Psychological interventions for depression and anxiety in patients with coronary heart disease, heart failure or atrial fibrillation.

BACKGROUND: Depression and anxiety occur frequently (with reported prevalence rates of around 40%) in individuals with coronary heart disease (CHD), heart failure (HF) or atrial fibrillation (AF) and are associated with a poor prognosis, such as decreased health-related quality of life (HRQoL), and increased morbidity and mortality. Psychological interventions are developed and delivered by psychologists or specifically trained healthcare workers and commonly include cognitive behavioural therapies and mindfulness-based stress reduction. They have been shown to reduce depression and anxiety in the general population, though the exact mechanism of action is not well understood. Further, their effects on psychological and clinical outcomes in patients with CHD, HF or AF are unclear. OBJECTIVES: To assess the effects of psychological interventions (alone, or with cardiac rehabilitation or pharmacotherapy, or both) in adults who have a diagnosis of CHD, HF or AF, compared to no psychological intervention, on psychological and clinical outcomes. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL databases from 2009 to July 2022. We also searched three clinical trials registers in September 2020, and checked the reference lists of included studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing psychological interventions with no psychological intervention for a minimum of six months follow-up in adults aged over 18 years with a clinical diagnosis of CHD, HF or AF, with or without depression or anxiety. Studies had to report on either depression or anxiety or both. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were depression and anxiety, and our secondary outcomes of interest were HRQoL mental and physical components, all-cause mortality and major adverse cardiovascular events (MACE). We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: Twenty-one studies (2591 participants) met our inclusion criteria. Sixteen studies included people with CHD, five with HF and none with AF. Study sample sizes ranged from 29 to 430. Twenty and 17 studies reported the primary outcomes of depression and anxiety, respectively. Despite the high heterogeneity and variation, we decided to pool the studies using a random-effects model, recognising that the model does not eliminate heterogeneity and findings should be interpreted cautiously. We found that psychological interventions probably have a moderate effect on reducing depression (standardised mean difference (SMD) -0.36, 95% confidence interval (CI) -0.65 to -0.06; 20 studies, 2531 participants; moderate-certainty evidence) and anxiety (SMD -0.57, 95% CI -0.96 to -0.18; 17 studies, 2235 participants; moderate-certainty evidence), compared to no psychological intervention. Psychological interventions may have little to no effect on HRQoL physical component summary scores (PCS) (SMD 0.48, 95% CI -0.02 to 0.98; 12 studies, 1454 participants; low-certainty evidence), but may have a moderate effect on improving HRQoL mental component summary scores (MCS) (SMD 0.63, 95% CI 0.01 to 1.26; 12 studies, 1454 participants; low-certainty evidence), compared to no psychological intervention. Psychological interventions probably have little to no effect on all-cause mortality (risk ratio (RR) 0.81, 95% CI 0.39 to 1.69; 3 studies, 615 participants; moderate-certainty evidence) and may have little to no effect on MACE (RR 1.22, 95% CI 0.77 to 1.92; 4 studies, 450 participants; low-certainty evidence), compared to no psychological intervention. AUTHORS' CONCLUSIONS: Current evidence suggests that psychological interventions for depression and anxiety probably result in a moderate reduction in depression and anxiety and may result in a moderate improvement in HRQoL MCS, compared to no intervention. However, they may have little to no effect on HRQoL PCS and MACE, and probably do not reduce mortality (all-cause) in adults who have a diagnosis of CHD or HF, compared with no psychological intervention. There was moderate to substantial heterogeneity identified across studies. Thus, evidence of treatment effects on these outcomes warrants careful interpretation. As there were no studies of psychological interventions for patients with AF included in our review, this is a gap that needs to be addressed in future studies, particularly in view of the rapid growth of research on management of AF. Studies investigating cost-effectiveness, return to work and cardiovascular morbidity (revascularisation) are also needed to better understand the benefits of psychological interventions in populations with heart disease.

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments.

