Alan H. Gradman

Aliskiren, a Novel Orally Effective Renin Inhibitor, Provides Dose-Dependent Antihypertensive Efficacy and Placebo-Like Tolerability in Hypertensive Patients

Background—Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. Methods and Results—The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] ≥95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (P<0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3±0.8, 11.8±0.8, and 11.5±0.8 mm Hg, respectively, versus 6.3±0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4±1.3, 15.8±1.2, and 15.7±1.2 mm Hg, respectively, versus 5.3±1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9±0.7 and 12.5±1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P<0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups. Conclusions—Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.

A Randomized, Placebo-Controlled, Double-Blind, Parallel Study of Various Doses of Losartan Potassium Compared With Enalapril Maleate in Patients With Essential Hypertension

The efficacy and safety of various doses of losartan potassium, a specific and selective angiotensin II receptor antagonist, were compared with those of placebo and enalapril maleate 20 mg in patients with mild to moderate essential hypertension in a randomized, double-blind, parallel study. We randomly allocated 576 patients at the end of a 4-week placebo baseline period to 8 weeks of once-daily double-blind treatment with losartan potassium 10, 25, 50, 100, or 150 mg, enalapril maleate 20 mg, or placebo. After 8 weeks of treatment, mean reductions from baseline in supine systolic/diastolic pressure 24 hours after dosing (trough) for losartan potassium 10, 25, 50, 100, and 150 mg, enalapril maleate 20 mg, and placebo were 7.6/7.9, 7.8/6.8, 13.0/10.1, 8.9/9.9, 10.5/9.7, 14.7/11.2, and 3.8/5.6 mm Hg, respectively. Compared with mean changes in supine diastolic pressure in the placebo group, losartan potassium 50 to 150 mg and enalapril maleate 20 mg produced clinically important and statistically significant reductions (P < or = .01) in blood pressure. At 24 hours after dosing, the blood pressure changes obtained with losartan potassium 50 mg were essentially identical to those obtained with enalapril maleate 20 mg. While there was a dose-related effect with losartan potassium from 10 to 50 mg at peak (6 hours after dosing), doses of 10 and 25 mg were not consistently different from placebo 24 hours after dosing. To assess the once-daily effect of losartan potassium, trough-to-peak ratios of the mean changes in supine diastolic pressure after 8 weeks of treatment were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Renin Inhibition in Hypertension

Fifty years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiological effects occur when renin and pro-renin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive. Molecular modeling was used to develop aliskiren, a potent, low-molecular-weight, nonpeptide, direct renin inhibitor with sufficient bioavailability to produce sustained suppression of plasma renin activity after oral administration. In patients with hypertension, aliskiren produces dose-dependent blood pressure (BP) reduction and 24-h BP control up to a dose of approximately 300 mg once daily; at these doses, aliskiren shows placebo-like tolerability. Its antihypertensive potency is approximately equivalent to that of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics. After abrupt withdrawal, persistent BP reduction and prolonged suppression of plasma renin activity is observed. When combined with diuretics, fully additive BP reduction is seen. When given with an angiotensin receptor blocker, aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade. Clinical trials are currently underway assessing the effects of aliskiren combined with an angiotensin receptor blocker on intermediate markers of end organ damage, and long-term end point trials are planned. The results of these studies will ultimately determine the place of renin inhibition and aliskiren in the treatment of hypertension and related cardiovascular disorders. The effect of aliskiren on receptor-bound renin and pro-renin is the subject of active investigation.

Combined enalapril and felodipine extended release (ER) for systemic hypertension

This multicenter, placebo-controlled, double-blind trial of factorial design evaluated the safety and efficacy of combination treatment with the angiotensin-converting enzyme inhibitor, enalapril, and the vascular selective calcium antagonist felodipine extended release (ER) in patients with essential hypertension. After a 4-week, single-blind placebo baseline period, 707 patients with sitting diastolic blood pressures (BPs) in the range of 95 to 115 mm Hg received placebo, enalapril (5 or 20 mg), felodipine ER (2.5, 5, or 10 mg), or their combinations for an 8-week double-blind treatment period. All doses of enalapril and felodipine ER had a statistically significant (p < 0.05) additive effect in reducing both systolic and diastolic BP. The trough to peak ratios for the combinations ranged from 0.63 (enalapril 5 mg-felodipine ER 2.5 mg) to 0.79 (enalapril 20 mg-felodipine ER 10 mg) and were consistent with effective BP control with 1 dose/day. Patients aged > or = 65 years demonstrated a greater reduction in diastolic BP. Combinations of enalapril-felodipine ER were associated with less drug-induced peripheral edema (4.1%) compared to felodipine ER monotherapy (10.8%). There were no serious drug-related adverse effects observed during the study. In this trial, the combination of enalapril and felodipine ER effectively lowered BP and was generally well tolerated with an excellent safety profile when used in the treatment of hypertension.

Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension

Background:  Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension.

Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials ∗

BACKGROUND Abciximab during percutaneous coronary revascularization reduces ischemic complications, but concern exists regarding increased bleeding risk should emergency coronary surgical procedures be required. METHODS Outcomes were assessed among 85 patients who required coronary artery bypass grafting operations after coronary intervention in two randomized placebo-controlled trials of abciximab. Comparisons were made between patients in the pooled placebo and abciximab groups. RESULTS The incidence of coronary surgical procedures was 2.17% and 1.28% among patients randomized to placebo and abciximab, respectively (p = 0.021). Platelet transfusions were administered to 32% and 52% of patients in the placebo and abciximab groups, respectively (p = 0.059). Rates of major blood loss were 79% and 88% in the placebo and abciximab groups, respectively (p = 0.27); transfusions of packed red blood cells or whole blood were administered in 74% and 80% of patients, respectively (p = 0.53). Surgical reexploration for bleeding was required in 3% and 12% of patients, respectively. Death and myocardial infarction tended to occur less frequently among patients who had received abciximab. CONCLUSIONS Urgent coronary artery bypass grafting operations can be performed without an incremental increase in major hemorrhagic risk among patients on abciximab therapy.

Antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide in adult African Americans with mild to moderate hypertension.

BACKGROUND African Americans with hypertension, particularly those with more severe blood pressure elevations, are generally less responsive to monotherapy from any antihypertensive class. These patients usually require treatment with drugs from > or = 2 antihypertensive classes to achieve adequate blood pressure control. OBJECTIVE The purpose of this study was to assess the antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide (HCTZ) in African American adults with mild to moderate hypertension. METHODS In this 12-week, multicenter, double-blind, randomized, parallel-group, placebo-controlled study, African American patients were randomized in a 3:3:1 ratio to I of 3 treatment groups: placebo, losartan monotherapy (50 to 150 mg), or losartan plus HCTZ (50/0 to 50/12.5 to 100/25 mg). Doses were titrated at weeks 4 and 8 if sitting diastolic blood pressure (SiDBP) was > or = 90 mm Hg. Safety was assessed by determining the incidence of clinical and laboratory Adverse events and evaluating mean changes in pulse, body weight, electrocardiographic parameters, and laboratory test results. RESULTS A total of 440 patients were randomized-188 to placebo, 193 to losartan monotherapy, and 59 to losartan/HCTZ; 391 completed the study. At week 12, the response rate with losartan monotherapy was 45.8%, with a significant (P < or = 0.01) lowering in mean SiDBP by 6.6 mm Hg compared with placebo; the response rate with placebo was 27.2%, with a mean SiDBP reduction of 3.9 mm Hg. Sitting systolic blood pressure (SiSBP) was significantly lowered with losartan monotherapy, by 6.4 mm Hg, compared with placebo (reduction of 2.3 mm Hg). The response rate with losartan/ HCTZ was 62.7%, with reductions in SiSBP and SiDBP of 16.8 mm Hg and 10.8 mm Hg, respectively (P < or = 0.01 vs placebo and losartan monotherapy). The incidence of clinical adverse events was comparable in the 3 treatment groups. CONCLUSIONS The results of this study suggest that in African American patients, losartan monotherapy was significantly more effective than placebo in lowering SiSBP and SiDBP. Moreover, the losartan/ HCTZ combination regimen resulted in significant and clinically meaningful additional reductions in SiSBP and SiDBP compared with losartan monotherapy or placebo. Losartan monotherapy and the losartan/HCTZ regimens were generally as well tolerated as placebo.

Managing cardiovascular and renal risk: the potential of direct renin inhibition.

Aliskiren is the first direct renin inhibitor for the treatment of hypertension. Clinical experience from studies in over 14,000 patients has shown that aliskiren, alone or in combination with other antihypertensive therapies, provides effective blood pressure lowering with a good safety and tolerability profile.The ultimate aim of antihypertensive therapy, however, is to reduce the risk of adverse cardiovascular and renal outcomes.The effect of aliskiren on surrogate markers of organ damage and clinical outcomes is being assessed in the ongoing ASPIRE HIGHER programme, the largest clinical trials programme in the cardio-renal disease area. Results from the ALOFT, AVOID and ALLAY studies suggest that aliskiren has positive effects on markers of cardiovascular and renal damage in patients with type 2 diabetes and nephropathy, heart failure and left ventricular hypertrophy.ASPIRE HIGHER also includes four large-scale studies assessing the potential outcome benefits of aliskiren, and the results of these trials will help define the clinical utility of aliskiren in the treatment of cardiovascular and renal diseases. In this article, we review the antihypertensive efficacy of aliskiren and explore its potential in the management of cardiovascular and renal risk.

Rationale for Triple‐Combination Therapy for Management of High Blood Pressure

J Clin Hypertens (Greenwich).

Initial Combination Therapy Reduces the Risk of Cardiovascular Events in Hypertensive Patients: A Matched Cohort Study

This study evaluated the effects of initial versus delayed treatment with a drug combination on blood pressure (BP) control and the risk of cardiovascular (CV) events in hypertensive patients. Clinical trials suggest that the time to BP control is an important determinant of long-term outcomes, but real-world evidence is scarce. Using electronic medical charts (2005–2009), we retrospectively analyzed 1762 adult patients with BP elevation initiating combination therapy matched 1:1 with similar patients initiating monotherapy and later switched to combination therapy. Incidence rate ratios of CV events (myocardial infarction, stroke/transient ischemic attack, or hospitalization for heart failure) or all-cause death and Kaplan-Meier analyses of time to BP control were compared between cohorts. Hazard ratios indicating the effects of initial treatment on CV events and BP control were estimated using time-varying Cox proportional hazard models. Initial combination therapy was associated with a significant reduction in the risk of CV events or death (incidence rate ratio, 0.66 [95% confidence interval, 0.52–0.84]; P=0.0008). After 6 months of therapy, 40.3% and 32.6% of patients with initial versus delayed combination treatment reached BP control, respectively. Achieving target BP was associated with a statistically significant risk reduction of 23% for CV events or death (hazard ratio, 0.77 [95% confidence interval, 0.61–0.96]; P=0.0223); the residual effect of initial combination therapy did not reach statistical significance (hazard ratio, 0.84 [95% confidence interval, 0.68–1.03]; P=0.0935). Initial combination therapy was associated with a significant risk reduction of cardiovascular events. More rapid achievement of target BP was found to be the main contributor to the estimated risk reduction.