Prognostic Effects of Cardiac Rehabilitation in Patients With Heart Failure (from a Multicenter Prospective Cohort Study)

Abstract

The prognostic effects of cardiac rehabilitation (CR) are inconsistent in recent reports on heart failure (HF). Generally, participants in previous trials were relatively young and had HF with reduced ejection fraction. Herein, we examined the effects of CR on HF prognosis using a nationwide cohort study. This multicenter prospective cohort study included hospitalized patients with acute HF or worsening chronic HF. Patients who underwent CR once or more times weekly for 6 months after discharge were included in the CR group. The main study end point was a composite of all-cause mortality and HF rehospitalization during a 2-year follow-up period. We performed propensity score matching to compare the survival rates between the CR and non-CR groups. Of the 2,876 enrolled patients, 313 underwent CR for 6 months. After propensity score matching using confounding factors, 626 patients (313 pairs) were included in the survival analysis (median age: 74 years). CR was associated with a reduced risk of composite outcomes (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.48 to 0.91; p = 0.011), all-cause mortality (HR 0.53; 95% CI 0.30 to 0.95; p = 0.032), and HF rehospitalization (HR 0.66; 95% CI 47 to 0.92; p = 0.012). Subgroup analysis showed similar CR effects in patients with HF with preserved ejection fraction (≥50%) and HF with reduced ejection fraction (<40%). In the landmark analysis, CR did not reduce the aforementioned end points beyond 6 months after discharge (log-rank test: composite outcomes, p = 0.943; all-cause mortality, p = 0.258; HF rehospitalization, p = 0.831). CR is a standard treatment for HF regardless of HF type; however, further challenges may affect the long-term prognostic effects of CR. The prognostic effects of cardiac rehabilitation (CR) are inconsistent in recent reports on heart failure (HF). Generally, participants in previous trials were relatively young and had HF with reduced ejection fraction. Herein, we examined the effects of CR on HF prognosis using a nationwide cohort study. This multicenter prospective cohort study included hospitalized patients with acute HF or worsening chronic HF. Patients who underwent CR once or more times weekly for 6 months after discharge were included in the CR group. The main study end point was a composite of all-cause mortality and HF rehospitalization during a 2-year follow-up period. We performed propensity score matching to compare the survival rates between the CR and non-CR groups. Of the 2,876 enrolled patients, 313 underwent CR for 6 months. After propensity score matching using confounding factors, 626 patients (313 pairs) were included in the survival analysis (median age: 74 years). CR was associated with a reduced risk of composite outcomes (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.48 to 0.91; p = 0.011), all-cause mortality (HR 0.53; 95% CI 0.30 to 0.95; p = 0.032), and HF rehospitalization (HR 0.66; 95% CI 47 to 0.92; p = 0.012). Subgroup analysis showed similar CR effects in patients with HF with preserved ejection fraction (≥50%) and HF with reduced ejection fraction (<40%). In the landmark analysis, CR did not reduce the aforementioned end points beyond 6 months after discharge (log-rank test: composite outcomes, p = 0.943; all-cause mortality, p = 0.258; HF rehospitalization, p = 0.831). CR is a standard treatment for HF regardless of HF type; however, further challenges may affect the long-term prognostic effects of CR. Cardiac rehabilitation (CR) is a comprehensive disease management program that is highly recommended by heart failure (HF) guidelines.1Yancy CW Jessup M Bozkurt B Butler J Casey Jr, DE Colvin MM Drazner MH Filippatos GS Fonarow GC Givertz MM Hollenberg SM Lindenfeld J Masoudi FA McBride PE Peterson PN Stevenson LW Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines and the Heart Failure Society of Amer.J Am Coll Cardiol. 2017; 70: 776-803Crossref PubMed Scopus (923) Google Scholar Meta-analyses have demonstrated the favorable effects mainly in young patients who have HF with reduced left ventricular ejection fraction (HFrEF).2Taylor RS Walker S Smart NA Piepoli MF Warren FC Ciani O Whellan D O'Connor C Keteyian SJ Coats A Davos CH Dalal HM Dracup K Evangelista LS Jolly K Myers J Nilsson BB Passino C Witham MD Yeh GY ExTraMATCH II Collaboration. Impact of exercise rehabilitation on exercise capacity and quality-of-life in heart failure: individual participant meta-analysis.J Am Coll Cardiol. 