Editorial - Circulation: Cardiovascular Quality and Outcomes

Editorial Does Ivabradine SIGNIFY Improvements in Quality of Life? Colleen M. Norris, PhD; Kevin R. Bainey, MD, MSc

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n his 2015 commencement address to Columbia College of Physicians and Surgeons, Dr Harlan Krumholz collectively challenged healthcare professionals to “join him in putting the conception of a patient to rest and ushering in a notion of people who we can engage, empower, and strengthen as partners. We are not there to impose our values, we are there to help them pursue a course that is consistent with their wishes”.1 As such, health-related quality of life (QOL) measurement (HRQOL) has become a key tool to help invoke these expectations. Fortunately, this has been made somewhat easier with development of the Seattle Angina Questionnaire (SAQ).2 Developed by Dr John Spertus, the SAQ has been translated into over 80 languages and has become the gold standard for quantifying patient-reported health status and HRQOL in patients with stable coronary artery disease (CAD). The SAQ has become the HRQOL measurement tool used in randomized controlled trials to collect patient-reported health status among tested revascularization and pharmacological strategies. Developed in 1994, the SAQ is a 19-item multidimensional, self-administered questionnaire that evaluates 5 dimensions of HRQOL, including physical limitations related to angina symptoms (chest pain, chest tightness, and shortness of breath), angina stability, angina frequency, treatment satisfaction, and QOL.2 Its reliability, validity, and responsiveness have been well established for patients with CAD, including its superiority when compared with previously established patient-reported measures of angina.3 For patients with stable CAD (defined as those with established pattern of angina, a history of myocardial infarction, or angiographically documented coronary plaque burden), the symptoms and functional limitations of angina can significantly impair QOL long term. However, clinical trials evaluating treatments and new therapies for patients with stable angina have traditionally focused on morbidity or mortality end points (ie, death or myocardial infarction). We performed a cursory Medline search using the search term Seattle Angina Questionnaire, and filtered by randomized controlled trials, we identified 138 studies using the SAQ scales, predominantly the physical limitation scale, as a secondary end point or substudy

of a trial comparing mortality/morbidity advantages of new therapies. The consistent delegation of HRQOL outcomes as less important secondary end points has devalued their impact, with less implication for evidence-based practice. This notion has been highlighted by the COURAGE HRQOL substudy. The overall randomized trial found optimal medical management had similar long-term benefits when compared with PCI (primary end point: death or myocardial infarction).4 Given the focus on hard end points, patient-reported QOL outcomes (which one could argue are patient-focused) received a modicum of attention. Still, the COURAGE HRQOL substudy found that PCI demonstrated significant incremental benefits in functional health status compared with the medically managed patients (mean differences of ≈5 points) where the authors affirm patient-reported angina relief should become the primary goal of treatment for patients having chronic stable angina with CAD. A new and exciting therapeutic opportunity following in the heels of the COURAGE HRQOL substudy is presented in this issue of Circulation: Cardiovascular Quality and Outcomes. Tendera et al report on the effect of ivabradine on angina-related QOL in patients participating in the SIGNIFY Quality of Life substudy.5 The results of the SIGNIFY trial, which included 19 102 patients with CAD, were neutral with no effect of ivabradine on the primary composite end point of cardiovascular death or nonfatal myocardial infarction.6 The concluding sentence of the abstract published in the New England Journal of Medicine states: “Among patients who had stable CAD without clinical heart failure, the addition of ivabradine to standard background therapy to reduce the heart rate did not improve outcomes.”7 However, we argue that the results of the SIGNIFY HRQOL substudy presented by Tendera et al indicate treatment with ivabradine produced consistent improvements in important self-reported outcomes related to anginal frequency and overall QOL. Several key features of this study deserve further consideration. First, the SIGNIFY HRQOL substudy used a prespecified subgroup of patients with at least Canadian Cardiovascular Class II angina at baseline (ie, having angina symptoms) from the SIGNIFY randomized, double-blind, placebo controlled trial. As such, it was recognized that the presence of angina would have substantial impact on QOL and may accentuate the effects of a tested anti-anginal agent. Second, QOL was assessed using the validated CAD diseasespecific SAQ performed at serial time points (at baseline, 6, and 12 months) to record patient-reported QOL and health status. Of note, it is impressive that 12-month QOL measurements were reported for 79% of the Ivabradine group and 80% of the placebo group, which provides a rich source of data. Third, the patients completed the SAQ before any other investigations in the main trial—hence, avoids any potential bias. Fourth, the frequency of clinically significant differences in

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Heart Health and Stroke Strategic Clinical Network, Alberta Health Services (C.M.N.) and Canadian VIGOUR Centre (K.R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. Correspondence to Colleen M. Norris, PhD (Epidemiology), 4–127 Clinical Sciences Bldg, University of Alberta, Edmonton, AB, T6G2G3. E-mail [email protected] (Circ Cardiovasc Qual Outcomes. 2016;9:00-00. DOI: 10.1161/CIRCOUTCOMES.115.002412.) © 2015 American Heart Association, Inc. Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org DOI: 10.1161/CIRCOUTCOMES.115.002412

