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Abstract Aims Patients with HFrEF and worsening HF events (WHFE) are at particularly high risk and urgently need disease‐modifying therapy. CHART‐HF assessed treatment patterns and reasons for medication decisions among HFrEF patients with and without WHFE. Methods and results CHART‐HF collected retrospective electronic medical records of outpatients with HF and EF

Abstract Background Functional health status is increasingly being recognized as a viable endpoint in heart failure (HF) trials. We sought to assess its prognostic impact and relationship with traditional clinical outcomes in patients with HF. Methods MEDLINE and Cochrane central were searched up to January 2021 for post hoc analyses of trials or observational studies that assessed independent association between baseline health/functional status, and mortality and hospitalization in patients with HF across the range of left ventricular ejection fractions to evaluate the prognostic ability of NYHA class [II, III, IV], KCCQ, MLHFQ, and 6MWD. Hazard ratios (HR) with 95% confidence intervals were pooled. Results Twenty-two studies were included. Relative to NYHA I, NYHA class II (HR 1.54 [1.16–2.04]; p 45) was significantly associated with increased mortality (HR 1.30 [1.14–1.47]; p

Heart failure (HF) is a leading cause of hospitalization in older adults. Patients are at high risk of readmission and death following hospitalization for HF. There is no standard approach of health care delivery during the hospital-to-home transition period, leaving missed opportunities in care optimization. In this review, we discuss contemporary randomized clinical trials that tested decongestion strategies, disease-modifying therapies, and health care services that inform the care of patients with worsening HF. We provide evidence-informed recommendations for optimizing therapies and improving outcomes during and following hospitalization for HF. These include adequate decongestion with loop diuretics and select sequential nephron blockade strategies based on early evaluation of diuretic response; initiation of disease-modifying pharmacotherapies prior to hospital discharge with close follow-up and optimization after discharge; cardiac rehabilitation; and transitional or palliative care referral post-hospitalization. Evidence-based implementation strategies to facilitate broad uptake include digital health tools and algorithm-driven optimization of pharmacotherapies.

Abstract Aims Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline‐directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real‐world TITRATE‐HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long‐term outcomes in patients with de novo, chronic, and worsening HF. Methods and results A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow‐up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF‐related hospitalizations, HF‐related urgent visits with a need for intravenous diuretics, all‐cause mortality, and cardiovascular mortality. Conclusions TITRATE‐HF is a real‐world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.

Background: Based on available data from randomized clinical trials, patients with heart failure with reduced ejection fraction (HFrEF) and worsening HF events (WHFE) have substantial disease burden and poor outcomes. WHFE clinical outcome data in non-clinical trial patients, more representative of the US clinical practice, has not been demonstrated. Methods and results: CHART-HF collected data from two complementary, non-clinical trial cohort with HFrEF (LVEF

Background There are limited data on substance use (SU) and cardiovascular disease (CVD)–related mortality trends in the United States. We aimed to evaluate SU+CVD–related deaths in the United States using the Centers for Disease Control and Prevention Wide‐Ranging, Online Data for Epidemiologic Research database. Methods and Results The Multiple Cause‐of‐Death Public Use record death certificates were used to identify deaths related to both SU and CVD. Crude, age‐adjusted mortality rates, annual percent change, and average annual percent changes with a 95% CI were analyzed. Between 1999 and 2019, there were 636 572 SU+CVD‐related deaths (75.6% men, 70.6% non‐Hispanic White individuals, 65% related to alcohol). Age‐adjusted mortality rates per 100 000 population were pronounced in men (22.5 [95% CI, 22.6–22.6]), American Indian or Alaska Native individuals (37.7 [95% CI, 37.0–38.4]), nonmetropolitan/rural areas (15.2 [95% CI, 15.1–15.3]), and alcohol‐related death (9.09 [95% CI, 9.07 to 9.12]). The overall SU+CVD‐related age‐adjusted mortality rates increased from 9.9 (95% CI, 9.8–10.1) in 1999 to 21.4 (95% CI, 21.2–21.6) in 2019 with an average annual percent change of 4.0 (95% CI, 3.7–4.3). Increases in SU+CVD‐related average annual percent change were noted across all subgroups and were pronounced among women (4.8% [95% CI, 4.5–5.1]), American Indian or Alaska Native individuals, younger individuals, nonmetropolitan areas, and cannabis and psychostimulant users. Conclusions There was a prominent increase in SU+CVD‐related mortality in the United States between 1999 and 2019. Women, non‐Hispanic American Indian or Alaska Native individuals, younger individuals, nonmetropolitan area residents, and users of cannabis and psychostimulants had pronounced increases in SU+CVD mortality.

