Beverly Smith

Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial

BACKGROUND The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk. METHODS 15?245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity. Patients from 31 countries were followed up for a mean of 4.2 years. FINDINGS Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month; 1.5/1.3 mm Hg after 1 year; p<0.001 between groups). The primary composite endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1000 patient-years) and 789 in the amlodipine group (10.4%, 24.7 per 1000 patient-years; hazard ratio 1.04, 95% CI 0.94-1.15, p=0.49). INTERPRETATION The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk.

Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test whether, for the same achieved blood pressures, regimens based on valsartan or amlodipine would have differing effects on cardiovascular endpoints in high risk hypertension. But inequalities in blood pressure, favouring amlodipine, throughout the multiyear trial precluded comparison of outcomes. A technique of serial median matching, applied at 6 months when treatment adjustments intended to achieve control of blood pressure were complete, created 5006 valsartan-amlodipine patient pairs matched exactly for systolic blood pressure, age, sex, and the presence or absence of previous coronary disease, stroke, or diabetes. Subsequent combined cardiac events, myocardial infarction, stroke, and mortality were almost identical in the two cohorts, but admission to hospital for heart failure was significantly lower with valsartan. Reaching blood pressure control (systolic <140 mm Hg) by 6 months, independent of drug type, was associated with significant benefits for subsequent major outcomes; the blood pressure response after just 1 month of treatment predicted events and survival.

Effect of the Direct Renin Inhibitor Aliskiren, the Angiotensin Receptor Blocker Losartan, or Both on Left Ventricular Mass in Patients With Hypertension and Left Ventricular Hypertrophy

Background— Left ventricular (LV) hypertrophy, a marker of cardiac end-organ damage, is associated with an increased risk of cardiovascular morbidity and mortality. Inhibitors of the renin-angiotensin-aldosterone system may reduce LV mass to a greater extent than other antihypertensive agents. We compared the effect of aliskiren, the first orally active direct renin inhibitor, the angiotensin-receptor blocker losartan, and their combination on the reduction of LV mass in hypertensive patients. Methods and Results— We randomized 465 patients with hypertension, increased ventricular wall thickness, and body mass index >25 kg/m2 to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 months. Patients were treated to standard blood pressure targets with add-on therapy, excluding other inhibitors of the renin-angiotensin-aldosterone system and β-blockers. Patients underwent cardiovascular magnetic resonance imaging for assessment of LV mass at baseline and at study completion. The primary objective was to compare change in LV mass index from baseline to follow-up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow-up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups (6.5±14.9/3.8±10.1 mm Hg in the aliskiren group; 5.5±15.6/3.7±10.7 mm Hg in the losartan group; 6.6±16.6/4.6±10.5 mm Hg in the combination arm; P<0.0001 within groups, P=0.81 between groups). LV mass index was reduced significantly from baseline in all treatment groups (4.9-, 4.8-, and 5.8 g/m2 reductions in the aliskiren, losartan, and combination arms, respectively; P<0.0001 for all treatment groups). The reduction in LV mass index in the combination group was not significantly different from that with losartan alone (P=0.52). Aliskiren was as effective as losartan in reducing LV mass index (P<0.0001 for noninferiority). Safety and tolerability were similar across all treatment groups. Conclusions— Aliskiren was as effective as losartan in promoting LV mass regression. Reduction in LV mass with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy, independent of blood pressure lowering. These findings suggest that aliskiren was as effective as an angiotensin receptor blocker in attenuating this measure of myocardial end-organ damage in hypertensive patients with LV hypertrophy.

Long-Term Antihypertensive Efficacy and Safety of the Oral Direct Renin Inhibitor Aliskiren A 12-Month Randomized, Double-Blind Comparator Trial With Hydrochlorothiazide

Background— Diuretics are recommended as first-line agents for the treatment of hypertension. This randomized, double-blind, multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension. Methods and Results— After a 2- to 4-week placebo run-in, 1124 patients (mean sitting diastolic blood pressure [BP] 95 to 109 mm Hg) were randomized to aliskiren 150 mg (n=459), hydrochlorothiazide 12.5 mg (n=444), or placebo (n=221) once daily. Forced titration (to aliskiren 300 mg or hydrochlorothiazide 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or hydrochlorothiazide 25 mg. From week 12, amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method. BP reductions (mean sitting systolic BP/mean sitting diastolic BP) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 (−20.3/−14.2 versus −18.6/−13.0 mm Hg; P<0.05) and were also greater at week 52 (−22.1/−16.0 versus −21.2/−15.0 mm Hg; P<0.05 for mean sitting diastolic BP). At the end of the monotherapy period (week 12), aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP (−17.4/−12.2 versus −14.7/−10.3 mm H; P<0.001). Adverse event rates were similar with aliskiren- (65.2%) and hydrochlorothiazide-based therapy (61.5%). Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy (17.9% versus 0.9%; P<0.0001). Conclusions— Aliskiren treatment, both as monotherapy and with optional addition of amlodipine, provided significantly greater BP reductions than the respective hydrochlorothiazide regimens. Aliskiren-based therapy was well tolerated. Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension.