Importance: Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals. Objective: To systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases. Data sources: The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023. Study Selection: Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded. Data Extraction and Synthesis: Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes. Main Outcomes and Measures: Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized. Results: Thirty-seven surrogate markers listed in FDA's table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result. Conclusions and Relevance: Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

Exercise-based cardiac rehabilitation for adults with heart failure.

BACKGROUND: People with heart failure experience substantial disease burden that includes low exercise tolerance, poor health-related quality of life (HRQoL), increased risk of mortality and hospital admission, and high healthcare costs. The previous 2018 Cochrane review reported that exercise-based cardiac rehabilitation (ExCR) compared to no exercise control shows improvement in HRQoL and hospital admission amongst people with heart failure, as well as possible reduction in mortality over the longer term, and that these reductions appear to be consistent across patient and programme characteristics. Limitations noted by the authors of this previous Cochrane review include the following: (1) most trials were undertaken in patients with heart failure with reduced (< 45%) ejection fraction (HFrEF), and women, older people, and those with heart failure with preserved (≥ 45%) ejection fraction (HFpEF) were under-represented; and (2) most trials were undertaken in a hospital or centre-based setting. OBJECTIVES: To assess the effects of ExCR on mortality, hospital admission, and health-related quality of life of adults with heart failure. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO and Web of Science without language restriction on 13 December 2021. We also checked the bibliographies of included studies, identified relevant systematic reviews, and two clinical trials registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared ExCR interventions (either exercise only or exercise as part of a comprehensive cardiac rehabilitation) with a follow-up of six months or longer versus a no-exercise control (e.g. usual medical care). The study population comprised adults (≥ 18 years) with heart failure - either HFrEF or HFpEF. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were all-cause mortality, mortality due to heart failure, all-cause hospital admissions, heart failure-related hospital admissions, and HRQoL. Secondary outcomes were costs and cost-effectiveness. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 60 trials (8728 participants) with a median of six months' follow-up. For this latest update, we identified 16 new trials (2945 new participants), in addition to the previously identified 44 trials (5783 existing participants). Although the existing evidence base predominantly includes patients with HFrEF, with New York Heart Association (NYHA) classes II and III receiving centre-based ExCR programmes, a growing body of trials includes patients with HFpEF with ExCR undertaken in a home-based setting. All included trials employed a usual care comparator with a formal no-exercise intervention as well as a wide range of active comparators, such as education, psychological intervention, or medical management. The overall risk of bias in the included trials was low or unclear, and we mostly downgraded the certainty of evidence of outcomes upon GRADE assessment. There was no evidence of a difference in the short term (up to 12 months' follow-up) in the pooled risk of all-cause mortality when comparing ExCR versus usual care (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.71 to 1.21; absolute effects 5.0% versus 5.8%; 34 trials, 36 comparisons, 3941 participants; low-certainty evidence). Only a few trials reported information on whether participants died due to heart failure. Participation in ExCR versus usual care likely reduced the risk of all-cause hospital admissions (RR 0.69, 95% CI 0.56 to 0.86; absolute effects 15.9% versus 23.8%; 23 trials, 24 comparisons, 2283 participants; moderate-certainty evidence) and heart failure-related hospital admissions (RR 0.82, 95% CI 0.49 to 1.35; absolute effects 5.6% versus 6.4%; 10 trials; 10 comparisons, 911 participants; moderate-certainty evidence) in the short term. Participation in ExCR likely improved short-term HRQoL as measured by the Minnesota Living with Heart Failure (MLWHF) questionnaire (lower scores indicate better HRQoL and a difference of 5 points or more indicates clinical importance; mean difference (MD) -7.39 points, 95% CI -10.30 to -4.77; 21 trials, 22 comparisons, 2699 participants; moderate-certainty evidence). When pooling HRQoL data measured by any questionnaire/scale, we found that ExCR may improve HRQoL in the short term, but the evidence is very uncertain (33 trials, 37 comparisons, 4769 participants; standardised mean difference (SMD) -0.52, 95% CI -0.70 to -0.34; very-low certainty evidence). ExCR effects appeared to be consistent across different models of ExCR delivery: centre- versus home-based, exercise dose, exercise only versus comprehensive programmes, and aerobic training alone versus aerobic plus resistance programmes. AUTHORS' CONCLUSIONS: This updated Cochrane review provides additional randomised evidence (16 trials) to support the conclusions of the previous 2018 version of the review. Compared to no exercise control, whilst there was no evidence of a difference in all-cause mortality in people with heart failure, ExCR participation likely reduces the risk of all-cause hospital admissions and heart failure-related hospital admissions, and may result in important improvements in HRQoL. Importantly, this updated review provides additional evidence supporting the use of alternative modes of ExCR delivery, including home-based and digitally-supported programmes. Future ExCR trials need to focus on the recruitment of traditionally less represented heart failure patient groups including older patients, women, and those with HFpEF.