Abstract Aims We investigated titration patterns of angiotensin‐converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) and beta‐blockers, quality of life (QoL) over 6 months, and associated 1 year outcome [all‐cause mortality/heart failure (HF) hospitalization] in a real‐world population with HF with reduced ejection fraction (HFrEF). Methods and results Participants with HFrEF (left ventricular ejection fraction 80% of patients, mineralocorticoid receptor antagonist in about half of patients, and statins in >90% of patients. At baseline, only 11% and 9% received 100% GRD for each drug class, respectively, with about half (47%) achieving ≥50% GRD for ACEis/ARBs or beta‐blockers. At 6 months, a large majority remained in the ‘stay low’ category, one third remained in ‘stay high’, whereas 10–16% up‐titrated and 4–6% down‐titrated. Patients with lower (vs. higher) N‐terminal pro‐beta‐type natriuretic peptide levels were more likely to be up‐titrated or be in ‘stay high’ for ACEis/ARBs and beta‐blockers (P = 0.002). Ischaemic aetiology, prior HF hospitalization, and enrolment in Singapore (vs. New Zealand) were independently associated with higher odds of ‘staying low’ (all P

Abstract Aims Heart failure (HF) remains a major public health problem with increasing prevalence in China. This study evaluated the clinical performance and quality measures for HF management to identify gaps in the standardization of care for patients hospitalized for HF in China. Methods and results Following the results of China‐HF stage I (2012–2015), the second stage of the China‐HF was launched in 2017. Among 113 hospitals with ≥100 cases, the China‐HF Stage II assessed the quality of care measures for HF and compared results with previous data in China and the US‐based Get with The Guidelines‐Heart Failure (GWTG‐HF) registries. In total, 34 938 patients hospitalized with HF were enrolled from January 2017 to October 2020. Echocardiographic left ventricular function and natriuretic peptide test were performed in 93.7% and 93.0% of the cases, respectively. Adherence to standardized guidelines in China‐HF stage II was higher than that in the China‐HF stage I, but generally lower than GWTG‐HF registry with 78.2% of eligible patients was prescribed oral diuretics, 78.7% renin‐angiotensin‐system inhibitors, and 82.2% beta‐blockers. Implantable cardioverter‐defibrillators and cardiac resynchronization devices were implanted in 3.9% and 14.6%, respectively. In contrast, the proportion of eligible patients discharged with spironolactone (87.8%) was higher than GWTG‐HF. The median length of hospitalization was 9 (6, 12) days, and 938 (2.8%) patients died or withdrew from treatment during hospitalization. Conclusions Despite significant improvements in the use of guideline‐recommended testing and therapy, there remain major gaps in quality of care for patients hospitalized for HF in China that are generally larger than gaps observed in the United States.

Background Many patients with heart failure (HF) have severely reduced ejection fraction but do not meet threshold for consideration of advanced therapies (ie, stage D HF). The clinical profile and health care costs associated with these patients in US practice is not well described. Methods and Results We examined patients hospitalized for worsening chronic heart failure with reduced ejection fraction ≤40% from 2014 to 2019 in the GWTG‐HF (Get With The Guidelines‐Heart Failure) registry, who did not receive advanced HF therapies or have end‐stage kidney disease. Patients with severely reduced EF defined as EF ≤30% were compared with those with EF 31% to 40% in terms of clinical profile and guideline‐directed medical therapy. Among Medicare beneficiaries, postdischarge outcomes and health care expenditure were compared. Among 113 348 patients with EF ≤40%, 69% (78 589) had an EF ≤30%. Patients with severely reduced EF ≤30% tended to be younger and were more likely to be Black. Patients with EF ≤30% also tended to have fewer comorbidities and were more likely to be prescribed guideline‐directed medical therapy (“triple therapy” 28.3% versus 18.2%, P