2019; 73: 1430-1443Crossref PubMed Scopus (57) Google Scholar, 3Long L Mordi IR Bridges C Sagar VA Davies EJ Coats AJ Dalal H Rees K Singh SJ Taylor RS. Exercise-based cardiac rehabilitation for adults with heart failure.Cochrane Database Syst Rev. 2019; 1CD003331PubMed Google Scholar, 4Taylor RS Long L Mordi IR Madsen MT Davies EJ Dalal H Rees K Singh SJ Gluud C Zwisler AD. Exercise-based rehabilitation for heart failure: cochrane systematic review, meta-analysis, and trial sequential analysis.JACC Heart Fail. 2019; 7: 691-705Crossref PubMed Scopus (48) Google Scholar Still, available evidence regarding the effects of CR on the long-term prognosis of older patients or HF with preserved ejection fraction (HFpEF) is limited. Previous studies on HFpEF suggested that CR increases exercise capacity, which is a surrogate measure of clinical events.5Haykowsky MJ Brubaker PH Stewart KP Morgan TM Eggebeen J Kitzman DW. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction.J Am Coll Cardiol. 2012; 60: 120-128Crossref PubMed Scopus (206) Google Scholar,6Kitzman DW Brubaker P Morgan T Haykowsky M Hundley G Kraus WE Eggebeen J Nicklas BJ. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial.JAMA. 2016; 315: 36-46Crossref PubMed Scopus (346) Google Scholar Another retrospective cohort study demonstrated the prognostic effects of CR in both HFrEF and HFpEF.7Kamiya K Sato Y Takahashi T Tsuchihashi-Makaya M Kotooka N Ikegame T Takura T Yamamoto T Nagayama M Goto Y Makita S Isobe M. Multidisciplinary cardiac rehabilitation and long-term prognosis in patients with heart failure.Circ Heart Fail. 2020; 13e006798Crossref PubMed Scopus (13) Google Scholar However, in that report, the effects of CR were analyzed in patients who underwent CR at least once within 3 months after discharge, which is less than the recommended frequency of effective CR. Additionally, the prognostic effects beyond 6 months remains uncertain. Therefore, this study aimed to examine the effects of CR for 6 months on the prognosis of HF in a cohort that included older patients with HFpEF. This prospective observational study was part of a multicenter cohort study to develop FraiLty-bAsed proGnoStic criteria in Heart faIlure Patients known as the FLAGSHIP study. The FLAGSHIP study's design is described elsewhere.8Yamada S Adachi T Izawa H Murohara T Kondo T FLAGSHIP collaboratorsA multicenter prospective cohort study to develop frailty-based prognostic criteria in heart failure patients (FLAGSHIP): rationale and design.BMC Cardiovasc Disord. 2018; 18: 159Crossref PubMed Scopus (11) Google Scholar The present analysis included ambulatory patients hospitalized due to acute HF or worsening chronic HF. Patients who were able to walk for 20 meters with or without the assistance of a walking aid at hospital discharge were considered as “ambulatory”. The exclusion criteria included severe cognitive impairment, defined as a mini-mental state examination9Folstein MF Folstein SE McHugh PR. Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician.J Psychiatr Res. 1975; 12: 189-198Crossref PubMed Scopus (67568) Google Scholar score <17 points; severe mental disorders; difficulty in answering questionnaires; and assumed short-term mortality (e.g., severe aortic valve stenosis without surgical indication or terminal-stage cancer). The FLAGSHIP study protocol was organized according to the Guidelines for the Epidemiological Research proposed by the Japanese Ministry of Health, Labour and Welfare. The study protocol was approved by the ethics committee of the Nagoya University School of Medicine (approval No. 2014–0421), and it complies with the principles of the Declaration of Helsinki. Ethical approval was also obtained from each participating hospital and each patient provided written informed consent. In Japan, health insurance is mandatory and has covered CR for HF since 2007. CR is covered for 150 days in the Japanese health care system, and outpatient CR is covered for up to 60 minutes per session, 3 times a week. Participating hospitals provided in- and outpatient CR according to the guidelines of the Japanese Circulation Society.10JCS Joint Working GroupGuidelines for rehabilitation in patients With cardiovascular disease (JCS 2012).Circ J. 2014; 78: 2022-2093Crossref PubMed Scopus (126) Google Scholar Based on the standard CR program recommended by the aforementioned guidelines, CR included exercise training, patient education, and patient counseling. Exercise training comprised preparatory exercises, aerobic exercise, and cool-down. Exercise intensity was set at each patient's anaerobic threshold which was measured using cardiopulmonary exercise testing, the Karvonen formula, or an intensity of 11 to 13 on the Borg scale. Furthermore, resistance training was generally added to aerobic exercise. In this study, each patient's CR participation frequency was assessed by physical therapists at each