Evaluation of the causes of sex disparity in heart failure trials.

OBJECTIVES: Cardiovascular disease is one of the leading causes of mortality and morbidity in women. Despite this, even in contemporary research, female patients are poorly represented in trials. This study aimed to explore reasons behind the sex disparity in heart failure (HF) trials. METHODS: HF trials published in seven high-impact clinical journals (impact factor >20), between 2000 and 2020, were identified. Trials with over 300 participants of both sexes were included. Large HF registries, as well as population statistics, were also identified using the same criteria. RESULTS: We identified 146 HF trials, which included 248 620 patients in total. The median proportion of female patients was 25.8%, with the lowest proportions seen in trials enrolling patients with ischaemic cardiomyopathy (17.9%), severe systolic dysfunction (left ventricular ejection fraction (LVEF) <35%) (21.4%) and those involving an invasive procedure (21.1%). The highest proportion of women was seen in trials assessing HF with preserved LVEF (51.6%), as well as trials including older participants (40.5%). Significant differences were seen between prevalence of female trial participants and population prevalence in all LVEF categories (25.8% vs 49.0%, p<0.01). CONCLUSIONS: A significant sex disparity was identified in HF trials, most visible in trials assessing patients with severely reduced LVEF and ischaemic aetiology. This is likely due to a complex interplay between enrolment bias and biological variation. Furthermore, the degree of both these aspects may vary according to trial type. Going forward, we should encourage all HF trials to appraise their recruitment log and suggest reasons for any reported sex disparity.

International Consortium for Health Outcomes Measurement (ICHOM): Standardized Patient-Centered Outcomes Measurement Set for Heart Failure Patients.

Whereas multiple national, international, and trial registries for heart failure have been created, international standards for clinical assessment and outcome measurement do not currently exist. The working group's objective was to facilitate international comparison in heart failure care, using standardized parameters and meaningful patient-centered outcomes for research and quality of care assessments. The International Consortium for Health Outcomes Measurement recruited an international working group of clinical heart failure experts, researchers, and patient representatives to define a standard set of outcomes and risk-adjustment variables. This was designed to document, compare, and ultimately improve patient care outcomes in the heart failure population, with a focus on global feasibility and relevance. The working group employed a Delphi process, patient focus groups, online patient surveys, and multiple systematic publications searches. The process occurred over 10 months, employing 7 international teleconferences. A 17-item set has been established, addressing selected functional, psychosocial, burden of care, and survival outcome domains. These measures were designed to include all patients with heart failure, whether entered at first presentation or subsequent decompensation, excluding cardiogenic shock. Sources include clinician report, administrative data, and validated patient-reported outcome measurement tools: the Kansas City Cardiomyopathy Questionnaire; the Patient Health Questionnaire-2; and the Patient-Reported Outcomes Measurement Information System. Recommended data included those to support risk adjustment and benchmarking across providers and regions. The International Consortium for Health Outcomes Measurement developed a dataset designed to capture, compare, and improve care for heart failure, with feasibility and relevance for patients and clinicians worldwide.

Does rhythm matter in acute heart failure? An insight from the British Society for Heart Failure National Audit.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with acute heart failure (AHF). The presence of AF is associated with adverse prognosis in patients with chronic heart failure (CHF) but little is known about its impact in AHF. METHODS: Data were collected between April 2007 and March 2013 across 185 (> 95%) hospitals in England and Wales from patients with a primary death or a discharge diagnosis of AHF. We investigated the association between the presence of AF and all-cause mortality during the index hospital admission, at 30 days and 1 year post-discharge. RESULTS: Of 96,593 patients admitted with AHF, 44,642 (46%) were in sinus rhythm (SR) and 51,951 (54%) in AF. Patients with AF were older (mean age 79.8 (79.7-80) versus 74.7 (74.5-74.7) years; p < 0.001), than those in SR. In a multivariable analysis, AF was independently associated with mortality at all time points, in hospital (HR 1.15, 95% CI 1.09-1.21, p < 0.0001), 30 days (HR 1.13, 95% CI 1.08-1.19, p < 0.0001), and 1 year (HR 1.09, 95% CI 1.05-1.12, p < 0.0001). In subgroup analyses, AF was independently associated with worse 30-day outcome irrespective of sex, ventricular phenotype and in all age groups except in those aged between 55 and 74 years. CONCLUSION: AF is independently associated with adverse prognosis in AHF during admission and up to 1 year post-discharge. As the clinical burden of concomitant AF and AHF increases, further refinement in the detection, treatment and prevention of AF-related complications may have a role in improving patient outcomes.