Abstract Aims Hospitalization for heart failure (HF) constitutes a major healthcare and economic burden. Trends and characteristics of hospitalizations for HF for the recent years are not clear. We sought to determine the trends and characteristics of hospitalization for HF in the United States. Method and results A retrospective analysis of the National Inpatient Sample weighted data between 1 January 2004 and 31 December 2018, which included hospitalized adults ≥ 18 years with primary discharge diagnosis of HF using International Classification of Diseases‐9/10 administrative codes. Main outcomes were trends in hospitalizations for HF (per 1000 person) and inpatient mortality (%) between 2004 and 2018. Conclusions Hospitalizations for HF have been increasing across both sexes and age groups since 2013, whereas inpatient mortality has been decreasing over the study period. Blacks have the highest risk of hospitalization for HF, and Whites have the highest in‐hospital mortality. There are significant racial and geographic disparities related to hospitalizations for HF.

Abstract Aims Recent trials have evaluated sodium–glucose co‐transporter 2 inhibitors in patients with heart failure (HF). We sought to assess the robustness of findings from these trials using the fragility index (FI). Methods and results Fragility index is defined as the minimum number of patients that must be moved from the ‘non‐event’ to the ‘event’ group to turn a statistically significant result to non‐significant. In addition to FI, fragility quotient [(FQ); FI divided by the sample size] was calculated to assess the proportion of events that must be moved to change the significance. For statistically non‐significant outcomes, reverse fragility index (RFI) and reverse fragility quotient (RFQ) were calculated. Robustness of findings after pooling data from all three trials was also assessed. A robust reduction in first HF hospitalization or cardiovascular mortality was seen with dapagliflozin (FI = 62 and FQ = 0.013), empagliflozin (FI = 50 and FQ = 0.013), and sotagliflozin (FI = 60 and FQ = 0.049). Dapagliflozin nominally improved all‐cause and cardiovascular mortality, with modest FI (n = 8 and 5) and FQ (0.002 and 0.001). Empagliflozin and sotagliflozin did not demonstrate statistically significant reductions in all‐cause mortality, with modest RFI (empagliflozin: RFI = 26 and RFQ = 0.007; sotagliflozin: RFI = 6 and RFQ = 0.005). A similar trend was seen with cardiovascular mortality (empagliflozin: RFI = 24 and RFQ = 0.006; sotagliflozin: RFI = 7 and RFQ = 0.006). Upon meta‐analysis, the result for first HF hospitalization or cardiovascular mortality was robust (FI = 95 and FQ = 0.010). The reductions in all‐cause (FI = 12 and FQ = 0.001) and cardiovascular mortality (FI = 9 and FQ = 0.001), while statistically significant, were fragile. Conclusion Improvement in the composite outcome of first HF hospitalization or cardiovascular death was highly concordant and robust across sodium–glucose co‐transporter 2 inhibitor trials. In contrast, secondary endpoints of all‐cause and cardiovascular mortality were statistically fragile, underscoring the need to power trials for mortality to fully understand the benefit of therapies on fatal events.

Abstract Background There is uncertainty and limited data regarding initiation of sodium-glucose cotransporter 2 (SGLT2) inhibitors among patients hospitalized with acute heart failure (AHF). This systematic review and meta-analysis aim to establish the efficacy and safety of SGLT2 inhibitors initiated in patients hospitalized for AHF. Methods PubMed/Medline, Embase, and Cochrane library were searched using the following terms: (“sglt2" and "acute heart failure") and (“sglt2" and "worsening heart failure") from inception till November 15th, 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of initiating an SGLT2 inhibitor compared with placebo in patients with AHF. Major cardiovascular and diabetes scientific meetings in 2021 were also searched for relevant studies. Prespecified efficacy outcomes were all-cause mortality, rehospitalization for heart failure, and improvement in Kansas City Cardiomyopathy Questionnaire (KCCQ) scale score. Prespecified safety outcomes were acute kidney injury (AKI), hypotension, and hypoglycemia. Random effects odds ratio (OR) and mean difference with 95% confidence intervals (CIs) were calculated. Results Three RCTs with a total of 1831 patients were included. Initiation of SGLT2 inhibitors in patients with AHF reduced the risk of rehospitalization for heart failure (OR 0.52; 95% CI [0.42, 0.65]) and improved Kansas City Cardiomyopathy Questionnaire scores (mean difference 4.12; 95% CI [0.1.89, 6.53]). There was no statistically significant effect for initiation of SGLT2 inhibitors in patients with AHF on all-cause mortality (OR 0.70; 95% CI [0.46, 1.08]). Initiation of SGLT2 inhibitors in patients with AHF did not increase the acute kidney injury (OR 0.76; 95% CI [0.50, 1.16]), hypotension (OR 1.17; 95% CI [0.80, 1.71]), or hypoglycemia (OR 1.51; 95% CI [0.86, 2.65]). Conclusion Initiation of SGLT2 inhibitors in patients hospitalized for AHF during hospitalization or early post-discharge (within 3 days) reduces the risk of rehospitalization for heart failure and improves patient-reported outcomes with no excess risk of adverse effects.

