William Lionel Daley

Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial

BACKGROUND Diastolic dysfunction might represent an important pathophysiological intermediate between hypertension and heart failure. Our aim was to determine whether inhibitors of the renin-angiotensin-aldosterone system, which can reduce ventricular hypertrophy and myocardial fibrosis, can improve diastolic function to a greater extent than can other antihypertensive agents. METHODS Patients with hypertension and evidence of diastolic dysfunction were randomly assigned to receive either the angiotensin receptor blocker valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant antihypertensive agents that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic blood pressure and under 80 mm Hg diastolic blood pressure. The primary endpoint was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue doppler imaging. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00170924. FINDINGS 186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12.8 (SD 17.2)/7.1 (9.9) mm Hg reduction in blood pressure in the valsartan group and a 9.7 (17.0)/5.5 (10.2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0.60 (SD 1.4) cm/s from baseline in the valsartan group (p<0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p<0.0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p=0.29). INTERPRETATION Lowering blood pressure improves diastolic function irrespective of the type of antihypertensive agent used.

Prediction of the Localization of High-Risk Coronary Atherosclerotic Plaques on the Basis of Low Endothelial Shear Stress An Intravascular Ultrasound and Histopathology Natural History Study

Background— Low endothelial shear stress (ESS) promotes the development of atherosclerosis; however, its role in the progression of atherosclerotic plaques and evolution to inflamed high-risk plaques has not been studied. Our hypothesis was that the lowest values of ESS are responsible for the development of high-risk coronary atherosclerotic plaques associated with excessive expansive remodeling. Methods and Results— Twenty-four swine, treated with streptozotocin to induce diabetes and fed a high-fat diet, were allocated into early (n=12) and late (n=12) atherosclerosis groups. Intima-media thickness was assessed by intravascular ultrasound in the coronary arteries at weeks 4 and 8 in the early group and weeks 23 and 30 in the late group. Plaques started to develop after week 8, leading to marked heterogeneity in plaque severity at week 30. ESS was calculated in plaque-free subsegments of interest (n=142) in the late group at week 23. Coronary arteries (n=31) of this group were harvested at week 30, and the subsegments of interest were identified and analyzed histopathologically. Low ESS was an independent predictor of the development of high-risk plaques, characterized by intense lipid accumulation, inflammation, thin fibrous cap, severe internal elastic lamina degradation, and excessive expansive remodeling. The severity of high-risk plaque characteristics at week 30 was significantly correlated with the magnitude of low ESS at week 23. Conclusions— The magnitude of low ESS determines the complexity and heterogeneity of atherosclerotic lesions and predicts the development of high-risk plaque.

Recommendations for Evaluating Compliance and Persistence With Hypertension Therapy Using Retrospective Data

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. The World Health Organization Global Burden of Disease Study estimates that nonoptimal blood pressure [(BP) ie, systolic BP of >115 mm Hg] is responsible annually for 7.1 million deaths and the loss of 64.3 disability-adjusted life years worldwide.1 The associated economic burden of hypertension is also substantial. The average annual medical care cost for individuals with hypertension has been estimated at

Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus.

3900 (in year 2000 US dollars) in Canada,2 with similar values (

A Noninferiority Comparison of Valsartan/Hydrochlorothiazide Combination Versus Amlodipine in Black Hypertensives

3787) for the United States.3 The increase in medical care costs is greater for those with moderate-to-severe BP elevation (diastolic BP >104 mm Hg) than for those with mild disease.4 Although a broad range of hypertension medications have been demonstrated to reduce BP, and BP control is an achievable goal,5 reports suggest that up to two thirds of patients with hypertension are not successfully treated, that is, achieve BP control.6–8 According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7), BP control rates are far below the “healthy people” goal of 50% set in 2000.9 A major (and modifiable) reason for lack of BP control is failure by patients to use medications as prescribed.10 Appropriate use of medications includes compliance, taking medications at the prescribed frequency/interval and dose/dosing regimen, and persistence, continuing their use for the specified treatment time period, which, in the case of hypertension therapy, is usually lifelong.11 Poor compliance with hypertension medications is associated with adverse health outcomes.12 Studies have demonstrated that poor BP control is associated with greater healthcare costs.13 For example, in the United States, inadequate control of hypertension has been estimated to result in &40 000 cardiovascular events, >8000 …

Attenuation of inflammation and expansive remodeling by Valsartan alone or in combination with Simvastatin in high-risk coronary atherosclerotic plaques