collaborating hospital based on medical records. We assessed CR frequency within 6 months of discharge because this was generally the same time as the final follow-up examinations in clinical practices in Japan. Patients who underwent CR once or more per week for 6 months after discharge were enrolled in the CR group. Hence, patients who did not complete 6-month CR or died within 6 months were included in the non-CR group for the present analysis. If outpatient CR was interrupted temporarily for any reason, including rehospitalization or canceling a session for illness but was resumed thereafter (≥1 session/week), the patient was included in the CR group. Patient characteristics, including age, gender, body mass index, and clinical details (main HF etiology, co-morbidities, previous admission due to HF, and medications at discharge) were collected from medical records. Echocardiographic and were collected method was to the left ventricular ejection fraction on on and were also to the from the Japanese Heart Failure because hospitals of in clinical a was with or defined as a Japanese Heart Failure Society on Heart Failure to using and in the for the and treatment of heart Scholar were also collected as In the FLAGSHIP study, physical was assessed in each patient discharge using and physical on in the FLAGSHIP study are described elsewhere.8Yamada S Adachi T Izawa H Murohara T Kondo T FLAGSHIP collaboratorsA multicenter prospective cohort study to develop frailty-based prognostic criteria in heart failure patients (FLAGSHIP): rationale and design.BMC Cardiovasc Disord. 2018; 18: 159Crossref PubMed Scopus (11) Google Scholar and were assessed based on the walking and was assessed using the measure for of Y S M H Y Izawa H Murohara of the measure for of for patients with heart failure: a PubMed Scopus Google Scholar measure for of is a that in patients with HF. a of that physical in patients with chronic HF and a scale. is from to with more severe The score is and with the peak oxygen measured by the cardiopulmonary exercise Y S K S Y Y N T A Murohara of for disease in patients with chronic heart Cardiol. 2012; 60: PubMed Scopus Google Scholar physical was assessed using the for H Adachi T Y of a for walking in patients with 2019; PubMed Scopus Google Scholar which with a scale. The score of this to has a to with and a with physical H Adachi T Y of a for walking in patients with 2019; PubMed Scopus Google Scholar cognitive was assessed using the mini-mental state MF Folstein SE McHugh PR. Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician.J Psychiatr Res. 1975; 12: 189-198Crossref PubMed Scopus (67568) Google Scholar which is a standard from to was assessed using a from to was defined as a score MT M and of a of the Am PubMed Google Scholar The main study end point was a composite of HF rehospitalization and all-cause within of end points were HF rehospitalization and all-cause A follow-up for each patient was performed using the medical of hospitals that the and HF rehospitalization was by the at each of the If patients did not at the prognostic were obtained from a to the patients months. was for each patient after HF rehospitalization the patients or to follow-up or the of the The follow-up was defined as the time from discharge the main end point the patients to or the final Patients with on were = with or without were described as the or in patient between the CR group and the non-CR group were using or as patients were not to the CR propensity score matching was performed to reduce the risk of in treatment and for each patient were using analysis with the CR group as the and as The of were to for by patients with was according to the and A of of propensity after Res. 2016; PubMed Scopus Google Scholar we performed using IR P using and for PubMed Scopus Google Scholar we the of each patient using each of the 20 complete we the of the 20 for each patient and we based on each patient's We performed available matching with a of of the standard for of were considered to In the survival were using the method and were using the for each study and 95% confidence were using a The was using the We also performed a analysis in which patients who died within 6 months were and matching was performed using the described Another analysis was performed based on HFrEF HF with ejection fraction = to and HFpEF beyond 6 we also landmark at 6 months. Patients with individual end point 6 months were from the landmark analysis. were performed with College A p of was considered A of 2,876 patients who were hospitalized due to acute HF or worsening chronic HF were included in this study and after matching are in of patients were due to HF and The from discharge to the time of rehospitalization was days to and the