Abstract Aims This study aimed to investigate the reporting of subgroup analyses in heart failure (HF) randomized controlled trials (RCTs) and to determine the strength and credibility of subgroup claims. Methods and results All primary HF RCTs published in nine high‐impact journals from 1 January 2008 to 31 December 2017 were included. Multivariable regression analysis was used to identify factors that may favour the reporting of results in specific subgroups. Strength of the subgroup effect claimed was classified into (i) strong, (ii) likely, or (iii) suggestive. Credibility of subgroup claim was scored using a pre‐specified 10 pointer criteria. Of the 261 HF RCTs studied, 107 (41%) reported subgroup analyses. Twenty‐five (23%) RCTs claimed a subgroup effect for the primary outcome of which six (24%) made a strong claim, eight (32%) claimed a likely effect, and 11 (44%) suggested a possible subgroup effect. Seven of the 25 RCTs did not employ interaction testing for subgroup claims of the primary outcome. Three out of 10 pre‐specified credibility criteria were satisfied by half of the trials. Fourteen trials justified the choice of subgroups, and 10 explicitly stated they were underpowered to detect differences within subgroups. Source of funding did not influence the frequency of reporting subgroup analyses (OR 0.53, 95% CI 0.78–3.62, P = 0.52). Conclusions Appropriate credibility criteria were rarely met even by HF RCTs that held strong subgroup claims. Subgroup analyses should be pre‐specified, be adequately powered, present interaction terms, and be replicated in independent data before being integrated into clinical decision making.

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. Methods and results This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS‐HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter‐quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P

Abstract Aims Discontinuation or non‐publication of trials may hinder scientific progress and violates the commitment made to research participants. We sought to identify the prevalence of discontinuation and non‐publication of heart failure (HF) clinical trials. Methods and results We conducted a cross‐sectional search of ClinicalTrials.gov to identify all completed and discontinued HF clinical trials. We limited our search to only include trials that were completed by 31 December 2017. Trials were investigated to identify reasons for discontinuation. Informative termination was defined as trial termination due to safety or efficacy concerns. Data pertaining to the trial phase, funding, intervention, enrolment, and trial completion date were extracted for each trial. A total of 572 trials were included. Of these, 21% (n = 118) were discontinued before completion. Patient accrual was the most frequently cited reason (n = 42; 36%) for trial discontinuation, followed by informative termination (n = 16; 14%) and funding (n = 14; 12%). Overall, 24 780 patients were enrolled in trials that were terminated. Of trials that were completed and not terminated, nearly one‐third (n = 131/454; 29%) were not published. Seventy‐nine (24%) trials were published within 12 months, 192 (59%) within 24 months, and 252 (78%) trials within 36 months. Conclusions Discontinuation and non‐publication of HF trials is common. This raises ethical concerns towards participants who volunteer for research and are exposed to potential risks, inconvenience, and discomfort without furthering scientific progress.

