Safety and tolerability of canakinumab, an IL-1ß inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies.

BACKGROUND: We aimed to assess the safety and tolerability of different doses of canakinumab versus placebo in patients with type 2 diabetes mellitus (T2DM). METHODS: Data were pooled from three studies in 1026 T2DM patients with different routes of administration, treatment regimens and follow-up duration. Canakinumab groups were categorised as low (0.03 mg/kg i.v. once; N = 20), intermediate (0.1 and 0.3 mg/kg i.v. once, 5 and 15 mg s.c. monthly; N = 247), medium (1.5 mg/kg i.v. once, 50 mg s.c. monthly and 150 mg s.c. once; N = 268), and high doses (10 mg/kg i.v. once and 150 mg s.c. monthly; N = 137) and compared with placebo (N = 354). Incidences of adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs, deaths, AEs of special interest related to interleukin-1ß inhibition and T2DM disease, and laboratory abnormalities related to haematology and biochemistry parameters were reported. Safety was also analysed by age (<65, ≥65) and gender. RESULTS: Average exposure across all groups was ≈ 6 months (maximum ~17 months). No dose response in AEs was observed but a trend towards more patients having at least one AE across canakinumab groups relative to placebo (P = 0.0152) was observed. SAEs were few and the incidence rate for most canakinumab groups was lower than that of placebo group except for the high-dose group (0.94% versus 0.58% per month in placebo). A total of five patients discontinued treatment due to AEs across treatment groups. No death was reported in any of the three studies. A small, non-significant increase in the incidence rate of infection AEs was observed on canakinumab groups relative to placebo. Canakinumab was associated with mostly mild decreases in WBC, neutrophils and platelet counts. Additionally, mild increases in SGPT, SGOT and bilirubin were reported. Overall, despite small differences, no clinically relevant findings were observed with respect to laboratory values and vital signs. CONCLUSIONS: This pooled analysis demonstrated that canakinumab was safe and well tolerated over a treatment period up to 1.4 years at the four pooled doses evaluated, in agreement with safety findings reported in the individual studies.

Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): design and baseline characteristics.

AIMS: Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial. METHODS AND RESULTS: PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate <60 mL/min/1.73 m2 , diabetes, prior myocardial infarction, atrial fibrillation, LVEF <30%, Killip class ≥III, ST-elevation myocardial infarction without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints (cardiovascular death, HF hospitalization or outpatient development of HF). Randomization of 5669 patients occurred 4.3 ± 1.8 days from presentation with index AMI. The mean age was 64 ± 12 years, 24% were women. The majority (76%) qualified with ST-segment elevation myocardial infarction; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were in Killip class ≥II. CONCLUSIONS: Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and cardiovascular death following AMI.

Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension.

