Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.

AIMS: We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid-range ejection fraction [HFmrEF; ejection fraction (EF) 40-49%]. METHODS AND RESULTS: In 7598 patients enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow-up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient-years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient-years in HFrEF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75-0.91; P < 0.001], 7.4 vs. 9.7 per 100 patient-years in HFmrEF (HR 0.76, 95% CI 0.61-0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient-years in HFpEF (HR 0.95, 95% CI 0.79-1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58-0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33-0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59-1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%. CONCLUSION: Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712

Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland

Aims: To evaluate whether the survival rates of patients with heart failure (HF) in the community are better than those with a diagnosis of the 4 most common cancers in men and women in a contemporary primary care cohort in Scotland. Methods and Results: The data were obtained from the Primary Care Clinical Informatics Unit from a database of 1.75 million people registered with 393 general practices in Scotland. Sex-specific survival modeling was undertaken using Cox proportional hazards models, adjusted for potential confounders. A total of 56,658 patients were eligible to be included in the study with 147,938 person years follow up (median follow up 2.04 years). In men, heart failure (reference group; 5yrs survival 37.7%) had worse mortality outcomes than patients with prostate cancer (HR 0.61, 95%CI 0.57-0.65; 5yrs survival 49.0%), and bladder cancer (HR 0.88, 95%CI 0.81-0.96; 5yrs survival 36.5%), but better than lung cancer (HR 3.86, 95%CI 3.65-4.07; 5yrs survival 2.8%) and colorectal cancer (HR 1.23 95%CI 1.16-1.31; 5 yrs survival 25.9%). In women, patients with HF (reference group; 5yrs survival 31.9%) had worse mortality outcomes than patients with breast cancer (HR 0.55 95%CI 0.51-0.59; 5yrs survival 61.0%), but better outcomes than lung cancer (HR 3.82, 95%CI 3.60-4.05; 5yrs survival 3.6%), ovarian cancer (HR 1.98, 95%CI 1.80-2.17; 5yrs survival 19%) and colorectal cancer (HR 1.21, 95%CI 1.13-1.29; 5yrs survival 28.4%). Conclusions: Despite advances in management, heart failure remains as ‘malignant’ as some of the common cancers in both men and women

N-terminal pro-B-type natriuretic peptide and prognosis in Caucasian vs. Asian patients with heart failure

Aims N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the most frequently used biomarker in heart failure (HF), but its prognostic utility across ethnicities is unclear. Methods and results This study included 546 Caucasians with HF from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure and 578 Asians with HF from the Singapore Heart Failure Outcomes and Phenotypes study. NT-proBNP was measured at discharge after HF hospitalization. The studied outcome was a composite of all-cause mortality and HF hospitalization at 18 months. Compared with Caucasian patients, Asian patients were younger (63 +/- 12 vs. 71 +/- 11 years); less often female (26% vs. 39%); and had lower body mass index (26 vs. 27 kg/m(2)), better renal function (61 +/- 37 vs. 54 +/- 20 mL/min/1.73 m(2)), lower rates of atrial fibrillation (25% vs. 46%), strikingly higher rates of diabetes (59% vs. 30%), and higher rates of hypertension (76% vs. 44%). Despite these clear inter-group differences in individual drivers of NT-proBNP, average levels were similar in Asians [2709 (1350, 6302) pg/mL] and Caucasians [2545 (1308, 5484) pg/mL] (P = 0.514). NT-proBNP was strongly associated with outcome [hazard ratio 1.28 (per doubling), 95% confidence interval 1.18-1.39, P <0.001], regardless of ethnicity (P-interaction = 0.719). NT-proBNP was similarly associated with outcome in HF with reduced and preserved ejection fraction in Asian (P-interaction = 0.776) and Caucasian patients (P-interaction = 0.558). Conclusions NT-proBNP has similar prognostic performance in Asians and Caucasians with HF despite ethnic differences in known clinical determinants of plasma NT-proBNP

Effectiveness and cost-effectiveness of serum B-type natriuretic peptide testing and monitoring in patients with heart failure in primary and secondary care:an evidence synthesis, cohort study and cost-effectiveness mode