Background Clinical prediction models have been developed for hospitalization for heart failure in type 2 diabetes. However, a systematic evaluation of these models’ performance, applicability, and clinical impact is absent. Methods and Results We searched Embase, MEDLINE, Web of Science, Google Scholar, and Tufts’ clinical prediction registry through February 2021. Studies needed to report the development, validation, clinical impact, or update of a prediction model for hospitalization for heart failure in type 2 diabetes with measures of model performance and sufficient information for clinical use. Model assessment was done with the Prediction Model Risk of Bias Assessment Tool, and meta‐analyses of model discrimination were performed. We included 15 model development and 3 external validation studies with data from 999 167 people with type 2 diabetes. Of the 15 models, 6 had undergone external validation and only 1 had low concern for risk of bias and applicability (Risk Equations for Complications of Type 2 Diabetes). Seven models were presented in a clinically useful manner (eg, risk score, online calculator) and 2 models were classified as the most suitable for clinical use based on study design, external validity, and point‐of‐care usability. These were Risk Equations for Complications of Type 2 Diabetes (meta‐analyzed c‐statistic, 0.76) and the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (meta‐analyzed c‐statistic, 0.78), which was the simplest model with only 5 variables. No studies reported clinical impact. Conclusions Most prediction models for hospitalization for heart failure in patients with type 2 diabetes have potential concerns with risk of bias or applicability, and uncertain external validity and clinical impact. Future research is needed to address these knowledge gaps.

Abstract Aims We sought to conduct a meta‐analysis regarding the safety and efficacy of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors in patients with heart failure (HF). Methods and results MEDLINE, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov were searched from their inception to November 2020 for placebo‐controlled randomized controlled trials of SGLT2 inhibitors. Randomized controlled trials were selected if they reported at least one of the prespecified outcomes in patients with HF. Hazard ratios (HRs) or risk ratios and their corresponding 95% confidence intervals were pooled using a random‐effects model. A total of seven trials including 16 820 HF patients (N = 8884 in the SGLT2 inhibitor arms; N = 7936 in the placebo arms) were included. In the overall HF cohort, SGLT2 inhibitors compared with placebo significantly reduced the risk of the composite endpoint of first HF hospitalization or cardiovascular death [HR: 0.77 (0.72–0.83); P

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real‐world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines–Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker. Over 12‐month follow‐up, compared with a discharge prescription of angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all‐cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72–0.94; P=0.004) but not all‐cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89–1.07; P=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91–1.18; P=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all‐cause mortality (adjusted HR, 0.69; 95% CI, 0.60–0.79; P

Background Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS‐HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24‐hour ultrafiltration‐based fluid removal above versus below the median. Patients were stratified by EF (≤40% or >40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (≤24 hours) response to ultrafiltration. Cox‐proportional hazards models were used to identify associations between fluid removal 40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy.

Background In 1993, the US Food and Drug Administration established guidelines to increase diversity by sex and race/ethnicity of participants in clinical trials supporting novel drug approvals. In this study we investigated the 10‐year trends of participation of women and minorities in pivotal trials supporting approval of new molecular entities in cardiometabolic drugs from January 2008 to December 2017. Methods and Results A list of new molecular entities was abstracted from publicly available data at Drugs@Fda. Sex and race/ethnicity data were collected from trial publications. Linear regression analysis was performed to assess the relation between drug approval year and proportion of women and minorities enrolled. Thirty‐five novel cardiovascular (n=24) and diabetes mellitus (n=11) drugs were approved by the US Food and Drug Administration during the study period. The median number of participants supporting each drug was 5930 (interquartile range, 3175–10 942). Women represented 36% (n=108 052) of trial participants (n=296 163). Women were underrepresented compared with their proportion of the disease population in trials of coronary heart disease (participation‐to‐prevalence ratio, 0.52), heart failure (participation‐to‐prevalence ratio, 0.58), and acute coronary syndrome (participation‐to‐prevalence ratio, 0.68). Among trial participants, 81% were white, 4% black, 12% Asian, and 11% Hispanic/Latino. There was no significant association between enrollment of women (P=0.29) or underrepresented minorities (P=0.45) with the drug approval year. Conclusions Over the past decade (2008–2017), women and minorities, particularly blacks, have continued to be inadequately represented in pivotal cardiometabolic clinical trials that support US Food and Drug Administration approval of new molecular entities. This may have major implications in determining efficacy of such therapies in these groups, and may impair generalizability of trial results to routine clinical practice.