to the time of all-cause mortality was days to and prognosis according to HF are in and matching 313 The of CR participation was confidence interval to after matching were between the for were this threshold was considered to of patients were due to HF and died in the cohort = The from discharge to the time of rehospitalization was days to and the to the time of all-cause mortality was days to of study participants and after propensity score = = = = to to to to to to to to HF to to to to to to to to to to to to to cardiac to to to to to to to to to to to to to to to to walking to to to to to to to to to to to to of session within 6 are as with standard in or with in was defined as or = = II = body mass = = chronic CR = cardiac = = = heart = left ventricular ejection = = = for of = = for in a are as with standard in or with in was defined as or = = II = body mass = = chronic CR = cardiac = = = heart = left ventricular ejection = = = for of = = for the survival for each study end point in the The CR group of outcomes (log-rank test: p The for a composite in patients was = after patients who died within 6 months after discharge, CR was associated with a reduced risk of the composite and HF rehospitalization, but not with all-cause mortality A showed the effects of CR on the study outcomes the based on rehabilitation and study outcomes according to Patients with of were from the analysis. = heart failure with ejection The of the landmark analysis are in A survival analysis showed that CR participation was not associated with a of composite outcomes, all-cause mortality, or HF rehospitalization beyond 6 months from The for a composite was within 6 months = and after that = The main of this multicenter prospective cohort study was that participation in CR for 6 months after discharge was associated with a reduced of clinical available clinical evidence and that CR is a standard HF In the landmark analysis did not the long-term effects of CR on the of to effects the is a in the prognostic effects of CR in recent reports on patients with HF. recent systematic by Taylor RS Long L Mordi IR Madsen MT Davies EJ Dalal H Rees K Singh SJ Gluud C Zwisler AD. Exercise-based rehabilitation for heart failure: cochrane systematic review, meta-analysis, and trial sequential analysis.JACC Heart Fail. 2019; 7: 691-705Crossref PubMed Scopus (48) Google Scholar and Long L Mordi IR Bridges C Sagar VA Davies EJ Coats AJ Dalal H Rees K Singh SJ Taylor RS. Exercise-based cardiac rehabilitation for adults with heart failure.Cochrane Database Syst Rev. 2019; 1CD003331PubMed Google Scholar suggested that CR the prognosis of patients with HF. recent showed that CR was not associated with reduced of mortality or rehospitalization in patients with RS Walker S Smart NA Piepoli MF Warren FC Ciani O O'Connor C Whellan D Keteyian SJ Coats A Davos CH Dalal HM Dracup K Evangelista L Jolly K Myers J RS Nilsson BB Passino C Witham MD Yeh GY Zwisler ExTraMATCH II Collaboration. Impact of cardiac rehabilitation in patients with heart failure on mortality and an individual patient of J Heart Fail. 2018; PubMed Scopus Google B K M M S B B Society of and cardiac rehabilitation in patients with reduced left ventricular ejection fraction: the Cardiac in Heart Failure a systematic and J Cardiol. 2020; PubMed Scopus Google Scholar Therefore, is to examine the effects of CR on in patients with HF. Generally, randomized trials to to the prognostic effects of CR due to the and we performed a analysis using observational and effects of CR in patients with HF. between CR participation and reduced clinical in this study were with of a recent nationwide study in K Sato Y Takahashi T Tsuchihashi-Makaya M Kotooka N Ikegame T Takura T Yamamoto T Nagayama M Goto Y Makita S Isobe M. Multidisciplinary cardiac rehabilitation and long-term prognosis in patients with heart failure.Circ Heart Fail. 2020; 13e006798Crossref PubMed Scopus (13) Google Scholar In study, we defined CR participation for 6 months after discharge and effects of CR on the clinical evidence CR as a standard treatment for HF Exercise training, a of had effects including and and and with N exercise to heart 2012; PubMed Scopus Google Scholar, G Goto of exercise in the of cardiovascular and Heart J. PubMed Scopus Google Scholar, C J C physical and Am Coll Cardiol. 2018; PubMed Scopus Google Scholar HF guidelines that patient regarding and CW Jessup M Bozkurt B Butler J Casey Jr, DE Colvin MM Drazner MH Filippatos GS Fonarow GC Givertz MM Hollenberg SM Lindenfeld J Masoudi FA McBride PE Peterson PN Stevenson LW Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines and the Heart Failure Society of Amer.J Am Coll Cardiol. 