VALUE trial: Long-term blood pressure trends in 13,449 patients with hypertension and high cardiovascular risk

Abstract Background The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study compares cardiovascular outcomes in 15,314 eligible patients from 31 countries randomized to valsartan or amlodipine-based treatment. Methods The blood pressure (BP) trends are analyzed in 13,449 of VALUE study patients who had baseline BP and 24 months BP and treatment data. Results In a cohort of 12,570 patients, baseline 24 and 30 months BP, but not 30 months treatment data, were available. Of 13,449 patients, 92% ( N = 12,398) received antihypertensive therapy at baseline. The baseline BP was 153.5/86.9 mm Hg in treated compared to 168.1.8/95.3 mm Hg in 1051 untreated patients. After 6 months both groups had indistinguishable BP values. At 12 months the BP decreased to 141.2/82.9 mm Hg ( P P v 12 months), and to 138/79 mm Hg at 30 months ( P v 24 months). The systolic BP control ( Conclusions The achieved BP control exceeds values reported in most published large-scale trials. The VALUE study is executed in regular clinical settings and 92% of the patients received antihypertensive drugs at baseline. When an explicit BP goal is set, and a treatment algorithm is provided, the physicians can achieve better control rates than in their regular practice.

Associations of albuminuria in patients with chronic heart failure: findings in the ALiskiren Observation of heart Failure Treatment study.

To examine the relationships between baseline characteristics and urinary albumin excretion in the extensively phenotyped patients in the ALiskiren Observation of heart Failure Treatment (ALOFT) study.

Neurohumoral effects of aliskiren in patients with symptomatic heart failure receiving a mineralocorticoid receptor antagonist: the Aliskiren Observation of Heart Failure Treatment study

We evaluated the influence of concomitant mineralocorticoid receptor antagonists (MRAs) on the safety and neurohumoral effects of a direct renin inhibitor in the ALiskiren Observation of Heart Failure Treatment (ALOFT) study.

Suppression of aldosterone mediates regression of left ventricular hypertrophy in patients with hypertension

Background: High circulating aldosterone levels stimulate myocardial fibrosis and left ventricular hypertrophy (LVH). However, it is not clear whether suppression of aldosterone directly contributes to LVH regression in hypertensive patients. Methods: The Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial randomised 465 hypertensive overweight subjects with LVH to the direct renin inhibitor aliskiren 300 mg, losartan 100 mg or the combination and followed patients for 9 months. All patients were treated to standard blood pressure targets. Left ventricular (LV) mass index (LVMI) and LV wall thickness (LVWT) were assessed by cardiac magnetic resonance. A subset of 136 patients who had plasma aldosterone concentration (ALDO) measured at baseline and study end was analysed. Results: At baseline, plasma ALDO was modestly related to systolic blood pressure, LVMI, and wall thickness (all, p < 0.05). Aliskiren, either alone or in combination, was associated with a significantly greater reduction from baseline to 9 months in plasma aldosterone than losartan alone (p < 0.02). Reduction in ALDO was related to reduction in LVMI even after adjustment for baseline ALDO, BP reduction and treatment group (p for trend = 0.042). Conclusion: In hypertensive patients with increased LVWT, aliskiren alone or in combination with the angiotensin receptor blocker losartan provides greater reduction in aldosterone compared to losartan alone. Moreover, suppression of aldosterone was associated with reduction of LVH, independently of the change in SBP, suggesting that suppression of aldosterone, a known mediator of LVH, may be particularly important for LVH regression and as a target for therapy.

Influence of diabetes on efficacy of aliskiren, losartan or both on left ventricular mass regression

Hypothesis/Introduction: We investigated whether diabetes modified the effectiveness of renin–angiotensin–aldosterone system (RAAS) inhibition on left ventricular hypertrophy (LVH) regression in hypertensive patients in the Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial. Materials and methods: Participants (n=465) with LVH and a BMI > 25 kg/m2 were randomized to aliskiren 300mg, losartan 100mg or both daily for 36 weeks, and LVH regression was assessed by cardiac magnetic resonance imaging. Renin concentration, plasma renin activity and aldosterone were assessed in a subset of patients. Results: Patients with diabetes mellitus (DM) (n=111, 24%) were older (61±9 vs. 58±11 years, p=0.03), had higher BMI (32.2±4.2 vs. 30.7 ± 4 kg/m2, p=0.004), higher systolic blood pressure (148±14 vs. 145±14mmHg, p=0.03) and lower eGFR (79±16 vs. 84±16ml/min, p=0.03) at baseline. Combination therapy with aliskiren plus losartan was associated with greater LVH reduction than losartan alone in patients with DM (p=0.01), but not in patients without DM (p=0.91; unadjusted interaction p=0.06; adjusted p = 0.038). In a subset of 138 participants, plasma aldosterone was reduced to a greater extent in patients with DM (p-interaction = 0.004). Conclusions: Patients with DM and LVH may derive differential benefit with dual RAAS inhibition with a combination of aliskiren and losartan compared with losartan alone with respect to LVH reduction. Whether these findings will result in improved outcomes will be further explored in larger studies.