Hypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality in women in developed countries. This pooled analysis assessed the antihypertensive efficacy, safety and tolerability of monotherapy with the direct renin inhibitor aliskiren (150 mg and 300 mg) over 8-12 weeks in women with mild-to-moderate hypertension (mean sitting diastolic blood pressure (msDBP)X95 and o110 mm Hg) across eight randomized and double-blind trials. Safety and tolerability were assessed in the five placebo-controlled trials in the analysis. In the 1527 women enrolled in these studies, aliskiren 150 mg and 300 mg produced significantly greater blood pressure (BP) reductions (14.1/11.0 and 16.1/12.3 mm Hg, respectively) compared with placebo (7.2/7.6 mm Hg; Po0.0001). BP reductions with aliskiren monotherapy in women were similar to those observed in men, and consistent across subgroups of age, metabolic syndrome and obesity. The overall incidence of adverse events in women was similar with aliskiren treatment (150 mg, 42.3%; 300 mg, 46.0%) and placebo (39.0%); adverse events with aliskiren were more frequent in women than in men, consistent with previous studies of gender differences in drug tolerability. In conclusion, aliskiren monotherapy at 150 mg and 300 mg doses provided effective, dose-dependent BP-lowering in women with mild-to-moderate hypertension, and it was well tolerated.

AimsWe 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. Methods and resultsPatients with stable New York Heart Association class II -IV heart failure (HF), plasma B-type natriuretic peptide (BNP) concentration .100 pg/mL, and treated with an angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker) and b-blocker were randomized to once-daily, double-blind treatment with aliskiren 150 mg or placebo, added to optimal HF therapy, for 12 weeks. Safety, tolerability, and effects of aliskiren on neurohumoral biomarkers were assessed in patients who received (MRA+) and did not receive (MRA2) MRA treatment at baseline. Of the 302 randomized patients, 101 were receiving MRA treatment (aliskiren, n ¼ 52; placebo, n ¼ 49). Mineralocorticoid receptor antagonist status did not affect the ability of aliskiren 150 mg, added to standard HF therapy, to lower BNP, N-terminal proBNP, plasma renin activity, and urinary aldosterone. For example, the end-of-study to baseline ratio of geometric mean for BNP was: MRA+ group: aliskiren 0.68 [95% confidence interval (CI) 0.47, 0.98], placebo 0.85 (0.58, 1.24); MRA2 group: aliskiren 0.62 (0.45, 0.84), placebo 0.85 (0.63, 1.15), interaction P ¼ 0.720. The incidence of pre-specified adverse events (renal dysfunction, symptomatic hypotension, and hyperkalaemia) was low, and there were no significant differences between aliskiren and placebo in either MRA subgroup. ConclusionAliskiren 150 mg added to standard HF therapy was well tolerated over 12 weeks and provided beneficial changes in neurohumoral biomarkers regardless of concomitant MRA treatment.--

For many years there has been a consensus among the Clinical Research community that ITT analysis represents the correct approach for the vast majority of trials. Recent worldwide regulatory guidance for pharmaceutical industry trials has allowed discussion of alternatives to the ITT approach to analysis; different treatment effects can be considered which may be more clinically meaningful and more relevant to patients and prescribers. The key concept is of a trial “estimand”, a precise description of the estimated treatment effect. The strategy chosen to account for patients who discontinue treatment or take alternative medications which are not part of the randomised treatment regimen are important determinants of this treatment effect. One strategy to account for these events is treatment policy, which corresponds to an ITT approach. Alternative equally valid strategies address what the treatment effect is if the patient actually takes the treatment or does not use specific alternative medication. There is no single right answer to which strategy is most appropriate, the solution depends on the key clinical question of interest. The estimands framework discussed in the new guidance has been particularly useful in the context of the current COVID-19 pandemic and has clarified what choices are available to account for the impact of COVID-19 on clinical trials. Specifically, an ITT approach addresses a treatment effect that may not be generalisable beyond the current pandemic.