Characteristics and outcome of acute heart failure patients according to the severity of peripheral oedema.

BACKGROUND: Most trials of patients hospitalized for heart failure focus on breathlessness (alveolar pulmonary oedema) but worsening peripheral oedema is also an important presentation. We investigated the relationship between the severity of peripheral oedema on admission and outcome amongst patients with a primary discharge death or diagnosis of heart failure. OBJECTIVES: We tested the hypothesis that severity of peripheral oedema is associated with length of hospital stay and mortality. METHODS: Patient variables reported to the National Heart Failure Audit for England & Wales between April 2008 and March 2013 were included in this analysis. Peripheral oedema was classified as 'none', 'mild', 'moderate' or 'severe'. Length of stay, mortality during the index admission and for up to three years after discharge are reported. RESULTS: Of 121,214 patients, peripheral oedema on admission was absent in 24%, mild in 24%, moderate in 33% and severe in 18%. Median length of stay was, respectively, 6, 7, 9 and 12 days (P- < 0.001), index admission mortality was 7%, 8%, 10% and 16% (P- < 0.001) and mortality at a median follow-up of 344 (IQR 94-766) days was 39%, 46%, 52% and 59%. In an adjusted multi-variable Cox model, the hazard ratio for death was 1.51 for severe (P- < 0.001, CI 1.50-1.53), 1.21 for moderate (P- < 0.001, CI 1.20-1.22) and 1.04 (P- < 0.001, CI 1.02-1.05) for mild peripheral oedema compared to patients without peripheral oedema at presentation. CONCLUSION: Length of hospital stay and mortality during index admission and after discharge increased progressively with increasing severity of peripheral oedema at admission.

Mortality after admission for heart failure in the UK compared with Japan.

Objective: Mortality amongst patients hospitalised for heart failure (HHF) in Western and Asian countries may differ, but this has not been investigated using individual patient-level data (IPLD). We sought to remedy this through rigorous statistical analysis of HHF registries and variable selection from a systematic literature review. Methods and results: IPLD from registries of HHF in Japan (n=3781) and the UK (n=894) were obtained. A systematic literature review identified 23 models for predicting outcome of HHF. Five variables appearing in 10 or more reports were strongly related to prognosis (systolic blood pressure, serum sodium concentration, age, blood urea nitrogen and creatinine). To compare mortality in the UK and Japan, variables were imputed in a propensity model using inverse probability of treatment weighting (IPTW) and IPTW with logistic regression (doubly robust IPTW). Overall, patients in the UK were sicker and in-patient and post-discharge mortalities were greater, suggesting that the threshold for hospital admission was higher. Covariate-adjusted in-hospital mortality was similar in the UK and Japan (IPTW OR: 1.14, 95% CI 0.70 to 1.86), but 180-day postdischarge mortality was substantially higher in the UK (doubly robust IPTW OR: 2.33, 95% CI 1.58 to 3.43). Conclusions: Despite robust methods to adjust for differences in patient characteristics and disease severity, HHF patients in the UK have roughly twice the mortality at 180 days compared with those in Japan. Similar analyses should be done using other data sets and in other countries to determine the consistency of these findings and identify factors that might inform healthcare policy and improve outcomes.

Validation of U.S. mortality prediction models for hospitalized heart failure in the United Kingdom and Japan.

