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Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial

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Author(s): David C. Wheeler , MD, Gerard M. London , MD, Patrick S. Parfrey , MD, Geoffrey A. Block , MD, Ricardo Correa‐Rotter , MD, Bastian Dehmel , MD, Tilman B. Drüeke , MD, Jürgen Floege , MD, Yumi Kubo , MS, Kenneth W. Mahaffey , MD, William G. Goodman , MD, Sharon M. Moe , MD, Marie‐Louise Trotman , MS, Safa Abdalla , MD, Glenn M. Chertow , MD, Charles A. Herzog , MD, the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial Investigators

Publication date (Electronic): 17 November 2014

Journal: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: Blackwell Publishing Ltd

Keywords: atherosclerosis, cardiovascular diseases, heart failure, kidney, sudden death

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Abstract

Background

Premature cardiovascular disease limits the duration and quality of life on long‐term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial.

Methods and Results

EVOLVE was a randomized, double‐blind, placebo‐controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance.

Conclusions

Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes.

Clinical Trials Registration

Unique identifier: NCT00345839. URL: ClinicalTrials.gov.

Related collections

Most cited references 34

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Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials

Cholesterol Treatment Trialists' (CTT) Collaboration, Aldo Pietro Maggioni (2011)

Summary Background Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. Methods We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. Findings In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11–18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7–19; p<0·0001), in coronary revascularisation of 19% (95% CI 15–24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5–26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76–0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87–0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74–0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81–0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84–1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81–1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92–1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96–1·04; p=0·9), even at low LDL cholesterol concentrations. Interpretation Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2–3 mmol/L would reduce risk by about 40–50%. Funding UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

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Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.

Bengt C Fellström, Alan Jardine, Roland E Schmieder … (2009)

Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events. After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51). In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (ClinicalTrials.gov number, NCT00240331.) 2009 Massachusetts Medical Society

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FGF23 induces left ventricular hypertrophy.

Christian Faul, Ansel P Amaral, Behzad Oskouei … (2011)

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

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Author and article information

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (hwp): ahaoa

Journal ID (publisher-id): jah3

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: Blackwell Publishing Ltd

ISSN (Electronic): 2047-9980

Publication date Collection: December 2014

Publication date (Electronic): 17 November 2014

Volume: 3

Issue: 6

Electronic Location Identifier: e001363

Affiliations

University College London, London, UK (D.C.W.)

Hôpital Manhès, Paris, France (G.M.L.)

Health Sciences Center St. John's, Newfoundland, Canada (P.S.P.)

Denver Nephrology, Denver, CO (G.A.B.)

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.R.)

Amgen, Inc, Thousand Oaks, CA (B.D., Y.K., W.G.G., M.L.T.)

Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.)

Universitätsklinikum der RWTH Aachen, Aachen, Germany (F.)

Stanford University School of Medicine, Palo Alto, CA (K.W.M., S.A., G.M.C.)

Indiana University School of Medicine, Roudebush Veterans Administration Medical Center, Indianapolis, IN (S.M.M.)

Hennepin County Medical Center, University of Minnesota, Minneapolis, MN (C.A.H.)

Author notes

Correspondence to: Charles A. Herzog, MD, Chronic Disease Research Group, Minneapolis Medical Research Foundation, 914 South 8th St, Suite S‐406, Minneapolis, MN 55404. E‐mail: cherzog@ 123456cdrg.org

Accompanying Data S1, which lists the participating EVOLVE sites and affiliated investigators, are available at http://jaha.ahajournals.org/content/3/6/e001363/suppl/DC1

Article

Publisher ID: jah3752

DOI: 10.1161/JAHA.114.001363

PMC ID: 4338730

PubMed ID: 25404192

SO-VID: 9a3654ee-5183-41ee-9e35-6a1f137e76a7

Copyright © © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 10 September 2014

Date accepted : 21 October 2014

Categories

Subject: Original Research

Subject: Kidney in Cardiovascular Disease

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: atherosclerosis,cardiovascular diseases,heart failure,kidney,sudden death

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: atherosclerosis, cardiovascular diseases, heart failure, kidney, sudden death

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