2017; 70: 776-803Crossref PubMed Scopus (923) Google P H Coats Jessup M C P B P Guidelines for the and treatment of acute and chronic heart failure: the for the and treatment of acute and chronic heart failure of the Society of with the of the Heart Failure Association of the Heart J. 2016; PubMed Google Scholar of CR a in the quality of life and prognosis of patients with HF. cohort of patients, with a of 74 the of the of CR to older to of previous L Mordi IR Bridges C Sagar VA Davies EJ Coats AJ Dalal H Rees K Singh SJ Taylor RS. Exercise-based cardiac rehabilitation for adults with heart failure.Cochrane Database Syst Rev. 2019; 1CD003331PubMed Google RS Long L Mordi IR Madsen MT Davies EJ Dalal H Rees K Singh SJ Gluud C Zwisler AD. Exercise-based rehabilitation for heart failure: cochrane systematic review, meta-analysis, and trial sequential analysis.JACC Heart Fail. 2019; 7: 691-705Crossref PubMed Scopus (48) Google RS Walker S Smart NA Piepoli MF Warren FC Ciani O O'Connor C Whellan D Keteyian SJ Coats A Davos CH Dalal HM Dracup K Evangelista L Jolly K Myers J RS Nilsson BB Passino C Witham MD Yeh GY Zwisler ExTraMATCH II Collaboration. Impact of cardiac rehabilitation in patients with heart failure on mortality and an individual patient of J Heart Fail. 2018; PubMed Scopus Google B K M M S B B Society of and cardiac rehabilitation in patients with reduced left ventricular ejection fraction: the Cardiac in Heart Failure a systematic and J Cardiol. 2020; PubMed Scopus Google Scholar Furthermore, a analysis that CR the prognosis of patients with as as for with the clinical of CR in HFpEF This the of previous randomized trials that demonstrated the effects of CR on exercise MJ Brubaker PH Stewart KP Morgan TM Eggebeen J Kitzman DW. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction.J Am Coll Cardiol. 2012; 60: 120-128Crossref PubMed Scopus (206) Google Scholar,6Kitzman DW Brubaker P Morgan T Haykowsky M Hundley G Kraus WE Eggebeen J Nicklas BJ. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial.JAMA. 2016; 315: 36-46Crossref PubMed Scopus (346) Google G S L A S C M G M Exercise training exercise capacity and in patients with heart failure with preserved ejection fraction: of the training in heart Am Coll Cardiol. PubMed Scopus Google Scholar an prognostic of patients with cardiovascular J M D S Exercise capacity and mortality for exercise J PubMed Scopus Google Scholar However, because of the the of CR in patients with HF with ejection fraction to in A of this study was that CR participation was not associated with prognosis beyond 6 months after that the of the outpatient CR program is to 6 months in Japan, this that the effects of CR are after of the CR are for the of the 6-month analysis may have by survival because the landmark analysis who short-term end the of CR effects after 6 months the effects of CR on risk associated with long-term J J J P A M J M K C L J J K L J survival acute heart failure: the Heart Failure Database J PubMed Scopus Google J J L A J A P K J M J P C J M L S J. risk in acute heart J Cardiol. 2016; PubMed Scopus Google Scholar patients may not to exercise HF or CR it has that to of patients with chronic including HF, not to CR S In chronic nationwide by patients to and by to Google Scholar Another study suggested that CR patients physical and in which for disease S Y from a heart a study and the to PubMed Scopus Google Scholar Therefore, medical may to more on patient education, the long-term management of HF. This study has not because the CR participation in this study was than that in nationwide cohort in K Yamamoto T Tsuchihashi-Makaya M Ikegame T Takahashi T Sato Y Kotooka N Y H H Isobe M. of care and cardiac rehabilitation for patients with heart failure in an analysis of the J. 2019; PubMed Scopus Google Scholar regarding CR and participation beyond 6 months after discharge were not in medications and during follow-up were not CR frequency was based on medical and on the of and CR time were not Therefore, the of CR and study outcomes in this study. Additionally, the was analysis may to because patients who did not complete CR for 6 months were included in the non-CR group. may that were not measured in this study. In the of this study that CR is a standard treatment for a of patients with however, are further challenges that may affect the long-term prognosis of CR. We are to the patients for with the study and FLAGSHIP collaborating for This study is by a for Research from the Society for the of We did not from any for this study. The have of to with with survival according to left ventricular ejection fraction. = heart failure with ejection fraction. with of propensity score and and after propensity score heart II body mass for of chronic with for the study outcomes who died within 6 months.

Topics & Concepts