AIMS: Prognostic models for hospitalized heart failure (HHF) were developed predominantly for patients of European origin in the United States of America; it is unclear whether they perform similarly in other health care systems or for different ethnicities. We sought to validate published prediction models for HHF in the United Kingdom (UK) and Japan. METHODS AND RESULTS: Patients in the UK (n =894) and Japan (n =3158) were prospectively enrolled and were similar in terms of sex (∼60% men) and median age (∼77 years). Models predicted that British patients would have a higher mortality than Japanese, which was indeed true both for in-hospital (4.8% vs. 2.5%) and 180-day (20.7% vs. 9.5%) mortality. The model c-statistics for the published/derivation (range 0.70-0.76) and Japanese (range 0.75-0.77) cohorts were similar and higher than for the UK (0.62-0.75) but models consistently overestimated mortality in Japan. For in-hospital mortality, the OPTIMIZE-HF model performed best, providing similar discrimination in published/derivation, UK and Japanese cohorts [c-indices: 0.75 (0.74-0.77); 0.75 (0.68-0.81); and 0.77 (0.70-0.83), respectively], and least overestimated mortality in Japan. For 180-day mortality, the c-statistics for the ASCEND-HF model were similar in published/derivation (0.70) and UK [0.69 (0.64-0.74)] cohorts but higher in Japan [0.75 (0.71-0.79)]; calibration was good in the UK but again overestimated mortality in Japan. CONCLUSION: Calibration of published prediction models appears moderately accurate and unbiased when applied to British patients but consistently overestimates mortality in Japan. Identifying the reason why patients in Japan have a better than predicted prognosis is of great interest.

Cost-Effectiveness Analysis of Natriuretic Peptide Testing and Specialist Management in Patients with Suspected Acute Heart Failure.

OBJECTIVES: To determine the cost-effectiveness of natriuretic peptide (NP) testing and specialist outreach in patients with acute heart failure (AHF) residing off the cardiology ward. METHODS: We used a Markov model to estimate costs and quality-adjusted life-years (QALYs) for patients presenting to hospital with suspected AHF. We examined diagnostic workup with and without the NP test in suspected new cases, and we examined the impact of specialist heart failure outreach in all suspected cases. Inputs for the model were derived from systematic reviews, the UK national heart failure audit, randomized controlled trials, expert consensus from a National Institute for Health and Care Excellence guideline development group, and a national online survey. The main benefit from specialist care (cardiology ward and specialist outreach) was the increased likelihood of discharge on disease-modifying drugs for people with left ventricular systolic dysfunction, which improve mortality and reduce re-admissions due to worsened heart failure (associated with lower utility). Costs included diagnostic investigations, admissions, pharmacological therapy, and follow-up heart failure care. RESULTS: NP testing and specialist outreach are both higher cost, higher QALY, cost-effective strategies (incremental cost-effectiveness ratios of £11,656 and £2,883 per QALY gained, respectively). Combining NP and specialist outreach is the most cost-effective strategy. This result was robust to both univariate deterministic and probabilistic sensitivity analyses. CONCLUSIONS: NP testing for the diagnostic workup of new suspected AHF is cost-effective. The use of specialist heart failure outreach for inpatients with AHF residing off the cardiology ward is cost-effective. Both interventions will help improve outcomes for this high-risk group.

Variation in hospital performance for heart failure management in the National Heart Failure Audit for England and Wales.

OBJECTIVE: Investigation of variations in provider performance and its determinants may help inform strategies for improving patient outcomes. METHODS: We used the National Heart Failure Audit comprising 68 772 patients with heart failure with reduced left ventricular ejection fraction (HFREF), admitted to 185 hospitals in England and Wales (2007-2013). We investigated hospital adherence to three recommended key performance measures (KPMs) for inhospital care (ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) on discharge, ß-blockers on discharge and referral to specialist follow-up) individually and as a composite performance score. Hierarchical regression models were used to investigate hospital-level variation. RESULTS: Hospital-level variation in adherence to composite KPM ranged from 50% to 97% (median 79%), but after adjustments for patient characteristics and year of admission, only 8% (95% CI 7% to 10%) of this variation was attributable to variations in hospital features. Similarly, hospital prescription rates for ACE-I/ARB and ß-blocker showed low adjusted hospital-attributable variations (7% CI 6% to 9% and 6% CI 5% to 8%, for ACE-I/ARB and ß-blocker, respectively). Referral to specialist follow-up, however, showed larger variations (median 81%; range; 20%, 100%) with 26% of this being attributable to hospital-level differences (CI 22% to 31%). CONCLUSION: Only a small proportion of hospital variation in medication prescription after discharge was attributable to hospital-level features. This suggests that differences in hospital practices are not a major determinant of observed variations in prescription of investigated medications and outcomes. Future healthcare delivery efforts should consider evaluation and improvement of more ambitious KPMs.