Adapting an evidence-based, home cardiac rehabilitation programme for people with heart failure and their caregivers to the Danish context: DK:REACH-HF study.

AIMS: Adapting interventions with an existing evidence base offers a more efficient approach than development of a new intervention. The aim of this study was to describe the process of adapting a home-based cardiac rehabilitation (CR) programme (REACH-HF) intervention originally developed in the United Kingdom for people with heart failure (HF) to the Danish health system - the 'DK:REACH-HF' programme. METHODS AND RESULTS: We followed methodological framework for the conduct and reporting of studies adapting interventions, utilizing documentary analysis, qualitative interviews, stakeholder consultations, and mapping of the Danish policy context. Our study found broad support for the REACH-HF intervention as an alternative to existing centre-based CR. We also identified three key areas of adaptation for the Danish context. First, reduce the word-count of the intervention's resources by linking to existing publicly available CR materials. Second, whilst retaining REACH-HF core components, adapt its content and delivery to reflect differences between Denmark and United Kingdom. Thirdly, to develop a digital version of the intervention. CONCLUSION: Using an evidence-based approach, we successfully adapted the REACH-HF intervention to the context of the Danish healthcare setting, maintaining core components of the original intervention, and developing both a paper based and digital version of the programme material. To inform scaled national implementation of the DK:REACH-HF programme, we seek to undertake a pilot study to test the adapted intervention materials feasibility and acceptability to healthcare practitioners, patients, and their caregivers and confirm the positive impact on the outcomes of HF patients and caregivers.

Cost Effectiveness of Endovascular Ultrasound Renal Denervation in Patients with Resistant Hypertension.

BACKGROUND: Resistant hypertension (rHTN) is defined as blood pressure (BP) of ≥ 140/90 mmHg despite treatment with at least three antihypertensive medications, including a diuretic. Endovascular ultrasound renal denervation (uRDN) aims to control BP alongside conventional BP treatment with antihypertensive medication. This analysis assesses the cost effectiveness of the addition of the Paradise uRDN System compared with standard of care alone in patients with rHTN from the perspective of the United Kingdom (UK) health care system. METHODS: Using RADIANCE-HTN TRIO trial data, we developed a state-transition model. Baseline risk was calculated using Framingham and Prospective Cardiovascular Münster (PROCAM) risk equations to estimate the long-term cardiovascular risks in patients treated with the Paradise uRDN System, based on the observed systolic BP (SBP) reduction following uRDN. Relative risks sourced from a meta-analysis of randomised controlled trials were then used to project cardiovascular events in patients with baseline SBP ('control' patients); utility and mortality inputs and costs were derived from UK data. Costs and outcomes were discounted at 3.5% per annum. Modelled outcomes were validated against trial meta-analyses and the QRISK3 algorithm and real-world evidence of RDN effectiveness. One-way and probabilistic sensitivity analyses were conducted to assess the uncertainty surrounding the model inputs and sensitivity of the model results to changes in parameter inputs. Results were reported as incremental cost-effectiveness ratios (ICERs). RESULTS: A mean reduction in office SBP of 8.5 mmHg with uRDN resulted in an average improvement in both absolute life-years (LYs) and quality-adjusted life-years (QALYs) gained compared with standard of care alone (0.73 LYs and 0.67 QALYs). The overall base-case ICER with uRDN was estimated at £5600 (€6500) per QALY gained (95% confidence interval £5463-£5739 [€6341-€6661]); modelling demonstrated > 99% probability that the ICER is below the £20,000-£30,000 (€23,214-€34,821) per QALYs gained willingness-to-pay threshold in the UK. Results were consistent across sensitivity analyses and validation checks. CONCLUSIONS: Endovascular ultrasound RDN with the Paradise system offers patients with rHTN, clinicians, and healthcare systems a cost-effective treatment option alongside antihypertensive medication.

