Campaigns with oral polio vaccine may lower mortality and create unexpected results.

Three studies from Guinea-Bissau found conflicting effects of OPV-at-birth (OPV0) on child survival. One study from 2004 suggested excess male mortality among children receiving OPV0 compared with children receiving NoOPV0 during a period of shortage of OPV. However, two subsequent studies showed beneficial effects of OPV0. In 2004, two national OPV-campaigns had been conducted in Guinea-Bissau. In a reanalysis of the 2004-study, in a survival analysis the age-adjusted mortality rate of study participants was 67% (95% CI=42-81%) lower after the OPV-campaigns than before the campaigns. In the OPV0 group only 22% (655/3031 person-years (pyrs)) of follow-up time was "after" the OPV-campaigns whereas 55% (473/859 pyrs) of the time in the NoOPV0 group was post-campaign (p<0.0001, Chi2). Censoring for OPV-campaigns in the original study removed excess male mortality and made the three studies more homogeneous. Overall, there is now considerable evidence that OPV, like other live vaccines, has important beneficial non-specific effects

Does Heterogeneity Exist in Treatment Associations With Renin–Angiotensin–System Inhibitors or Beta-blockers According to Phenotype Clusters in Heart Failure with Preserved Ejection Fraction?

BACKGROUND: We explored the association between use of renin–angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young–low comorbidity burden (12%), atrial fibrillation–hypertensive (32%), older–atrial fibrillation (24%), obese–diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin–angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young–low comorbidity burden and atrial fibrillation–hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese–diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar. CONCLUSIONS: In patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design

Association between dosing and combination use of medications and outcomes in heart failure with reduced ejection fraction: data from the Swedish Heart Failure Registry.

AIMS: To assess the association between combination, dose and use of current guideline-recommended target doses (TD) of renin-angiotensin system inhibitors (RASi), angiotensin receptor-neprilysin inhibitors (ARNi) and β-blockers, and outcomes in a large and unselected contemporary cohort of patients with heart failure (HF) and reduced ejection fraction. METHODS AND RESULTS: Overall, 17 809 outpatients registered in the Swedish Heart Failure Registry (SwedeHF) from May 2000 to December 2018, with ejection fraction <40% and duration of HF ≥90 days were selected. Primary outcome was a composite of time to cardiovascular death and first HF hospitalization. Compared with no use of RASi or ARNi, the adjusted hazard ratio (HR) (95% confidence interval [CI]) was 0.83 (0.76-0.91) with <50% of TD, 0.78 (0.71-0.86) with 50%-99%, and 0.73 (0.67-0.80) with ≥100% of TD. Compared with no use of β-blockers, the adjusted HR (95% CI) was 0.86 (0.76-0.91), 0.81 (0.74-0.89) and 0.74 (0.68-0.82) with <50%, 50%-99% and ≥100% of TD, respectively. Patients receiving both an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB)/ARNi and a β-blocker at 50%-99% of TD had a lower adjusted risk of the primary outcome compared with patients only receiving one drug, i.e. ACEi/ARB/ARNi or β-blocker, even if this was at ≥100% of TD. CONCLUSION: Heart failure with reduced ejection fraction patients using higher doses of RASi or ARNi and β-blockers had lower risk of cardiovascular death or HF hospitalization. Use of two drug classes at 50%-99% of TD dose was associated with lower risk than one drug class at 100% of TD

Non-insulin antihyperglycaemic drugs and heart failure: an overview of current evidence from randomized controlled trials.

Type 2 diabetes mellitus (T2DM) is highly prevalent in the general population and especially in patients with heart failure (HF). It is not only a risk factor for incident HF, but is also associated with worse outcomes in prevalent HF. Therefore, antihyperglycaemic management in patients at risk of or with established HF is of importance to reduce morbidity/mortality. Following revision of the drug approval process in 2008 by the Food and Drug Administration and European Medicines Agency, several cardiovascular outcome trials on antihyperglycaemic drugs have recently investigated HF endpoints. Signals of harm in terms of increased risk of HF have been identified for thiazolidinediones and the dipeptidyl peptidase 4 inhibitor saxagliptin, and therefore, these drugs are not currently recommended in HF. Sulfonylureas also have an unfavourable safety profile and should be avoided in patients at increased risk of/with HF. Observational studies have assessed the use of metformin in patients with HF, showing potential safety and potential survival/morbidity benefits. Overall use of glucagon-like peptide 1 receptor agonists has not been linked with any clear benefit in terms of HF outcomes. Sodium-glucose cotransporter protein 2 inhibitors (SGLT2i) have consistently shown to reduce risk of HF-related outcomes in T2DM with and without HF and are thus currently recommended to lower risk of HF hospitalization in T2DM. Recent findings from the DAPA-HF trial support the use of dapagliflozin in patients with HF with reduced ejection fraction and, should ongoing trials with empagliflozin, sotagliflozin, and canagliflozin prove efficacy, will pave the way for SGLT2i as HF treatment regardless of T2DM

Digoxin use in contemporary heart failure with reduced ejection fraction: an analysis from the Swedish Heart Failure Registry.