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the SAQ dimensional scores between the placebo and treatment groups were reported. Tendera et al found that anti-anginal treatment with ivabradine significantly improved symptoms of anginal stability/frequency, treatment satisfaction, and overall QOL in patients with angina. These results are even more remarkable because patients in the SIGNIFY population were receiving appropriate levels of evidence-based anti-anginal therapy (87% β-blockers, 54% organic nitrates, 24% dihydopyridine calcium channel blockers) and had no indication for revascularization at study entry. However, ivabradine provides a novel pathway for further reducing the heart rate (inhibits the If current in the sinoatrial node), resulting in decreased demand of the myocardium and enhanced diastolic coronary blood flow. In combination with other antiischemic agents, the self-reporting SAQ dimensional scores have identified an additional therapy that improves the HRQOL of patients with stable angina. One may wonder about the incremental benefits that may be accrued in patients without medical optimization (ie, no β-blocker). The results of this study suggest that routine self-reported health status measurement would clearly improve our ability to provide patients with optimal therapy given their own preferences. It is time that patient-reported outcomes (particularly those measured in randomized controlled trials) receive the prominence and recognition they deserve. And while Tendera et al conducted a subgroup analysis, the significance of these results are no less important. In their editorial in Circulation: Cardiovascular Quality and Outcomes, Sepehrvand and Ezekowitz emphasize the importance of measuring and integrating HRQOL into daily practice, given the emerging importance of QOL over longevity.8 Better familiarity with HRQOL measurement tools in clinical practice will also add toward greater understanding and appreciation of health status outcomes as those presented by Tendera et al. There is an impressive body of evidence demonstrating that patient involvement leads to increased knowledge about treatment options, more realistic expectations regarding disease course and treatment, improved adherence to therapy, and enhanced patient satisfaction.9 It is now time to empower clinician’s knowledge of treatment options that have been reported by patients to improve symptoms, angina stability treatment satisfaction, and overall

QOL in patients with chronic stable angina. Life or death can become somewhat irrelevant with chronic disease—it is the quality that may matter the most.

Disclosures None.

References 1. Krumholz HM. 2015 Commencement Address: Columbia College of Physicians and Surgeons. Circ Cardiovasc Qual Outcomes. 2015;8:325– 328. doi: 10.1161/CIRCOUTCOMES.115.002117. 2. Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Fihn SD. Monitoring the quality of life in patients with coronary artery disease. Am J Cardiol. 1994;74:1240–1244. 3. Dougherty CM, Dewhurst T, Nichol WP, Spertus J. Comparison of three quality of life instruments in stable angina pectoris: Seattle angina questionnaire, short form health survey (sf-36), and quality of life index-cardiac version iii. J Clin Epidemiol. 1998;51:569–575. 4. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503–1516. doi: 10.1056/NEJMoa070829. 5. Tendera M, Chassany O, Ferrari R, Ford I, Gabriel Steg P, Tardif J-C, Fox K; on behalf of the SIGNIFY Investigators. Quality of life with ivabradine in patients with angina pectoris: the study assessing the morbidity– mortality benefits of the If inhibitor ivabradine in patients with coronary artery disease quality of life substudy. Circ Cardiovasc Qual Outcomes. 2016;9:xxx–xxx. doi: 10.1161/CIRCOUTCOMES.115.002091. 6. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the study assessing the morbidity-mortality benefits of the if inhibitor ivabradine in patients with coronary artery disease (SIGNIFY trial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart failure. Am Heart J. 2013;166:654–661.e6. doi: 10.1016/ j.ahj.2013.06.024. 7. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371:1091–1099. doi: 10.1056/ NEJMoa1406430. 8. Sepehrvand N, Ezekowitz JA. How to do more with less. Circ Cardiovasc Qual Outcomes. 2015;8:460–462. 9. O’Connor AM, Bennett CL, Stacey D, Barry M, Col NF, Eden KB, Entwistle VA, Fiset V, Holmes-Rovner M, Khangura S, LlewellynThomas H, Rovner D. Decision aids for people facing health treatment or screening decisions. Cochrane Database Syst Rev. 2009:CD001431. Key Words: coronary artery disease ◼ dyspnea ◼ myocardial infarction ◼ quality of life ◼ randomized controlled trial

Does Ivabradine SIGNIFY Improvements in Quality of Life? Colleen M. Norris and Kevin R. Bainey


Circ Cardiovasc Qual Outcomes. published online December 22, 2015; Circulation: Cardiovascular Quality and Outcomes is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-7705. Online ISSN: 1941-7713

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