Albert Kandra

Valsartan Improves Arterial Stiffness in Type 2 Diabetes Independently of Blood Pressure Lowering

Increased arterial stiffness, as estimated from aortic pulse wave velocity (Ao-PWV), and albuminuria are independent predictors for cardiovascular disease in type 2 diabetes mellitus (T2DM). Whether angiotensin receptor blockers (ARBs), drugs with cardio-renal protective effects, improve Ao-PWV to a greater extent than other equipotent antihypertensive medications remains unclear. After a 4-week washout phase, we compared the effects of valsartan (n=66), an ARB, with that of amlodipine (n=65), a calcium channel blocker on Ao-PWV in 131 T2DM patients with pulse pressure (PP) ≥60 mm Hg and raised albumin excretion rate (AER) in a 24-week randomized, double-blind, parallel group study. Hydrochlorothiazide (HCTZ) 25 mg/d was added to valsartan 160 mg and amlodipine 5 mg/od uptitrated to 10 mg/od after 4 weeks to ensure equivalent BP control. After 24 weeks brachial and central aortic PP had fallen to a similar extent with attained mean (SD) brachial and central PP of 61.6 (13.6) and 47.3 (14.1) mm Hg in the valsartan/HCTZ group and 61.5 (12.2) and 47.3 (9.9) mm Hg in the amlodipine group, respectively. Ao-PWV showed a significantly greater reduction, mean (95% CI), −0.9 m/s (−1.4 to −0.3) for valsartan/HCTZ compared to amlodipine (P=0.002). AER fell significantly only with Val/HCTZ from 30.8(20.4, 46.5) to 18.2(12.5, 26.3) mcg/min, (P=0.01) with between treatment difference in favor of Val/HCTZ of −15.3mcg/min (P<0.001). Changes in AER and Ao-PWV were not correlated. Valsartan/HCTZ improves arterial stiffness and AER to a significantly greater extent than amlodipine despite similar central and brachial BP control. These 2 effects, which appear independent of each other, may explain the specific cardio-renal protective properties of ARBs.

Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double‐blind placebo‐controlled trial

In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal‐related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy, 300 patients were included in a randomized multi‐centre trial. Patients were given oral pamidronate at a dose of 300 mg daily, or placebo, in addition to conventional intermittent melphalan/prednisolone (and in some cases alpha‐interferon) treatment. With a median treatment duration of about 550 d, no statisticallly significant reduction in skeletal‐related morbidity (defined as bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions) could be demonstrated. Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia. However, in patients treated with pamidronate there were fewer episodes of severe pain (P = 0.02) and a decreased reduction of body height of 1.5 cm (P = 0.02). The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general.

Efficacy and safety of amlodipine/valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: a randomized, double-blind, multicenter study: the EX-EFFeCTS Study.

Achieving blood pressure (BP) targets in stage 2 hypertension usually requires two or more drugs, which should be selected from different classes. This study compared the efficacy and tolerability of amlodipine/valsartan with amlodipine in patients with stage 2 hypertension. In this multicenter, randomized, double-blind, 8-week study, 646 patients with stage 2 hypertension (mean sitting systolic blood pressure [MSSBP] >/=160 mm Hg) received amlodipine/valsartan 5/160 mg or amlodipine 5 mg for 2 weeks, prior to being force-titrated to amlodipine/valsartan 10/160 mg or amlodipine 10 mg, respectively, for a further 6 weeks. Hydrochlorothiazide could be added at Week 4 if MSSBP was >/=130 mm Hg. At endpoint Week 4, reductions in MSSBP were significantly greater in patients receiving amlodipine/valsartan than in those receiving amlodipine (30.1 mm Hg vs. 23.5 mm Hg; P < .0001). Likewise, MSSBP reductions in patients with baseline MSSBP >/=180 mm Hg were also greater for amlodipine/valsartan at Week 4 (40.1 mm Hg vs. 31.7 mm Hg for amlodipine; P = .0018). Differences favoring amlodipine/valsartan were also seen for BP control. Amlodipine/valsartan was generally well tolerated. These findings support the rationale for combining agents with complementary mechanisms of action, such as amlodipine and valsartan, in the management of stage 2 hypertension.