Behaviour change techniques and intervention characteristics in digital cardiac rehabilitation: a systematic review and meta-analysis of randomised controlled trials.

Evidence suggests that digitally delivered cardiac rehabilitation (CR) is likely to be an effective alternative to centre-based CR. However, there is limited understanding of the behaviour change techniques (BCTs) and intervention characteristics included in digital CR programmes. This systematic review aimed to identify the BCTs and intervention characteristics that have been used in digital CR programmes, and to study those associated with effective programmes. Twenty-five randomised controlled trials were included in the review. Digital CR was associated with significant improvements in daily steps, light physical activity, medication adherence, functional capacity, and low-density lipoprotein-cholesterol when compared to usual care, and produced effects on these outcomes comparable to centre-based CR. The evidence for improved quality of life was mixed. Interventions that were effective at improving behavioural outcomes frequently employed BCTs relating to feedback and monitoring, goals and planning, natural consequences, and social support. Completeness of reporting on the TIDieR checklist across studies ranged from 42% to 92%, with intervention material descriptions being the most poorly reported item. Digital CR appears effective at improving outcomes for patients with cardiovascular disease. The integration of certain BCTs and intervention characteristics may lead to more effective interventions, however better intervention reporting is required.

Mapping interventional components and behavior change techniques used to promote self-management in people with multimorbidity: a scoping review.

Ageing populations and improved survival, have contributed to a rise in the number of people living with multimorbidity, raising issues related to polypharmacy, treatment burden, competing priorities and poor coordination of care. Self-management programs are increasingly included as an essential component of interventions to improve outcomes in this population. However, an overview of how interventions supporting self-management in patients with multimorbidity is missing. This scoping review focused on mapping the literature on patient-centered interventions for people living with multimorbidity. We searched several databases, clinical registries, and grey literature for RCTs published between 1990-2019 describing interventions that supported self-management in people with multimorbidity. We included 72 studies that were found to be very heterogeneous when it comes to the population, delivery modes and modalities, intervention elements and facilitators. The results pointed to an extensive use of cognitive behavioral therapy as a basis for interventions, as well as behavior change theories and disease management frameworks. The most coded behavior change techniques stemmed from the categories Social Support, Feedback and monitoring and Goals and Planning. To allow for implementation of effective interventions in clinical practice, improved reporting of intervention mechanisms in RCTs is warranted.

Caregiver presence in a home-based cardiac rehabilitation programme improves the health-related quality of life of patients with heart failure.

Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) is a home-based cardiac rehabilitation intervention designed for patients with heart failure and their caregivers. We present a pooled analysis of patients >18 years with a confirmed diagnosis of HF recruited to two REACH-HF randomized controlled trials. Where identified by patients and consented to participate, caregivers were randomly assigned with patients to receive the REACH-HF intervention plus usual care or usual care alone. Our analysis demonstrated that compared to control group, the REACH-HF group had a greater gain in their disease-specific health-related quality of life at follow-up.

Surrogate endpoints: a key concept in clinical epidemiology.

