Associations of health-related quality of life with major adverse cardiovascular and cerebrovascular events for individuals with ischaemic heart disease: systematic review, meta-analysis and evidence mapping

Objective To investigate the association between health-related quality of life (HRQoL) and major adverse cardiovascular and cerebrovascular events (MACCE) in individuals with ischaemic heart disease (IHD). Methods Medline(R), Embase, APA PsycINFO and CINAHL (EBSCO) from inception to 3 April 2023 were searched. Studies reporting association of HRQoL, using a generic or cardiac-specific tool, with MACCE or components of MACCE for individuals with IHD were eligible for inclusion. Risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale to assess the quality of the studies. Descriptive synthesis, evidence mapping and random-effects meta-analysis were performed stratified by HRQoL measures and effect estimates. Between-study heterogeneity was assessed using the Higgins I2 statistic. Results Fifty-one articles were included with a total of 134 740 participants from 53 countries. Meta-analysis of 23 studies found that the risk of MACCE increased with lower baseline HeartQoL score (HR 1.49, 95% CI 1.16 to 1.93) and Short Form Survey (SF-12) physical component score (PCS) (HR 1.39, 95% CI 1.28 to 1.51). Risk of all-cause mortality increased with a lower HeartQoL (HR 1.64, 95% CI 1.34 to 2.01), EuroQol 5-dimension (HR 1.17, 95% CI 1.12 to 1.22), SF-36 PCS (HR 1.29, 95% CI 1.19 to 1.41), SF-36 mental component score (HR 1.18, 95% CI 1.08 to 1.30). Conclusions This study found an inverse association between baseline values or change in HRQoL and MACCE or components of MACCE in individuals with IHD, albeit with between-study heterogeneity. Standardisation and routine assessment of HRQoL in clinical practice may help risk stratify individuals with IHD for tailored interventions. PROSPERO registration number CRD42021234638.


Differences between protocol and review
Primary published protocol of the systematic review had been updated after the initial literature search was performed.First, provided only few studies published data on HRQoL estimated during the acute stage of MI as well as within post-MI period, we decided to expand the study population and include patients with any type of IHD.Study exposure defined as HRQoL was slightly modified, including some additional generic and cardiac-specific instruments that are frequently used.Also, we initially considered the primary outcome as CVD death, recurring MI, coronary revascularization, stroke, atrial fibrillation, and heart failure.However, on review of the included studies, we made a unanimous decision to change the primary outcome and consider more broader endpoint consisted of all-cause death as well as hospitalization with unstable angina instead of atrial fibrillation (so including more universal 5-component MACCE and death, including cardiovascular death).
We planned to search studies from inception to May 2020, but expanded this period to the most recently published studies.Although we were intended to consider only prospective cohort studies, we included one retrospective study that met the main inclusion criteria.
As for meta-analysis, we also planned to carry out sensitivity analysis to determine whether the overall estimates between HRQoL and MACCE outcomes are influenced by outlier studies, subgroup analysis to determine heterogeneity based on type of HRQoL measure, study follow up period and design.Due to the paucity of available data, we were able to combine only few studies as the instruments used for measuring HRQoL and the scoring algorithms were disparate, as well as statistical approaches to estimate the associations with outcomes.

Electronic search strategy
Known relevant studies and their included studies were used to identify records within databases.Candidate search terms were identified by looking at words in the titles, abstracts, and subject indexing of those records.A draft search strategy was developed using those terms and additional search terms were identified from the results of that strategy.Search terms were also identified using the PubMed PubReMiner word frequency analysis tool.A search filter 1 2 was used to identify papers on prognosis and risk assessment papers in Medline and was also used for the other databases.The strategies were peer reviewed by another information specialist prior to execution using the PRESS Checklist 3 4 .Citations identified from the literature searches were imported to EndNote and duplicates were removed.
Final search strategy is presented below:
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Effect estimates transformations
When the effect estimates reported for different unit increments and(or) its directionality (increase/decrease) we re-calculated hazard ratios (odds ratios) through mathematical transformations of raw estimates derived from each study, such as exponentiation, root extraction, division of one by the estimate (whichever applicable), and log-transformation.