Interaction between baseline and early worsening of renal function and efficacy of renin–angiotensin–aldosterone system blockade in patients with heart failure: insights from the Val-HeFT study

We evaluated the effect of (dual) renin–angiotensin–aldosterone system (RAAS) blockade with valsartan and an ACE inhibitor [92.7% of patients were treated with an ACE inhibitor in the Valsartan in Heart Failure Trial (Val‐HeFT)] in patients with NYHA class II–IV heart failure (HF) and reduced EF on cardiovascular (CV) death and HF hospitalization by subgroups and by presence of early worsening of renal function (EWRF) and according to baseline estimated glomerular filtration rate (eGFR).

Prostate-specific antigen: A surrogate endpoint for screening new agents against prostate cancer?

An endpoint for clinical trials of prostate cancer which simplifies traditional endpoints (response of measurable lesions, progression rates, and death) is urgently needed. This is especially true for hormone‐unresponsive disease, for which many new drugs are presently in a development phase. This paper presents a rationale for the use of prostate‐specific antigen (PSA) in clinical trials of progressive prostate cancer under endocrine treatment.

Changes in Aortic Pulse Wave Velocity in Hypertensive Postmenopausal Women: Comparison Between a Calcium Channel Blocker vs Angiotensin Receptor Blocker Regimen

J Clin Hypertens (Greenwich). 2012;14:773–778. ©2012 Wiley Periodicals, Inc.

Clinical profile and prognostic significance of natriuretic peptide trajectory following hospitalization for worsening chronic heart failure: findings from the ASTRONAUT trial.

The purpose of this study was to determine the prognostic significance and associated clinical profile of early post‐discharge N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) trajectory among patients hospitalized for worsening chronic heart failure (HHF).

Use of automated blood pressure measurements in clinical trials and registration studies: data from the VALTOP Study.

BackgroundAuscultatory measurement of office blood pressure (BP) by mercury sphygmomanometers (AuscBPM) is still the gold standard in clinical trials and registration studies for antihypertensive drugs. The increasing availability of accurate automated oscillometric BP measuring devices has offered new perspectives in this field, although their usefulness in drug studies has not been systematically tested yet. MethodsDuring the course of Valsartan 320 mg EU Registration Study we used an electronic automated oscillometric BP measuring device (eBPM) as an alternative to conventional AuscBPM. Altogether 3776 patients were randomized into a double-blinded actively controlled parallel group study in 303 centers, and 54 422 BP readings were recorded by the validated, electronic, automated oscillometric device OMRON 705IT with digital printouts. Terminal digit preference and preference at therapeutic cutoff points were evaluated. The data were compared with the results of an earlier valsartan study similar in design but based on conventional AuscBPM. Furthermore, based on a simulation, four strategies for automated BP measurement with varying number of office readings (3–5) were analyzed to define an optimal method to collect BP at office visits. ResultseBPM eliminated terminal digit preference and dramatically reduced preferences for therapeutic cutoff points as compared with earlier valsartan trials with conventional AuscBPM. However, even with eBPM a minor bias with the therapeutic cutoff value was observed probably because of an observer bias during data documentation. The within-patient variability of three measurements sequentially taken at each visit was similar to other strategies including more measurements. ConclusionOn the basis of our data, we suggest that eBPM is a suitable alternative to AuscBPM in clinical trials and registration studies, and may carry specific advantages. Automatic data transfer of recorded values to electronic patient files may further minimize observer bias. Manufacturers should consider such findings for the development of professional devices.