Referral for Specialist Follow-up and Its Association With Post-discharge Mortality Among Patients With Systolic Heart Failure (from the National Heart Failure Audit for England and Wales).

For patients admitted with worsening heart failure (HF), early follow-up after discharge is recommended. Whether outcomes can be improved when follow-up is done by cardiologists is uncertain. We aimed to determine the association between cardiology follow-up and risk of death for patients with HF discharged from hospital. Using data from the National Heart Failure Audit (England and Wales), we investigated the effect of referral to cardiology follow-up on 30-day and 1-year mortality in 68,772 patients with HF and a reduced left ventricular ejection fraction discharged from 185 hospitals from 2007 to 2013. The primary analyses used instrumental variable analysis complemented by hierarchical logistic and propensity-matched models. At the hospital level, rates of referral to cardiologists varied from 6% to 96%. The median odds ratio (OR) for referral to cardiologist was 2.3 (95% confidence interval [CI] 2.1 to 2.5), suggesting that, on average, the odds of a patient being referred for cardiologist follow-up after discharge differed ∼2.3 times from one randomly selected hospital to another one. Based on the proportion of patients (per region) referred for cardiology follow-up, referral for cardiology follow-up was associated with lower 30-day (OR 0.70; 95% CI 0.55 to 0.89) and 1-year mortality (OR 0.81; 95% CI 0.68 to 0.95) compared with no plans for cardiology follow-up (i.e., standard follow-up done by family doctors). Results from hierarchical logistic models and propensity-matched models were consistent (30-day mortality OR 0.66; 95% CI 0.61 to 0.72 and 0.66; 95% CI 0.58 to 0.76 for hierarchical and propensity matched models, respectively). For patients with HF and a reduced left ventricular ejection fraction admitted to hospital with worsening symptoms, referral to cardiology services for follow-up after discharge is strongly associated with reduced mortality, both early and late.

Quantifying the added value of BNP in suspected heart failure in general practice: an individual patient data meta-analysis.

BACKGROUND: Diagnosing early stages of heart failure with mild symptoms is difficult. B-type natriuretic peptide (BNP) has promising biochemical test characteristics, but its diagnostic yield on top of readily available diagnostic knowledge has not been sufficiently quantified in early stages of heart failure. OBJECTIVES: To quantify the added diagnostic value of BNP for the diagnosis of heart failure in a population relevant to GPs and validate the findings in an independent primary care patient population. DESIGN: Individual patient data meta-analysis followed by external validation. The additional diagnostic yield of BNP above standard clinical information was compared with ECG and chest x-ray results. PATIENTS AND METHODS: Derivation was performed on two existing datasets from Hillingdon (n=127) and Rotterdam (n=149) while the UK Natriuretic Peptide Study (n=306) served as validation dataset. Included were patients with suspected heart failure referred to a rapid-access diagnostic outpatient clinic. Case definition was according to the ESC guideline. Logistic regression was used to assess discrimination (with the c-statistic) and calibration. RESULTS: Of the 276 patients in the derivation set, 30.8% had heart failure. The clinical model (encompassing age, gender, known coronary artery disease, diabetes, orthopnoea, elevated jugular venous pressure, crackles, pitting oedema and S3 gallop) had a c-statistic of 0.79. Adding, respectively, chest x-ray results, ECG results or BNP to the clinical model increased the c-statistic to 0.84, 0.85 and 0.92. Neither ECG nor chest x-ray added significantly to the 'clinical plus BNP' model. All models had adequate calibration. The 'clinical plus BNP' diagnostic model performed well in an independent cohort with comparable inclusion criteria (c-statistic=0.91 and adequate calibration). Using separate cut-off values for 'ruling in' (typically implying referral for echocardiography) and for 'ruling out' heart failure--creating a grey zone--resulted in insufficient proportions of patients with a correct diagnosis. CONCLUSION: BNP has considerable diagnostic value in addition to signs and symptoms in patients suspected of heart failure in primary care. However, using BNP alone with the currently recommended cut-off levels is not sufficient to make a reliable diagnosis of heart failure.