Descriptive synthesis of evidence
In the EPICOR and EPICOR Asia studies of 23489 individuals with ACS, a lower baseline EQ-5D score was associated with an increased risk of death 10 11 and a composite of death, nonfatal MI or non-fatal stroke at 2 years 12 .National studies in Denmark and the Netherlands also showed its prognostic value in hospitalized patients with stable IHD 13 and after elective CABG 14 , and the TIGRIS study demonstrated an inverse association of EQ-5D and EQ-VAS with all-cause mortality and a composite of cardiovascular death, MI, stroke or unstable angina requiring urgent revascularisation) at 1-3 years after MI 15 16 .In another cohort, EQ-VAS showed prognostic value when used in acute MI 17 , angina 18 , 1 month after PCI 19 and 6 months after surgery 20 .However, in a multicentre study of 2501 outpatients following CABG surgery the predictive role of EQ-VAS was not confirmed 14 .
The HeartQol global score was associated with all-cause mortality and cardiac events in a broad IHD cohort from Denmark at 1year 13 21 22 , 3 years 18 and 5 years of follow-up 23 .In 2 post-hoc analyses of the EPHESUS trial 24 25 in out-patients with post-MI heart failure, poor HRQoL as measured by the KCCQ at any of 1, 3 or 6 months, was associated with increased all-cause mortality and the composite endpoint of cardiovascular mortality or heart failure hospitalisation at 1 year 25 .Of 3 studies using DASI score [26][27][28] , 2 found associations between lower functional capacity and higher 2-year mortality following MI 27 and higher risk of death, non-fatal MI or stroke within 3 years of follow-up in stable IHD patients 28 .Small studies of QLMI 29 and its modification MacNew instrument 30 showed associations between lower HRQoL and increased risk of death or cardiac events within 18 and 6 months after MI, respectively.
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Association of HRQoL with MACCE by duration of follow-up
Two studies investigated differences in the magnitude of associations between HRQoL and cardiovascular outcomes by follow-up duration 12 30 .Poor HRQoL (lowest tertile of MacNew) post-PCI independently predicted a composite of death, non-fatal MI, CABG surgery and PCI, and a composite of death or non-fatal MI at 6 months, but failed to predict these outcomes at 2 years 30 .Similar associations were found for EQ-5D 12 and KCCQ 10 25 with risk of death at 1 and 2 years after ACS.By contrast, all 12 studies with more than 5 years of follow-up reported an inverse association of HRQoL and MACCE.
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)   The association between EQ-5D and EQ-VAS and 30-day mortality is significant for EQ-5D (p=0.048;R2 = 0.012), but not for EQ-VAS (p=0.06;R2 = 0.011).
C-index for predicting 30-day mortality for EQ-5D -0.39 (0.30-0. HR for physical limitation, per 20-unit decrease (worsening): death -1.1 (1.0-1.3),hospitalization for angina -1.2 (1.1-1.4),revascularization -1.2 (1.0-1.4),MI 1.1 (0.9-1.3), HF 1. # the study by Rasmussen et al. was considered as high quality despite the absence of comparison between poor and good HRQoL (this data has been published in a prior report which was accordingly cited in the manuscript (and which was also included in our systematic review).
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diabetes mellitus, IHDischemic heart disease, MI -Myocardial Infarction, NSTEMI -Non-ST-Elevation Myocardial Infarction, NSTEACS -Non-ST-Elevation acute coronary syndrome, PCIpercutaneous coronary intervention, RCTrandomised clinical trial, RFrisk factor, STEMI -ST Elevation Myocardial Infarction, EFleft ventricular ejection fraction, HFheart failure, SCrserum creatinine, ICDimplantable cardioverter-defibrillator, FDA -Food and Drug Administration, NYHA -New York Heart Association, ECGelectrocardiogram, Htnarterial hypertension, TIAtransient ischemic stroke, ACQUIPthe Ambulatory Care Quality Improvement Project, ALSWH -ALSWH -Australian Longitudinal Study on Women's Health, CORRAD -Coronary Surgery Database Radboud Hospital, UMCNthe Radboud University Nijmegen Medical Centre, EHS-CR -Euro Heart Survey on Coronary Revascularization, EPHESUSthe Eplerenone Post-AMI Heart Failure Efficacy and Survival Study, EPICORlong-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients, EXITthe randomized EXhaustion Intervention Trial, ICON1 -The study to Improve Clinical Outcomes in high-risk patieNts with acute coronary syndrome, MADIT-IIhe Multi-center Autonomic Defibrillator Implantation Trial II, MONICAmonitoring trends and determinants in cardiovascular disease project, MOSSthe Mediators of Social Support study, PREMIERthe Prospective Registry Evaluating Outcomes After Myocardial Iinfaction: Events and Recovery, PSOCS -Processes, Structures, and Outcomes of Care in Cardiac Surgery, RESEARCHthe Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital registry, SESAMIthe Socio-Economic and Acute Myo-cardial Infarction Study, SMART -The Second Manifestations of ARTerial disease study, SPHEREthe Secondary Prevention of Heart Disease in General Practice, STORMacute coronary Syndrome in paTients end Of life and Risk assesMent study, SYNTAXES -Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival, TIGRISlong-Term rIsk clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients, TRIUMPH -Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health StatusBMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)

Supplementary material to 'Associations of health-related quality of life with major adverse cardiovascular and cerebrovascular events for individuals with ischemic heart disease: Systematic review, meta-analysis and evidence mapping' 20 Supplementary Table 2a. Characteristics of included studies and cohorts Study description Inclusion and exclusion criteria Clinical and demographic characteristics of participants First author, publication year, study me, recruitment period Country(ies) N Group (time of enrollment after CV event)), disease stage, settings Specific inclusion criteria Specific exclusion criteria Age Male sex, % Race (White) Smoking (current) Htn DM Type of index MI Stable angina
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Abbreviations: ACSacute coronary syndrome, CABGcoronary artery bypass graft, CADcoronary artery disease, CKDchronic kidney disease, DM BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)Open Heart doi: 10.1136/openhrt-2023-002452 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)Open Heart doi: 10.1136/openhrt-2023-002452 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Open Heart doi: 10.1136/openhrt-2023-002452

Table 2b. Publications of associations of HRQoL with MACCE included in the systematic review
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Table 3 . Risk of bias assessment
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)RRs per one-step increase in functional impairment -1.28 (95% CI: 1.14−1.43)for the CV composite, 1.52 (95% CI: 1.29−1.79)for CV death BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)