Objective Renin–angiotensin system blockade is now standard in the management of the patient with type 2 diabetes mellitus. We aimed to investigate whether high doses of valsartan, an angiotensin receptor blocker, are superior to conventional doses to reduce urinary albumin excretion rates (UAER) in such patients. Patients and methods Three hundred and ninety-one hypertensive patients with type 2 diabetes mellitus and UAER 20–700 μg/min were randomized to 160, 320 or 640 mg valsartan. All received valsartan 160 mg for the first 4 weeks. Valsartan dose was then increased in two of three groups for 30 weeks. Overnight urine collections at baseline, 4, 16, and 30 weeks in triplicate were used to assess proteinuria. Results Comparable albuminuria reductions occurred in all groups at week 4 (P < 0.001). Subsequently, a highly significant albuminuria fall occurred with valsartan 320 and 640 mg (P < 0.001) versus a modest additional change with 160 mg (P = 0.03). At week 30, twice as many patients returned to normal albuminuria with valsartan 640 mg versus 160 mg (24 versus 12%; P < 0.01). High doses were well tolerated, with no dose-related increases in adverse events, including hypotension and hyperkalemia. Conclusion High doses of valsartan reduced albuminuria more than the more commonly used 160 mg dose, apparently independent of blood pressure. Thus, at least in type 2 diabetes mellitus, higher doses of valsartan are required to optimize tissue protection than for blood pressure control.

The design of an observational study of hypertension management, adherence and pressure control in Blood Pressure Success Zone Program participants.

The objective of the study was to demonstrate that reduction in mean 24-hour diastolic blood pressure with 160 mg valsartan and 12.5 mg hydrochlorothiazide was not inferior to 10 mg amlodipine in hypertensive blacks. A total of 482 blacks with stage 1 and stage 2 hypertension (mean seated blood pressure 140 to 180/90 to 110 mm Hg) were enrolled in a double-blind, randomized, prospective study. After a placebo run-in period, patients were randomized to 160 mg valsartan or 5 mg amlodipine for 2 weeks, then force-titrated to 160 mg valsartan and 12.5 mg hydrochlorothiazide or 10 mg amlodipine for an additional 10 weeks. Blood pressure was assessed by 24-hour ambulatory blood pressure monitoring. Other assessments included quality of life, peripheral edema, and safety. Noninferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in mean 24-hour diastolic blood pressure with both treatments (−10.2±8.6 mm Hg versus −9.1±8.3 mm Hg, respectively; P<0.001 for noninferiority), as well as in mean 24-hour systolic blood pressure (−15.9±12.1 mm Hg versus −14.5±12.2 mm Hg; P<0.001 for noninferiority). The proportion of patients reporting adverse events and the incidence of most events were similar in both treatment groups, although more patients treated with amlodipine reported peripheral edema (5.8% versus 1.7%; P=0.03) and joint swelling (2.9% versus 0%; P=0.008) compared with valsartan/hydrochlorothiazide. We conclude that a starting dose of valsartan/hydrochlorothiazide (160/12.5 mg) is as effective as high-dose amlodipine (10 mg) in reducing blood pressure in blacks with stage 1 and stage 2 hypertension, and valsartan/hydrochlorothiazide is better tolerated.

Rationale and design: The VALsartan In Diastolic Dysfunction (VALIDD) Trial: Evolving the management of diastolic dysfunction in hypertension

AIMS We investigated the role of Valsartan (V) alone or in combination with Simvastatin (S) on coronary atherosclerosis and vascular remodeling, and tested the hypothesis that V or V/S attenuate the pro-inflammatory effect of low endothelial shear stress (ESS). METHODS Twenty-four diabetic, hyperlipidemic swine were allocated into Early (n=12) and Late (n=12) groups. In each group animals were treated with Placebo (n=4), V (n=4) and V/S (n=4) and followed for 8 weeks in the Early group and 30 weeks in the Late group. Blood pressure, serum cholesterol and glucose were similar across the treatment subgroups. ESS was calculated in plaque-free subsegments of interest (n=109) in the Late group at week 23. Coronary arteries of this group were harvested at week 30, and the subsegments of interest were identified, and analyzed histopathologically. RESULTS V alone or with S reduced the severity of inflammation in high-risk plaques. Both regimens attenuated the severity of enzymatic degradation of the arterial wall, reducing the severity of expansive remodeling. V alone or with S attenuated the pro-inflammatory effect of low ESS. CONCLUSIONS V alone or with S exerts a beneficial effect of reducing and stabilizing high-risk plaque characteristics independent of a blood pressure- and lipid-lowering effect.

Therapeutic combination of amlodipine and benazepril/benazeprilat

Aims:  The Blood Pressure Success Zone (BPSZ) Program, a nationwide initiative, provides education in addition to a complimentary trial of one of three antihypertensive medications. The BPSZ Longitudinal Observational Study of Success (BPSZ‐BLISS) aims to evaluate blood pressure (BP) control, adherence, persistence and patient satisfaction in a representative subset of BPSZ Program participants. The BPSZ‐BLISS study design is described here.