Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial

RAID Trial Investigators

doi:10.1016/j.jacc.2018.04.086

Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial

RAID Trial Investigators

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

Background: Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives: This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods: This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results: Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions: In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality.

Original language	English
Pages (from-to)	636-645
Number of pages	10
Journal	Journal of the American College of Cardiology
Volume	72
Issue number	6
DOIs	https://doi.org/10.1016/j.jacc.2018.04.086
State	Published - 7 Aug 2018

Bibliographical note

Publisher Copyright:
© 2018 The Authors

Funding

This study was supported by grants from the National Heart, Lung, and Blood Institute: Clinical Coordination Center (Grant No. UO1 HL096607; PI: Dr. Zareba) and Data Coordination Center (Grant No. UO1 HL096610; PI: Dr. Moss). Study drug and additional financial support for drug distribution was provided by Gilead Sciences grant no. IN-US-259-0125 (to Dr. Zareba). Dr. Zareba has received research grant support from Gilead Sciences, Boston Scientific, and Zoll. Dr. Daubert has received research grant support from Biosense Webster, Gilead Sciences, Medtronic, Zoll, and St. Jude Medical; and has served as a consultant or on Speakers Bureau for the American College of Cardiology, ARCA Biopharma, Biosense Webster, Biotronik, Boston Scientific, Cardiofocus, Gilead Sciences, Medtronic, Northwestern University, Zoll, St. Jude, and Vytronus. Dr. Alexis has served on the clinical events committee for Gilead Sciences. Dr. Aktas has received research grant support from Boston Scientific and Medtronic. Dr. Mitchell has received research grant support from Boehringer Ingelheim and consulting fees from Boehringer Ingelheim, Bayer, and the BMS-Pfizer Alliance, Medtronic Inc., and Servier. Dr. Natale has served as a consultant for and received consulting honoraria from Biosense Webster, BSCI, St. Jude/Abbott, St. Jude Medical, Boston Scientific, Medtronic, and Itamar. Dr. Piccini has received research grant support from Gilead Sciences, St. Jude Medical, Spectranetics, ARCA Biopharma, Johnson & Johnson, Boston Scientific, Abbott, and Medtronic; and consulting fees from Medtronic, Sanofi, Bayer, Allergan, and Philips. Dr. Schuger has received research grants from Boston Scientific. Dr. Worley has received royalties from Merit Medical & Pressure Products; and consulting fees from Merit and Abbott. Dr. Moss has received researched grants from Gilead Sciences and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Funders	Funder number
ARCA Biopharma
BMS-Pfizer Alliance
Data Coordination Center	UO1 HL096610
Gilead Sciences and Boston Scientific
Gilead Sciences, St. Jude Medical
Spectranetics
St. Jude
National Heart, Lung, and Blood Institute	UO1 HL096607
Boehringer Ingelheim
Abbott Laboratories
Philips
Johnson and Johnson
Sanofi
Medtronic
Gilead Sciences	IN-US-259-0125
St. Jude Medical
Northwestern University
Biosense Webster
Allergan
Boston Scientific Corporation
Bayer Fund
Biotronik

Keywords

implantable cardioverter-defibrillator
ranolazine
ventricular fibrillation
ventricular tachycardia

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10.1016/j.jacc.2018.04.086

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@article{c6c9b53738e34b7ea30567541d31991d,

title = "Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial",

abstract = "Background: Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives: This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods: This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results: Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions: In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality.",

keywords = "implantable cardioverter-defibrillator, ranolazine, ventricular fibrillation, ventricular tachycardia",

author = "{RAID Trial Investigators} and Wojciech Zareba and Daubert, {James P.} and Beck, {Christopher A.} and Huang, {David T.} and Alexis, {Jeffrey D.} and Brown, {Mary W.} and Kathryn Pyykkonen and Scott McNitt and David Oakes and Changyong Feng and Aktas, {Mehmet K.} and Felix Ayala-Parades and Adrian Baranchuk and Marc Dubuc and Mark Haigney and Alexander Mazur and McPherson, {Craig A.} and Mitchell, {L. Brent} and Andrea Natale and Piccini, {Jonathan P.} and Merritt Raitt and Rashtian, {Mayer Y.} and Claudio Schuger and Stephen Winters and Worley, {Seth J.} and Ohad Ziv and Moss, {Arthur J.} and W. Zareba and K. Pyykkonen and A. Buttaccio and E. Perkins and D. DeGrey and S. Robertson and Moss, {A. J.} and M. Brown and R. Lansing and A. Oberer and B. Polonsky and V. Ross and A. Papernov and S. Schleede and C. Beck and C. Feng and {McNitt S}, S. and Hall, {W. J.} and A. Moss and J. Daubert and D. Huang and S. Winters and O. Ziv",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = aug,

day = "7",

doi = "10.1016/j.jacc.2018.04.086",

language = "אנגלית",

volume = "72",

pages = "636--645",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Inc.",

number = "6",

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TY - JOUR

T1 - Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators

T2 - The RAID Trial

AU - RAID Trial Investigators

AU - Zareba, Wojciech

AU - Daubert, James P.

AU - Beck, Christopher A.

AU - Huang, David T.

AU - Alexis, Jeffrey D.

AU - Brown, Mary W.

AU - Pyykkonen, Kathryn

AU - McNitt, Scott

AU - Oakes, David

AU - Feng, Changyong

AU - Aktas, Mehmet K.

AU - Ayala-Parades, Felix

AU - Baranchuk, Adrian

AU - Dubuc, Marc

AU - Haigney, Mark

AU - Mazur, Alexander

AU - McPherson, Craig A.

AU - Mitchell, L. Brent

AU - Natale, Andrea

AU - Piccini, Jonathan P.

AU - Raitt, Merritt

AU - Rashtian, Mayer Y.

AU - Schuger, Claudio

AU - Winters, Stephen

AU - Worley, Seth J.

AU - Ziv, Ohad

AU - Moss, Arthur J.

AU - Zareba, W.

AU - Pyykkonen, K.

AU - Buttaccio, A.

AU - Perkins, E.

AU - DeGrey, D.

AU - Robertson, S.

AU - Moss, A. J.

AU - Brown, M.

AU - Lansing, R.

AU - Oberer, A.

AU - Polonsky, B.

AU - Ross, V.

AU - Papernov, A.

AU - Schleede, S.

AU - Beck, C.

AU - Feng, C.

AU - McNitt S, S.

AU - Hall, W. J.

AU - Moss, A.

AU - Daubert, J.

AU - Huang, D.

AU - Winters, S.

AU - Ziv, O.

PY - 2018/8/7

Y1 - 2018/8/7

N2 - Background: Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives: This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods: This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results: Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions: In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality.

AB - Background: Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives: This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods: This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results: Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions: In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality.

KW - implantable cardioverter-defibrillator

KW - ranolazine

KW - ventricular fibrillation

KW - ventricular tachycardia

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AN - SCOPUS:85050338895

SN - 0735-1097

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EP - 645

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 6

ER -

Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial

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