Surrogate endpoints are biomarkers or intermediate outcomes that are used as substitutes for clinical outcomes of interest, often to expedite research or decision-making. In contrast, patient-important (or patient-centered) outcomes are health outcomes that are of direct relevance and importance to patients themselves; clinical trials may have measured the impact of the intervention on other endpoints related to, but different from, those of primary importance to patients. This article aims to elaborate on the use and understanding of surrogate endpoints. There should be a well-understood and scientifically grounded relationship between the surrogate (replacement) and the patient-important (target) endpoint it is intended to represent. It should be biologically plausible that changes in the surrogate will consistently and predictably reflect changes in the patient-important endpoint. The surrogate endpoint should show a threshold effect, meaning that a specific change (or state) in the surrogate with an intervention (relative to the comparator) is associated with a predictable (change in the) patient-important outcome. This helps establish a meaningful cutoff or target for the treatment effect on the surrogate endpoint. While surrogate endpoints offer advantages in certain situations, it is important to remember that their use requires careful validation to ensure they reliably predict the true clinical outcome. The validity of "surrogate endpoints" should be supported by robust scientific evidence and rigorous evaluation before these can be considered and labeled as surrogate endpoints.

Home-based versus centre-based cardiac rehabilitation.

BACKGROUND: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based and technology-supported cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation, especially during the SARS-CoV-2 pandemic. This is an update of a review previously published in 2009, 2015, and 2017. OBJECTIVES: To compare the effect of home-based (which may include digital/telehealth interventions) and supervised centre-based cardiac rehabilitation on mortality and morbidity, exercise-capacity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease SEARCH METHODS: We updated searches from the previous Cochrane Review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) on 16 September 2022. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials that compared centre-based cardiac rehabilitation (e.g. hospital, sports/community centre) with home-based programmes (± digital/telehealth platforms) in adults with myocardial infarction, angina, heart failure, or who had undergone revascularisation. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references for inclusion based on predefined inclusion criteria. Disagreements were resolved through discussion or by involving a third review author. Two authors independently extracted outcome data and study characteristics and assessed risk of bias. Certainty of evidence was assessed using GRADE. MAIN RESULTS: We included three new trials in this update, bringing a total of 24 trials that have randomised a total of 3046 participants undergoing cardiac rehabilitation. A further nine studies were identified and are awaiting classification. Manual searching of trial registers until 16 September 2022 revealed a further 14 clinical trial registrations - these are ongoing. Participants had a history of acute myocardial infarction, revascularisation, or heart failure. Although there was little evidence of high risk of bias, a number of studies provided insufficient detail to enable assessment of potential risk of bias; in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported. No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in our primary outcomes up to 12 months of follow-up: total mortality (risk ratio [RR] = 1.19, 95% confidence interval [CI] 0.65 to 2.16; participants = 1647; studies = 12/comparisons = 14; low-certainty evidence) or exercise capacity (standardised mean difference (SMD) = -0.10, 95% CI -0.24 to 0.04; participants = 2343; studies = 24/comparisons = 28; low-certainty evidence). The majority of evidence (N=71 / 77 comparisons of either total or domain scores) showed no significant difference in health-related quality of life up to 24 months follow-up between home- and centre-based cardiac rehabilitation. Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate-certainty evidence). There was a similar level of trial completion (RR 1.03, 95% CI 0.99 to 1.08; participants = 2638; studies = 22/comparisons = 26; low-certainty evidence) between home-based and centre-based participants. The cost per patient of centre- and home-based programmes was similar. AUTHORS' CONCLUSIONS: This update supports previous conclusions that home- (± digital/telehealth platforms) and centre-based forms of cardiac rehabilitation formally supported by healthcare staff seem to be similarly effective in improving clinical and health-related quality of life outcomes in patients after myocardial infarction, or revascularisation, or with heart failure. This finding supports the continued expansion of healthcare professional supervised home-based cardiac rehabilitation programmes (± digital/telehealth platforms), especially important in the context of the ongoing global SARS-CoV-2 pandemic that has much limited patients in face-to-face access of hospital and community health services. Where settings are able to provide both supervised centre- and home-based programmes, consideration of the preference of the individual patient would seem appropriate. Although not included in the scope of this review, there is an increasing evidence base supporting the use of hybrid models that combine elements of both centre-based and home-based cardiac rehabilitation delivery. Further data are needed to determine: (1) whether the short-term effects of home/digital-telehealth and centre-based cardiac rehabilitation models of delivery can be confirmed in the longer term; (2) the relative clinical effectiveness and safety of home-based programmes for other heart patients, e.g. post-valve surgery and atrial fibrillation.

