This multicenter, double‐blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo‐adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time‐matched analysis) and for values averaged across the dosing period (baseline‐averaged analysis). In time‐matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <1 0 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline‐averaged analysis was consistent with time‐matched analysis. Instances of QTcF interval >450 milliseconds or a >30‐millisecond increase from baseline with aliskiren (≤1%) were similar or lower than placebo (≤4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4‐fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.

Drugs in clinical development that potentially have effects on cardiac safety based on nonclinical data or findings in phase I, may require systematic cardiac safety assessments throughout phases II and III. Of major concern are drugs which cause the lethal, but rare, ventricular arrhythmia, torsades de pointes (TdP). Indeed, drugs intended for the general population that cause a one in one million incidence of TdP can be a significant public health concern (,). This risk cannot be adequately addressed in typical drug development programs by arrhythmia monitoring or adverse event reporting. However, drugs known to cause TdP are known to reproducibly perturb cardiac ventricular repolarization, an effect that is manifest on the standard 12-lead electrocardiogram (ECG) as prolongation of the QTc interval. Thus, QTc and the degree to which it is prolonged, is used as a surrogate marker for a drug's potential to cause TdP. This chapter will focus on the use of standard 12-lead ECGs in phases II and III clinical development to assess a drug's effect on cardiac intervals, durations, and morphologic patterns.

PURPOSE:To quantify global myocardial perfusion using magnetic resonance imaging (MRI) in patients with heart failure due to idiopathic dilated cardiomyopathy (IDC) and to compare myocardial perfusion and microvascular reactivity with healthy subjects. MATERIALS AND METHODS:A total of 19 subjects (healthy volunteers (N = 12) and IDC patients (N = 7)) were studied using cine MRI to measure left ventricular (LV) mass and a velocity-encoded cine MRI technique to measure coronary sinus flow at rest and after dipyridamole-induced hyperemia. Absolute values of total myocardial blood flow (MBF) were calculated from coronary sinus flow and LV mass. RESULTS:At baseline, MBF was not significantly different in patients with IDC (0.48 +/- 0.07 mL/minute/g) and healthy subjects (0.55 +/- 0.19 mL/minute/g, P= 0.41). After dipyridamole administration, MBF in IDC patients increased to a level significantly less than that in normal volunteers (1.05 +/- 0.35 mL/minute/g vs. 1.99 +/- 1.05 mL/minute/g, P < 0.05). Consequently, MBF reserve was impaired in patients with IDC (2.19 +/- 0.77) compared to that in healthy subjects (3.51 +/- 1.29, P < 0.05). A moderate correlation was found between MBF reserve and LV ejection fraction (r = 0.48, P < 0.05). CONCLUSION:MBF reserve is reduced in patients with IDC, indicating that coronary microcirculatory flow is impaired. This integrated MRI approach allows quantitative measurement of global MBF in humans and may have the potential to study the effects of pharmacological interventions on myocardial perfusion.

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.

Aliskiren is the first in a new class of orally effective, non-peptide renin inhibitors. This dose-finding study compared the antihypertensive efficacy and safety of aliskiren with placebo and with the AT1-receptor blocker, irbesartan. The study was a randomized, multi-centre, 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 mmHg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with either once-daily oral doses of aliskiren (150 mg, 300 mg or 600 mg), irbesartan 150 mg, or placebo. The primary efficacy variable of the study was the change from baseline in trough mean sitting DBP. All doses of aliskiren significantly lowered mean sitting DBP and systolic BP (SBP) compared with placebo. Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting DBP by 9.5 ± 8.0, 12.0 ± 8.5 and 11.7 ± 8.8 mmHg respectively versus 6.5 ± 9.0 mmHg for placebo (p< 0.005 versus placebo). Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting SBP by 10.8 ± 12.4, 15.5 ± 13.1 and 15.6 ± 14.3 mmHg respectively versus 5.1 ± 16.2 mmHg for placebo (p< 0.001 versus placebo). The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (9.0 ± 7.9 and 12.5 ± 14.2 mmHg reduction in mean sitting DBP and SBP respectively for irbesartan). The effects on mean sitting DBP of aliskiren 300 mg and 600 mg were significantly greater than those obtained with irbesartan 150 mg (p< 0.05). Aliskiren was comparable to placebo and irbesartan with respect to overall safety and tolerability. The percentage of patients reporting adverse events (AEs) was 26.8%, 36.2% and 33.1% with aliskiren 150 mg, 300 mg and 600 mg respectively, compared with 36.6% for irbesartan and 32.1% for placebo. The number of patients discontinuing therapy due to AEs was similar in all groups (range 2.2–3.9%). The results of this study show that once-daily oral treatment with aliskiren lowers blood pressure effectively and that aliskiren 150 mg is comparable in efficacy to irbesartan 150 mg, with an overall safety and tolerability profile comparable to irbesartan and placebo in patients with mild-to-moderate hypertension. Am J Hypertens (2004) 17, 108A–108A; doi: 10.1016/j.amjhyper.2004.03.279

Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.

European Journal of Heart FailureVolume 2, Issue S1 p. 10-10 AbstractsFree Access Racial differences in plasma renin activity, angiotensin II and aldosterone in chronic heart failure Martin P. Bedigian, Martin P. Bedigian Novartis Pharmaceuticals, East Hanover, New Jersey, United StatesSearch for more papers by this authorTom Chiang, Tom Chiang Novartis Pharmaceuticals, East Hanover, New Jersey, United StatesSearch for more papers by this authorNancy R. Feliciano, Nancy R. Feliciano Novartis Pharmaceuticals, East Hanover, New Jersey, United StatesSearch for more papers by this author Martin P. Bedigian, Martin P. Bedigian Novartis Pharmaceuticals, East Hanover, New Jersey, United StatesSearch for more papers by this authorTom Chiang, Tom Chiang Novartis Pharmaceuticals, East Hanover, New Jersey, United StatesSearch for more papers by this authorNancy R. Feliciano, Nancy R. Feliciano Novartis Pharmaceuticals, East Hanover, New Jersey, United StatesSearch for more papers by this author First published: 19 May 2004 https://doi.org/10.1016/S1388-9842(00)80032-XAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume2, IssueS1June 2000Pages 10-10 RelatedInformation