Aliskiren is the first direct renin inhibitor approved for the treatment of hypertension. Blood pressure (BP) control in stage 2 hypertension with aliskiren monotherapy has not been reported. This was a post hoc analysis of the subgroup of patients with stage 2 systolic hypertension (baseline mean sitting systolic BP [msSBP] ≥160 mmHg) who completed the 12-week monotherapy phase of a 6-month, double-blind, randomized study. A total of 175 patients were randomized to aliskiren 150 mg (n = 88) or ramipril 5 mg (n = 87) with optional up-titration to aliskiren 300 mg or ramipril 10 mg, respectively, at weeks 6 and 12. In the subgroup of patients with stage 2 systolic hypertension, aliskiren lowered msSBP and mean sitting diastolic BP (msDBP) by 22.3/12.7 mmHg from baseline to week 12; compared with a reduction of 18.1/10.2 mmHg with ramipril. The maximum BP reductions achieved with aliskiren were 60.0/34.0 mmHg (from a baseline of 172.7/107.3 mmHg). Aliskiren was noninferior (P < 0.0001) to ramipril for SBP reduction with nonsignificant superiority (P = 0.052), and superior (P = 0.043) to ramipril for DBP reduction. The proportion of patients who achieved BP control (<140/90 mmHg) after 12 weeks of monotherapy was larger with aliskiren (34/88, 38.6%) than with ramipril (22/87, 25.3%; P = 0.038). In this post hoc analysis, 12 weeks of monotherapy with aliskiren 150-300 mg provided effective mean BP reductions (22/13 mmHg) and was superior to ramipril 5-10 mg in controlling BP in patients with stage 2 systolic hypertension.

Aliskiren causes neurohumoral suppression in heart failure, even in patients treated with ≥recommended-dose of ACE inhibitor.

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The ICH E9(R1) addendum on Estimands and Sensitivity Analyses in Clinical Trials has introduced a new estimand framework for the design, conduct, analysis, and interpretation of clinical trials. We share Pharmaceutical Industry experiences of implementing the estimand framework in the first two years since the final guidance became available with key lessons learned and highlight what else needs to be done to continue the journey in embedding the estimand framework in clinical trials. Emerging best practices and points to consider on strategies for implementing a new estimand thinking process are provided. Whilst much of the focus of implementing ICH E9(R1) to date has been on defining estimands, we highlight some of the important aspects relating to the choice of statistical analysis methods and sensitivity analyses to ensure estimands can be estimated robustly with minimal bias. In particular, we discuss the implications if complete follow-up is not possible when the treatment policy strategy is being used to handle intercurrent events. ICH E9(R1) was introduced just before the start of the COVID-19 pandemic, but a positive outcome from the pandemic has been an acceleration in the adoption of the estimand framework, including differentiating intercurrent events related or not related to the pandemic. In summary, much has been learned on the estimand journey and continued sharing of case studies will help to further advance the understanding and increase awareness across all clinical researchers of the estimand framework.

Background: Studies in transgenic rats expressing the human (pro)renin receptor have shown elevated plasma aldosterone levels in these animals despite unaffected plasma renin concentration or activity. It has been speculated that this is mediated through a direct effect of (pro)renin on aldosterone synthesis via the (pro)renin receptor ((P)RR). Other studies have shown an increased expression of adrenal CYP11B2 mRNA in these animals compared to wildtype despite unchanged levels of angiotensin II (Ang II). We evaluated the effect of (pro)renin on the expression of the main steroidogenic enzymes in an adrenocortical cell line (H295R).Methods: First, the expression of the (P)RR was tested by RT-PCR. Second, H295R cells (10^5 cells/mL) were serum-starved for 24 hours and subsequently incubated with Ang II (100 nM), phorbol-12-myristate-13-acetate (PMA, 10 nM), renin (1 and 10 nM), or prorenin (1 nM) for 6, 24 and 48 hours. After RNA isolation by standard methods, the expression of STAR, CYP11A1, HSD3B2, CYP21A2, CYP11B2, and CYP17A1 was measured by quantitative RT-PCR. To investigate whether an effect on aldosterone synthesis could be attributed to activation of the local renin-angiotensinsystem (RAS), ACE activity in H295R cells was assessed by measurement of Ang II formation after incubation with Ang I (10-8 M for 30, 60, 180 and 360 minutes).