Exercise-based cardiac rehabilitation for adults with heart failure - 2023 Cochrane systematic review and meta-analysis.

AIMS: Despite strong evidence, access to exercise-based cardiac rehabilitation (ExCR) remains low across global healthcare systems. We provide a contemporary update of the Cochrane review randomized trial evidence for ExCR for adults with heart failure (HF) and compare different delivery modes: centre-based, home-based (including digital support), and both (hybrid). METHODS AND RESULTS: Databases, bibliographies of previous systematic reviews and included trials, and trials registers were searched with no language restrictions. Randomized controlled trials, recruiting adults with HF, assigned to either ExCR or a no-exercise control group, with follow-up of ≥6 months were included. Two review authors independently screened titles for inclusion, extracted trial and patient characteristics, outcome data, and assessed risk of bias. Outcomes of mortality, hospitalization, and health-related quality of life (HRQoL) were pooled across trials using meta-analysis at short-term (≤12 months) and long-term follow-up (>12 months) and stratified by delivery mode. Sixty trials (8728 participants) were included. In the short term, compared to control, ExCR did not impact all-cause mortality (relative risk [RR] 0.93; 95% confidence interval [CI] 0.71-1.21), reduced all-cause hospitalization (RR 0.69; 95% CI 0.56-0.86, number needed to treat: 13, 95% CI 9-22), and was associated with a clinically important improvement in HRQoL measured by the Minnesota Living with Heart Failure Questionnaire (MLWHF) overall score (mean difference: -7.39; 95% CI -10.30 to -4.47). Improvements in outcomes with ExCR was seen across centre, home (including digitally supported), and hybrid settings. A similar pattern of results was seen in the long term (mortality: RR 0.87, 95% CI 0.72-1.04; all-cause hospitalization: RR 0.84, 95% CI 0.70-1.01, MLWHF: -9.59, 95% CI -17.48 to -1.50). CONCLUSIONS: To improve global suboptimal levels of uptake for HF patients, global healthcare systems need to routinely recommend ExCR and offer a choice of mode of delivery, dependent on an individual patient's level of risk and complexity.

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Health care resource utilization and costs in patients with painful diabetic neuropathy treated with 10 kHz spinal cord stimulation therapy.

BACKGROUND: Diabetic peripheral neuropathy, a common comorbidity of diabetes, is a neurodegenerative disorder that targets sensory, autonomic, and motor nerves frequently associated with painful diabetic neuropathy (PDN). PDN carries an economic burden as the result of reduced work and productivity. A recent multicenter randomized controlled trial, SENZA-PDN (NCT03228420), assessed the impact of high-frequency (10 kHz) spinal cord stimulation (SCS) on pain relief. The effects of high-frequency SCS on health care resource utilization and medical costs are not known. OBJECTIVE: To evaluate the effect of high-frequency (10 kHz) SCS on health care resource utilization (HRU) and medical costs in patients with PDN using data from the SENZA-PDN trial. METHODS: Participants with PDN were randomly assigned 1:1 to receive either 10 kHz SCS plus conventional medical management (CMM) (SCS treatment group) or CMM alone (CMM treatment group). Patient outcomes and HRU up to the 6-month follow-up are reported here. Costs (2020 USD) for each service was estimated based on publicly available Medicare fee schedules, Medicare claims data, and literature. HRU metrics of inpatient and outpatient contacts and costs are reported as means and SDs. Univariate and bivariate analyses were used to compare SCS and CMM treatment groups at 6 months. RESULTS: At 6-month follow up, the SCS arm experienced approximately half the mean rate of hospitalizations per patient compared with the CMM treatment group (0.08 vs 0.15; P = 0.066). The CMM treatment group's total health care costs per patient were approximately 51% higher compared with the SCS treatment group (equivalent to mean annual cost per patient of $9,532 vs $6,300). CONCLUSIONS: Our analysis of the SENZA-PDN trial indicates that the addition of 10 kHz SCS therapy results in lower rates of hospitalization and consequently lower health care costs among patients with PDN compared with those receiving conventional management alone.