BACKGROUND: Patients with hypertension may require combination therapy to attain the blood pressure targets recommended by US and European treatment guidelines. Combination therapy with a calcium channel blocker and an angiotensin II-receptor blocker would be expected to provide enhanced efficacy. OBJECTIVES: Two studies were conducted to compare the efficacy of various combinations of amlodipine and valsartan administered once daily with their individual components and placebo in patients with mild to moderate essential hypertension (mean sitting diastolic blood pressure [MSDBP] >/=95 and < 110 mm Hg). A secondary objective was to evaluate safety and tolerability. METHODS: The 2 studies were multinational, multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group trials. In study 1, patients were randomized to receive amlodipine 2.5 or 5 mg once daily, valsartan 40 to 320 mg once daily, the combination of amlodipine 2.5 or 5 mg with valsartan 40 to 320 mg once daily, or placebo. In study 2, patients were randomized to receive amlodipine 10 mg once daily, valsartan 160 or 320 mg once daily, the combination of amlodipine 10 mg with valsartan 160 or 320 mg once daily, or placebo. The primary efficacy variable in both studies was change from baseline in MSDBP at the end of the study. Secondary variables included the change in mean sitting systolic blood pressure (MSSBP), response rate (the proportion of patients achieving an MSDBP <90 mm Hg or a >/= 10-mm Hg decrease from baseline), and control rate (the proportion of patients achieving an MSDBP <90 mm Hg). Safety was assessed in terms of adverse events (spontaneously reported or elicited by questioning), vital signs, and laboratory values. RESULTS: A total of 1911 patients were randomized to treatment in study 1 (1022 amlodipine + valsartan; 507 valsartan; 254 amlodipine; 128 placebo); 1250 were randomized to treatment in study 2 (419, 415, 207, and 209, respectively). In all treatment groups in both studies, the majority of patients were white (79.5% study 1, 79.4% study 2) and male (53.5% and 50.3%, respectively). The overall mean age was 54.4 years in study 1 and 56.9 years in study 2. The mean weight of patients in study 1 was higher than that in study 2 (88.8 vs 79.7 kg). The overall baseline mean sitting BP was 152.8/99.3 mm Hg in study 1 and 156.7/99.1 mm Hg in study 2. With the exception of a few combinations that included amlodipine 2.5 mg, the combination regimens in both studies were associated with significantly greater reductions in MSDBP and MSSBP compared with their individual components and placebo (P < 0.05). A positive dose response was observed for all combinations. The highest response rate in study 1 was associated with the highest dose of combination therapy (amlodipine 5 mg + valsartan 320 mg: 91.3%). Amlodipine 5 mg, valsartan 320 mg, and placebo were associated with response rates of 71.9%, 73.4%, and 40.9%, respectively. In study 2, the 2 doses of combination therapy were associated with similar response rates (amlodipine 10 mg + valsartan 160 mg: 88.5%; amlodipine 10 mg + valsartan 320 mg: 87.5%). Amlodipine 10 mg was associated with a response rate of 86.9%; valsartan 160 and 20 mg were associated with response rates of 74.9% and 72.0%, respectively; and placebo was associated with a response rate of 49.3%. Control rates followed a similar pattern. The incidence of peripheral edema with combination therapy was significantly lower compared with amlodipine monotherapy (5.4% vs 8.7%, respectively; P = 0.014), was significantly higher compared with valsartan monotherapy (2.1%; P < 0.001), and did not differ significantly from placebo (3.0%). CONCLUSIONS: In these adult patients with mild to moderate hypertension, the combination of amlodipine + valsartan was associated with significantly greater blood pressure reductions from baseline compared with amlodipine or valsartan monotherapy or placebo. The incidence of peripheral edema was significantly lower with combination therapy than with amlodipine monotherapy.

Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension.

BACKGROUND: Most patients with hypertension in the United States and Europe fail to achieve the recommended target blood pressure (BP) of <140/90 mm Hg. Combination therapy is required in approximately two thirds of all patients whose BP is >20/10 mm Hg above the goal. Combination therapy with agents having complementary mechanisms of action, such as a calcium channel blocker and an angiotensin II-receptor blacker, would be a potentially useful therapeutic option. OBJECTIVES: This study evaluated the overall safety profile of combination therapy with amlodipine plus valsartan compared with a combination of lisinopril plus hydrochlorothiazide (HCTZ) in patients with stage 2 hypertension (mean sitting diastolic BP [MSDBP] >or=110 and <120 mm Hg) over the short term (6 weeks). A secondary objective was to evaluate the efficacy of the 2 regimens in achieving BP reduction. METHODS: This was an international, multicenter, randomized, double-blind, active-controlled, parallel-group study. Patients were randomized to receive once-daily treatment with amlodipine 5 to 10 mg + valsartan 160 mg or lisinopril 10 to 20 mg + HCTZ 12.5 rig for 6 weeks. Safety assessments included monitoring of all adverse events, vital signs, and hematology and biochemistry variables. Efficacy variables included the changes from baseline in MSDBP and mean sitting systolic BP (MSSBP), the response rate (MSDBP <90 mm Hg, or a >or= 10-mm Hg reduction from baseline), and the rate of DBP control (<90 mm Hg). The overall rate of BP control (proportion of patients with MSSBP/MSDBP <140/90 mm Hg) was evaluated in a post hoc analysis. Efficacy variables were summarized at each visit and at the end of the study (week 6, applying last-observation-carried-forward methodology) using descriptive statistics for the intent-to-treat population (all randomized patients with a baseline BP measurement and at least 1 post baseline BP measurement). Subgroup analyses of BP changes were performed in prespecified age groups (<65 and >or=65 years) and post hoc in patients with a baseline systolic BP <180 and >or=180 mm Hg. RESULTS: : Of 130 patients who were randomized to treatment, 128 completed the study: 63 in the amlodipine + valsartan group and 65 in the lisinopril + HCTZ group. The majority of patients in both groups were white (amlodipine + valsartan: 59.4% lisinopril + HCTZ: 60.6%) and female (57.8% and 54.5%, respectively). The mean age was similar in the 2 groups (56.5 and 57.6 years), as was the mean weight (85.1 and 82.0 kg). Both regimens were generally well tolerated. Adverse events were mild to moderate in severity, and most were not considered related to study drug. At the 6-week end point, both the amlodipine + valsartan and lisinopril + HCTZ groups had achieved significant reductions from baseline in MSSBP (-35.8 [11.8] and -31.8 [14.7] mm Hg, respectively; both, P < 0.001) and MSDBP (-28.6 [7.7] and -27.6 [8.6] mm Hg; both, P < 0.001). Response rates were similar for the 2 treatment groups (100% and 95.5%), as were rates of DBP control (79.7% and 77.3%). CONCLUSIONS: : The combinations of amlodipine 5 to 10 rug + valsartan 160 mg and lisinopril 10 to 20 mg + HCTZ 12.5 mg were well tolerated and efficacious, and both treatments were associated with achievement of BP goals in the majority of these adult patients with stage 2 hypertension.