24-hour ambulatory blood-pressure effects of valsartan & hydrochlorothiazide combinations compared with amlodipine in hypertensive patients at increased cardiovascular risk: A Vast sub-study

BACKGROUND There is a lack of data on the effects of angiotensin-receptor blocker and diuretic combinations on ambulatory blood pressure (ABP) in hypertensive patients with additional cardiovascular risk factors. METHODS In a randomized, double-blind trial, the effects on 24-h ABP of the combination valsartan 160 mg od and hydrochlorothiazide 25 or 12.5 mg during 24 weeks of therapy were compared with the effects of amlodipine 10 mg monotherapy (group A10) in 474 stage-II hypertensive patients with additional cardiovascular risk factors. After a two-week single-blind placebo run-in period, patients were randomized to receive valsartan 160 mg od or amlodipine 5 mg od. At week 4, HCTZ 12.5 mg (group V160/HCTZ12.5) and 25 mg (group V160/HCTZ25) were added to the valsartan groups and in the A10 patients the amlodipine dose was force-titrated to 10 mg od. RESULTS All three treatments reduced 24-h BP as well as night-time and daytime BP levels from baseline. Twenty-four hour systolic blood pressure (SBP) was reduced by 15.9+/-1.0 mmHg (least-squares mean change+/-SE), 19.3+/-1.0 mmHg and 16.1+/-1.1 mmHg in the V160/HCTZ12.5, V160/HCTZ25 and A10 groups, respectively and 24-h diastolic blood pressure (DBP) was reduced by 9.3+/-0.6 mmHg, 11.4+/-0.6 mmHg and 9.6+/-0.7 mmHg in the three groups. The differences between the V160/HCTZ25 group and the A10 group were significant (p<0.05) for the changes in 24-h systolic BP as well as for changes in daytime systolic BP and night-time diastolic BP. Control rates defined as ABPM < or =130/80 mmHg were: 48.4%, 60.8% and 50.9% in the V160/HCTZ12.5, V160/25 and A10 groups, respectively. The differences in control rates between the V160/HCTZ25 group and the other two treatment groups were significant at p<0.05. CONCLUSIONS The fixed-dose combination of valsartan 160 mg+HCTZ 25 mg od is an attractive therapeutic option measured on the effects on 24-h ABPM, night-time and daytime BP reduction and control rates in hypertensive patients at additional cardiovascular risk.

Time of administration important? Morning versus evening dosing of valsartan.

Objective: Studies suggest that bedtime dosing of an angiotensin-converting enzyme (ACE)-inhibitor or angiotensin receptor blocker shows a more sustained and consistent 24-h antihypertensive profile, including greater night-time blood pressure (BP) reduction. We compared the antihypertensive effects of morning (a.m.) and evening (p.m.) dosing of valsartan on 24-h BP. Methods: This 26-week, multicentre, randomized, double-blind study evaluated the efficacy and safety of valsartan 320 mg, dosed a.m. or p.m., versus lisinopril 40 mg (a.m.), a long-acting ACE-inhibitor, in patients with grade 1–2 hypertension and at least one additional cardiovascular risk factor. Patients (n = 1093; BP = 156 ± 11/91 ± 8 mmHg; 62 years, 56% male, 99% white) received (1 : 1 : 1) valsartan 160 mg a.m. or p.m. or lisinopril 20 mg a.m. for 4 weeks, then force-titrated to double the initial dose for 8 weeks. At Week 12, hydrochlorothiazide (HCTZ) 12.5 mg was added for 14 weeks if office BP was more than 140/90 mmHg and/or ambulatory BP more than 130/80 mmHg. Results: Mean 24-h ambulatory SBP change from baseline to Weeks 12 and 26 was comparable between valsartan a.m. (–10.6 and –13.3 mmHg) and p.m. (–9.8 and –12.3 mmHg) and lisinopril (–10.7 and –13.7 mmHg). There was no benefit of valsartan p.m. versus a.m. on night-time BP, early morning BP and morning BP surge. Evening dosing also did not improve BP lowering in patients requiring add-on HCTZ or in nondippers at baseline. All treatments were well tolerated. Conclusion: Once-daily dosing of valsartan 320 mg results in equally effective 24-h BP efficacy, regardless of dosing time. Trial Registration: ClinicalTrials.gov Identifier: NCT00241124.