ECAP-controlled closed-loop versus open-loop SCS for the treatment of chronic pain: 36-month results of the EVOKE blinded randomized clinical trial.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group. CONCLUSION: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS. TRIAL REGISTRATION NUMBER: NCT02924129.

Long-term efficacy of high-frequency (10 kHz) spinal cord stimulation for the treatment of painful diabetic neuropathy: 24-Month results of a randomized controlled trial.

AIMS: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN). METHODS: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding. RESULTS: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection. CONCLUSIONS: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN. TRIAL REGISTRATION: ClincalTrials.gov Identifier, NCT03228420.

Durable multimodal and holistic response for physiologic closed-loop spinal cord stimulation supported by objective evidence from the EVOKE double-blind randomized controlled trial.

INTRODUCTION: Chronic pain patients may experience impairments in multiple health-related domains. The design and interpretation of clinical trials of chronic pain interventions, however, remains primarily focused on treatment effects on pain intensity. This study investigates a novel, multidimensional holistic treatment response to evoked compound action potential-controlled closed-loop versus open-loop spinal cord stimulation as well as the degree of neural activation that produced that treatment response. METHODS: Outcome data for pain intensity, physical function, health-related quality of life, sleep quality and emotional function were derived from individual patient level data from the EVOKE multicenter, participant, investigator, and outcome assessor-blinded, parallel-arm randomized controlled trial with 24 month follow-up. Evaluation of holistic treatment response considered whether the baseline score was worse than normative values and whether minimal clinical important differences were reached in each of the domains that were impaired at baseline. A cumulative responder score was calculated to reflect the total minimal clinical important differences accumulated across all domains. Objective neurophysiological data, including spinal cord activation were measured. RESULTS: Patients were randomized to closed-loop (n=67) or open-loop (n=67). A greater proportion of patients with closed-loop spinal cord stimulation (49.3% vs 26.9%) were holistic responders at 24-month follow-up, with at least one minimal clinical important difference in all impaired domains (absolute risk difference: 22.4%, 95% CI 6.4% to 38.4%, p=0.012). The cumulative responder score was significantly greater for closed-loop patients at all time points and resulted in the achievement of more than three additional minimal clinical important differences at 24-month follow-up (mean difference 3.4, 95% CI 1.3 to 5.5, p=0.002). Neural activation was three times more accurate in closed-loop spinal cord stimulation (p<0.001 at all time points). CONCLUSION: The results of this study suggest that closed-loop spinal cord stimulation can provide sustained clinically meaningful improvements in multiple domains and provide holistic improvement in the long-term for patients with chronic refractory pain. TRIAL REGISTRATION NUMBER: NCT02924129.

Global perspectives on heart disease rehabilitation and secondary prevention: a scientific statement from the Association of Cardiovascular Nursing and Allied Professions, European Association of Preventive Cardiology, and International Council of Cardiovascular Prevention and Rehabilitation.

Cardiovascular disease is a leading cause of death, morbidity, disability, and reduced health-related quality of life, as well as economic burden worldwide, with some 80% of disease burden occurring in the low- and middle-income country (LMIC) settings. With increasing numbers of people living longer with symptomatic disease, the effectiveness and accessibility of secondary preventative and rehabilitative health services have never been more important. Whilst LMICs experience the highest prevalence and mortality rates, the global approach to secondary prevention and cardiac rehabilitation, which mitigates this burden, has traditionally been driven from clinical guidelines emanating from high-income settings. This state-of-the art review provides a contemporary global perspective on cardiac rehabilitation and secondary prevention, contrasting the challenges of and opportunities for high vs. lower income settings. Actionable solutions to overcome system, clinician, programme, and patient level barriers to cardiac rehabilitation access in LMICs are provided.