Mode of death in patients with newly diagnosed heart failure in the general population.

BACKGROUND: Early prognosis for incident (new) heart failure (HF) patients in the general population is poor. Clinical trials suggest approximately half of chronic HF patients die suddenly but mode of death for incident HF cases in the general population has not been evaluated. AIMS: To describe mode of death in the first six months after a new diagnosis in the general population. METHODS: Two-centre UK population-based study. RESULTS: 396 incident HF patients were prospectively identified. Overall mortality rates were 6% [3-8%], 11% [8-14%] and 14% [11-18%] at 1, 3 and 6months respectively. There were 59 deaths over a median follow-up of 10months; 86% (n = 51) were cardiovascular (CV) deaths. Overall, the mode of death was progressive HF in 52% (n = 31), sudden death (SD) in 22% (n = 13), other CV death in 12% (n = 7), and non-CV death in 14% (n = 8). On multivariable analysis, progressive HF deaths were associated with older age, lower serum sodium, systolic hypotension, prolonged QRS duration at baseline and absence of ACE inhibitor therapy at the time of discharge or death. CONCLUSION: Early prognosis after a new diagnosis of HF in the general population is poor and progressive HF, rather than sudden death, accounts for the majority of deaths.

The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study.

OBJECTIVES: To determine the diagnostic accuracy of the measurement of plasma B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NTproBNP) in patients referred by their general practitioners (GPs) with symptoms suggestive of heart failure. Additionally, to compare the diagnostic accuracy of the resting 12-lead electrocardiogram (ECG) with that of the peptides. DESIGN: A diagnostic accuracy study. SETTING: Rapid-access heart failure clinics in five hospitals. PARTICIPANTS: 306 patients referred by their GPs with suspected heart failure. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values (PPV and NPV) and positive and negative likelihood ratios for BNP, NTproBNP and the ECG for the diagnosis of heart failure. Area under the receiver operating characteristics (ROC) curves for the two natriuretic peptides. RESULTS: The diagnosis of heart failure was confirmed in 104 (34%) patients. The area under the ROC curve was 0.84 [95% CI 0.79-0.89] for BNP and 0.85 [0.81-0.90] for NTproBNP. At the manufacturers' recommended decision cut-points, NTproBNP provided a higher NPV (0.97) than BNP (0.87), but at lower PPV (0.44 versus 0.59). An abnormal ECG did not add any further predictive value to that of NTproBNP. CONCLUSIONS: We have confirmed the value of the measurement of plasma BNP or NTproBNP as a 'rule-out' test for heart failure in patients currently referred by GPs to rapid access diagnostic clinics. A simple classification of the 12-lead ECG into 'normal' or 'abnormal' adds little value to ruling out heart failure in these circumstances. Further work is necessary to establish the best decision cut-points for use in clinical practice.

Special problems with antiarrhythmic drugs in the elderly: safety, tolerability, and efficacy.

With advancing age, atrial fibrillation is increasingly likely to indicate underlying cardiovascular disease and risk. An understanding of this is particularly important in the elderly patient, where likely triggers to atrial fibrillation and the influence of other pathologies on the safety and efficacy of proposed treatments will all contribute to optimal care of these patients. It is not yet clear whether rate control or cardioversion to sinus rhythm is the best strategy for the generality of patients with atrial fibrillation, and still less so for individuals. Age and comorbidity add complexities to this decision, which should inform the choice of drugs to be used. Further uncertainties arise from a literature that has often excluded elderly patients and derived its conclusions about mode of drug action from studies undertaken during sinus rhythm rather than atrial fibrillation. Despite these difficulties the careful evaluation of elderly patients with atrial fibrillation and their involvement in relevant choices should ensure optimum treatment for the individual.