In contrast, persistence in the two groups slowly but continuously separated over time. Estimated absolute difference in persistence at the end of the 34-weeks study between the two groups was 7.6% (95.9 vs. 88.3%) reflecting a 66% lower hazard of discontinuation in the intervention group (P = 0.073). BP control improved more in patients with the supportive measures. Conclusion Drug adherence improved initially with the use of supportive measures. However, this effect faded with time mainly because of the short-lived improvement in the quality of execution (compliance) achieved. In contrast, a longer lasting effect of the chosen supportive measures on persistence could be demonstrated, which, however, at least under the conditions of the present study, did not translate into a persistent improvement of medication adherence.

Efficacy and safety of the single pill combination of amlodipine 10 mg plus valsartan 160 mg in hypertensive patients not controlled by amlodipine 10 mg plus olmesartan 20 mg in free combination.

ABSTRACT Background and objective: For patients with moderate hypertension (grade 2, defined as systolic blood pressure [SBP] 160–179 mmHg and/or diastolic blood pressure [DBP] 100–109 mmHg), current guidelines recommend initial combination therapy and rapid dose-adjustment to achieve blood pressure goal. In this study we investigated the efficacy and tolerability of the single pill combination of amlodipine 10 mg plus valsartan 160 mg (A 10 + Val 160) in patients not controlled by the free combination of amlodipine 10 mg plus olmesartan 20 mg (A 10 + O 20). Methods: In this prospective, open-label, non-randomized trial, 257 patients with mean sitting DBP of 100–109 mmHg at trough entered a 4 week treatment phase with A 10 + O 20 in free combination once daily. Patients in whom DBP remained uncontrolled were switched in a second 4 week treatment phase to A 10 + Val 160. The primary efficacy variable was the reduction in DBP at week 8 compared to week 4 in the intent-to-treat population. Results: In the total cohort, baseline SBP/DBP of 164.2 ± 9.8/103.6 ± 2.1 mmHg decreased by 19.2 ± 12.4/14.1 ± 7.4 mmHg at week 4. In patients who did not achieve BP control (n = 175), subsequent treatment with A 10 + Val 160 for 4 weeks reduced SBP from 149.6 ± 11.1 at week 4 by 7.9 mmHg at week 8 (95% CI: 6.1–9.6, p < 0.0001) and DBP from 93.4 ± 3.9 mmHg by 9.1 mmHg (95% confidence interval: 8.1–10.2, p < 0.0001). The combination of A 10 + Val 160 was well tolerated, and the observed adverse events (15.3% of patients in phase 2) were consistent with the known drug profiles. Conclusions: In a study designed to reflect typical clinical practice, in patients not controlled by the free combination of A 10 + O 20, the single pill combination of A 10 + Val 160 produced a statistically and clinically significant additional BP reduction and was well tolerated. Potential limitations of the design (open-label, non-controlled design, short term treatment) have to be taken into account.

Combination of amlodipine 10 mg and valsartan 160 mg lowers blood pressure in patients with hypertension not controlled by an ACE inhibitor/CCB combination

Aims. This multicenter, open-label, single-arm trial assessed the efficacy of the combination of amlodipine 10 mg and valsartan 160 mg to provide additional blood pressure reduction and tolerability in patients with moderate hypertension not adequately responding to the combination of ramipril 5 mg and felodipine 5 mg. Results. Of 133 patients treated for 5 weeks with ramipril 5 mg and felodipine 5 mg, 105 failed to achieve mean sitting systolic blood pressure <140 mmHg. These non-responders were then treated for an additional 5 weeks with amlodipine 10 mg and valsartan 160 mg, which resulted in clinically and statistically significant additional reductions in mean sitting systolic blood pressure of 15.4 mmHg (p<0.0001) and mean sitting diastolic blood pressure of 7.0 mmHg (p<0.0001). Adverse event rates were low with both treatment regimens. Conclusions. In hypertensive patients not controlled at 5 weeks by ramipril 5 mg and felodipine 5 mg, significant additional blood pressure reductions were observed after 5 weeks of treatment with amlodipine 10 mg and valsartan 160 mg. The combination of amlodipine 10 mg and valsartan 160 mg was well tolerated.