Background: Heart failure (HF) affects around 500,000 people in the UK. HF medications are frequently underprescribed and B-type natriuretic peptide (BNP)-guided therapy may help to optimise treatment. Objective: To evaluate the clinical effectiveness and cost-effectiveness of BNP-guided therapy compared with symptom-guided therapy in HF patients. Design: Systematic review, cohort study and cost-effectiveness model. Setting: A literature review and usual care in the NHS. Participants: (a) HF patients in randomised controlled trials (RCTs) of BNP-guided therapy; and (b) patients having usual care for HF in the NHS. Interventions: Systematic review: BNP-guided therapy or symptom-guided therapy in primary or secondary care. Cohort study: BNP monitored (≥ 6 months’ follow-up and three or more BNP tests and two or more tests per year), BNP tested (≥ 1 tests but not BNP monitored) or never tested. Cost-effectiveness model: BNP-guided therapy in specialist clinics. Main outcome measures: Mortality, hospital admission (all cause and HF related) and adverse events; and quality-adjusted life-years (QALYs) for the cost-effectiveness model. Data sources: Systematic review: Individual participant or aggregate data from eligible RCTs. Cohort study: The Clinical Practice Research Datalink, Hospital Episode Statistics and National Heart Failure Audit (NHFA). Review methods: A systematic literature search (five databases, trial registries, grey literature and reference lists of publications) for published and unpublished RCTs. Results: Five RCTs contributed individual participant data (IPD) and eight RCTs contributed aggregate data (1536 participants were randomised to BNP-guided therapy and 1538 participants were randomised to symptom-guided therapy). For all-cause mortality, the hazard ratio (HR) for BNP-guided therapy was 0.87 [95% confidence interval (CI) 0.73 to 1.04]. Patients who were aged < 75 years or who had heart failure with a reduced ejection fraction (HFrEF) received the most benefit [interactions (p = 0.03): < 75 years vs. ≥ 75 years: HR 0.70 (95% CI 0.53 to 0.92) vs. 1.07 (95% CI 0.84 to 1.37); HFrEF vs. heart failure with a preserved ejection fraction (HFpEF): HR 0.83 (95% CI 0.68 to 1.01) vs. 1.33 (95% CI 0.83 to 2.11)]. In the cohort study, incident HF patients (1 April 2005–31 March 2013) were never tested (n = 13,632), BNP tested (n = 3392) or BNP monitored (n = 71). Median survival was 5 years; all-cause mortality was 141.5 out of 1000 person-years (95% CI 138.5 to 144.6 person-years). All-cause mortality and hospital admission rate were highest in the BNP-monitored group, and median survival among 130,433 NHFA patients (1 January 2007–1 March 2013) was 2.2 years. The admission rate was 1.1 patients per year (interquartile range 0.5–3.5 patients). In the cost-effectiveness model, in patients aged < 75 years with HFrEF or HFpEF, BNP-guided therapy improves median survival (7.98 vs. 6.46 years) with a small QALY gain (5.68 vs. 5.02) but higher lifetime costs (£64,777 vs. £58,139). BNP-guided therapy is cost-effective at a threshold of £20,000 per QALY. Limitations: The limitations of the trial were a lack of IPD for most RCTs and heterogeneous interventions; the inability to identify BNP monitoring confidently, to determine medication doses or to distinguish between HFrEF and HFpEF; the use of a simplified two-state Markov model; a focus on health service costs and a paucity of data on HFpEF patients aged < 75 years and HFrEF patients aged ≥ 75 years. Conclusions: The efficacy of BNP-guided therapy in specialist HF clinics is uncertain. If efficacious, it would be cost-effective for patients aged < 75 years with HFrEF. The evidence reviewed may not apply in the UK because care is delivered differently. Future work: Identify an optimal BNP-monitoring strategy and how to optimise HF management in accordance with guidelines; update the IPD meta-analysis to include the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) RCT; collect routine long-term outcome data for completed and ongoing RCTs. Trial registration: Current Controlled Trials ISRCTN37248047 and PROSPERO CRD42013005335. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 40. See the NIHR Journals Library website for further project information. The British Heart Foundation paid for Chris A Rogers’ and Maria Pufulete’s time contributing to the study. Syed Mohiuddin’s time is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West at University Hospitals Bristol NHS Foundation Trust. Rachel Maishman contributed to the study when she was in receipt of a NIHR Methodology Research Fellowship