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A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

ABSTRACT: Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1? (IL-1?) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1? signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier: NCT01731990.

SUBMITTER: Russell KS

PROVIDER: S-EPMC6791746 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

Russell Kerry S KS Yates Denise P DP Kramer Christopher M CM Feller Andrea A Mahling Ping P Colin Laurence L Clough Timothy T Wang Tianke T LaPerna Lucy L Patel Alpa A Lawall Holger H Shennak Mustafa M MM Fulmer James J Nikol Sigrid S Smith William B WB Müller Oliver J OJ Ratchford Elizabeth V EV Basson Craig T CT

Vascular medicine (London, England) 20190705 5

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1β (IL-1β) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1β signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean a ...[more]

PMID: 31277561

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Project description:Background Meta-analyses have shown that isometric handgrip training (IHT) can reduce brachial systolic and diastolic blood pressure (BP) by >6/4 mm Hg, respectively. However, whether IHT promotes these effects among patients with peripheral artery disease, who exhibit severe impairment in cardiovascular function, is currently unknown. This study aimed to evaluate the effects of IHT on the cardiovascular function of patients with peripheral artery disease. Methods and Results A randomized controlled trial with peripheral artery disease patients assigned to either the IHT or control group was conducted. The IHT group performed 3 sessions per week, for 8 weeks, of unilateral handgrip exercises, consisting of 4 sets of isometric contractions for 2 minutes at 30% of maximum voluntary contraction and a 4-minute interval between sets. The control group received a compression ball in order to minimize the placebo effects, representing sham training. The primary outcome was brachial BP. The secondary outcomes were central BP, arterial stiffness parameters, cardiac autonomic modulation, and vascular function. The IHT program reduced diastolic BP (75 [10] mm Hg preintervention versus 72 [11] mm Hg postintervention), with no change in the control group (74 [11] mm Hg preintervention versus 74 [11] mm Hg postintervention), with this between-group difference being significant (P=0.04). Flow-mediated dilation improved in the IHT group (6.0% [5.7] preintervention versus 9.7% [5.5] postintervention), with no change in the control group (7.6% [5.5] preintervention versus 7.4% [5.1] postintervention), with this between-group difference being significant (P=0.04). There was no change in other measured variables over the intervention period. Conclusions IHT reduced brachial diastolic BP and improved local vascular function in patients with peripheral artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02742220.

Project description:AimsThe effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).Methods and resultsIn this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up.ConclusionIn patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

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A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

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A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

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