Valsartan and retinal endothelial function in elderly hypertensive patients

Background. The aim of this study was to investigate the impact of short‐term treatment with the angiotensin II receptor blocker (ARB) valsartan on retinal endothelial function in elderly patients with mild to moderate essential hypertension. Methods. In an open‐labeled study, 20 elderly, male patients with arterial hypertension (WHO I–II) were treated with the ARB valsartan (80–160 mg once daily) over 8 days. Central retinal artery perfusion at rest and during flicker light stimulation was measured before and after treatment using pulsed wave Doppler sonography. Retinal capillary flow was assessed with scanning laser Doppler flowmetry at rest and following systemic infusion of the nitric oxide synthase (NOS) inhibitor NG‐monomethyl‐l‐arginine (L‐NMMA). Results. While valsartan significantly lowered blood pressure, central retinal artery perfusion at rest as well as after flicker light stimulation was similar before and after treatment. Similarly, retinal capillary flow at rest and after infusion of L‐NMMA did not change with valsartan after 7 days of treatment. Subgroup analysis revealed that changes in retinal capillary flow in response to L‐NMMA might be dependent on serum low‐density lipoprotein (LDL) cholesterol levels of study participants. After treatment with valsartan, retinal capillary flow in response to L‐NMMA decreased more in patients with low (<3.54 mmol/l) than with high LDL‐cholesterol levels (−12.6±20.2% vs 12.3±19.5%, p<0.05). Conclusion. Short‐term treatment with valsartan did not improve retinal endothelial function in elderly hypertensive patients.

Efficacy and Safety of Valsartan 160mg/Hydrochlorothiazide 25mg Combination in Patients with Hypertension not Adequately Controlled by Valsartan 160mg/ Hydrochlorothiazide 12.5mg

AbstractBackground and objective: Hypertension guidelines emphasise the need to treat high blood pressure (BP) early and aggressively, giving fixed-dose combinations special consideration. Hitherto, it has not been assessed in a sequential way whether hypertensive patients with inadequately controlled hypertension with an angiotensin II receptor antagonist/hydrochlorothiazide combination benefit from a dose increase of the diuretic. We investigated the efficacy and safety of valsartan 160mg/hydrochlorothiazide 25mg combination in patients with hypertension that was not adequately controlled by valsartan 160mg/hydrochlorothiazide 12.5mg. Patients and methods: This was a multicentre, single-group, prospective study of 646 patients with moderate hypertension (diastolic BP [DBP] 100–109mm Hg). Patients were treated for 4 weeks with valsartan 160mg/hydrochlorothiazide 12.5mg (phase 1: weeks 1–4). In case of non-response (DBP ≥90mm Hg; n = 224) patients were treated for a further 4 weeks with valsartan 160mg/hydrochlorothiazide 25mg (phase 2: weeks 5–8). The primary efficacy measure was a change in mean sitting trough DBP at study end compared with the beginning of phase 2 in the intention-to-treat (ITT) population (n = 221). Results: Mean age of patients at entry was 58.6 years; 53.7% of patients were female. In phase 1, systolic BP (SBP)/DBP decreased from a baseline value of 161.9/103.3mm Hg by −16.1/−12.4mm Hg (normalisation rate 38.3%, response rate 64.5%). In phase 2, in the ITT non-responder population the additional SBP/DBP decrease was −8.4/−8.3mm Hg. Overall, the normalisation rate in all patients was 55.4% and the responder rate was 76.3%.Tolerability of both the valsartan 160mg/hydrochlorothiazide 12.5mg and the valsartan 160mg/hydrochlorothiazide 25mg combinations was very good, and the switch to the higher dose did not result in an increase in adverse events (AEs) or laboratory abnormalities. Only 16.6% of patients in phase 1 and 10.3% of patients in phase 2 experienced one or more AEs. Conclusion: In patients with moderate hypertension, first-line therapy with the fixed-dose valsartan/hydrochlorothiazide combination leads to high normalisation and response rates. Patients with hypertension not controlled by valsartan 160mg/ hydrochlorothiazide 12.5mg clearly benefit from dose titration to valsartan 160mg/hydrochlorothiazide 25mg with a clinically relevant additional BP response and have excellent tolerability.