Amlodipine and valsartan combined and as monotherapy in stage 2, elderly, and black hypertensive patients: subgroup analyses of 2 randomized, placebo-controlled studies.

Patients with difficult to control hypertension typically require 2 or more agents to achieve goal blood pressure (BP) levels. Fixed-dose combination therapies with lower doses generally are well tolerated and more effective than higher-dose monotherapy. The authors performed prespecified and post hoc subgroup analyses of 2 double-blind, randomized, placebo-controlled trials that assessed the efficacy and safety of amlodipine and valsartan, alone and in combination, in patients with mild to moderate hypertension. Patients were randomized to amlodipine (study 1: 2.5 or 5 mg/d; study 2: 10 mg/d), valsartan (study 1: 40, 80, 160, or 320 mg/d; study 2: 160 or 320 mg/d), combination therapy across the same dose ranges, or placebo. Analyses were performed on changes from baseline in mean sitting systolic and diastolic BP and the occurrence of adverse events in specific subgroups of patients (ie, those with stage 2 hypertension [post hoc], the elderly [65 years or older], and blacks [both prespecified]). Amlodipine + valsartan combination therapy was associated with greater BP-lowering effects in the subgroups compared with each respective monotherapy and placebo. These findings were consistent with the primary efficacy analysis results from the overall study populations. Combination regimens were generally well tolerated by all patient subgroups.

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX-AHF-2 study.

Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.

Initial combination therapy with amlodipine/valsartan compared with monotherapy in the treatment of hypertension.

Achieving target blood pressure (BP) is influenced by baseline BP. Post hoc analyses of a placebo-controlled trial of amlodipine/valsartan versus monotherapies were conducted to characterize BP control by baseline BP. Hypertensive patients were randomized to amlodipine 10 mg, valsartan 160 or 320 mg, amlodipine/valsartan 10/160 or 10/320 mg, or placebo. Analysis of BP control rates focused on patients receiving the highest combination and monotherapy doses, with adverse events assessed for all doses. Analyses included 834 patients (mean age: 57 years; male: 51.3%; white: 79.4%; stage 2 hypertension: 61%; mean BP: 157/99 mm Hg). Two weeks after starting therapy, BP control (<140/90 mm Hg) rates were greater with amlodipine/valsartan 10/320 mg (49%) versus monotherapies (32%-38%) and placebo (16%). Consistent results were observed in stage 1 and 2 patients. Among patients receiving combination therapy, statistically significant differences were observed at endpoint versus comparators. At all baseline BP levels, the probability of achieving BP lower than 140/90 or lower than 130/80 mm Hg was greater with amlodipine/valsartan than monotherapies and placebo. Overall adverse events incidence was similar with combination versus monotherapies and placebo. Initial therapy with amlodipine/valsartan results in early, more effective BP control compared with monotherapy, irrespective of baseline BP.