AIMS: Digoxin is included in some heart failure (HF) guidelines but controversy persists about the true role for and impact of treatment with this drug, particularly in the absence of atrial fibrillation (AF). The aim of this study was to assess the association between clinical characteristics and digoxin use and between digoxin use and mortality/morbidity in a large, contemporary cohort of patients with HF with reduced ejection fraction (HFrEF) stratified by history of AF. METHODS AND RESULTS: Patients with HFrEF (EF < 40%) enrolled in the Swedish HF registry between 2005 and 2018 were analysed. The independent association between digoxin use and patient characteristics was assessed by logistic regression, and between digoxin use and outcomes [composite of all-cause mortality or HF hospitalization (HFH), all-cause mortality, and HFH] by Cox regressions in a 1:1 propensity score matched population. Digoxin use was analysed at baseline and as a time-dependent variable. Of 42 456 patients with HFrEF, 16% received digoxin, 29% in the AF group and 2.8% in the non-AF group. The main independent predictors of use were advanced HF, higher heart rate, history of AF, preserved renal function, and concomitant use of beta blockers. Digoxin use was associated with lower risk of all-cause death/HFH [hazard ratio (HR): 0.95; 95% confidence interval (CI): 0.91-0.99] in AF, but with higher risk in non-AF (HR: 1.24; 95% CI: 1.09-1.43). Consistent results were observed when digoxin use was analysed as a time-dependent variable. CONCLUSION: The great majority of digoxin users had a history of AF. Digoxin use was associated with lower mortality/morbidity in patients with AF, but with higher mortality/morbidity in patients without AF

Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial

Background: In the EMPA-REG OUTCOME trial, ejection fraction (EF) data were not collected. In the subpopulation with heart failure (HF), we applied a new predictive model for EF to determine the effects of empagliflozin in HF with predicted reduced (HFrEF) vs preserved (HFpEF) EF vs no HF. / Methods and Results: We applied a validated EF predictive model based on patient baseline characteristics and treatments to categorize patients with HF as being likely to have HF with mid-range EF (HFmrEF)/HFrEF (EF <50%) or HFpEF (EF ≥50%). Cox regression was used to assess the effect of empagliflozin vs placebo on cardiovascular death/HF hospitalization (HHF), cardiovascular and all-cause mortality, and HHF in patients with predicted HFpEF, HFmrEF/HFrEF and no HF. Of 7001 EMPA-REG OUTCOME patients with data available for this analysis, 6314 (90%) had no history of HF. Of the 687 with history of HF, 479 (69.7%) were predicted to have HFmrEF/HFrEF and 208 (30.3%) to have HFpEF. Empagliflozin's treatment effect was consistent in predicted HFpEF, HFmrEF/HFrEF and no-HF for each outcome (HR [95% CI] for the primary outcome 0.60 [0.31–1.17], 0.79 [0.51–1.23], and 0.63 [0.50–0.78], respectively; P interaction = 0.62). / Conclusions: In EMPA-REG OUTCOME, one-third of the patients with HF had predicted HFpEF. The benefits of empagliflozin on HF and mortality outcomes were consistent in nonHF, predicted HFpEF and HFmrEF/HFrEF

Trajectories in New York Heart Association functional class in heart failure across the ejection fraction spectrum: data from the Swedish Heart Failure Registry.

AIMS: To investigate incidence, predictors and prognostic implications of longitudinal New York Heart Association (NYHA) class changes (i.e. improving or worsening vs. stable NYHA class) in heart failure (HF) across the ejection fraction (EF) spectrum. METHODS AND RESULTS: From the Swedish HF Registry, 13 535 patients with EF and ≥2 NYHA class assessments were considered. Multivariable multinomial regressions were fitted to identify the independent predictors of NYHA change. Over a 1-year follow-up, 69% of patients had stable, 17% improved, and 14% worsened NYHA class. Follow-up in specialty care predicted improving NYHA class, whereas an in-hospital patient registration, lower EF, renal disease, lower mean arterial pressure, older age, and longer HF duration predicted worsening. The association between NYHA change and subsequent outcomes was assessed with multivariable Cox models. When adjusting for the NYHA class at baseline, improving NYHA class was independently associated with lower while worsening with higher risk of all-cause and cardiovascular mortality, and first HF hospitalization. After adjustment for the NYHA class at follow-up, NYHA class change did not predict morbidity/mortality. NYHA class assessment at baseline and follow-up predicted morbidity/mortality on top of the changes. Results were consistent across the EF spectrum. CONCLUSION: In a large real-world HF population, NYHA class trajectories predicted morbidity/mortality after extensive adjustments. However, the prognostic role was entirely explained by the resulting NYHA class, i.e. the follow-up value. Our results highlight that considering one-time NYHA class assessment, rather than trajectories, might be the preferable approach in clinical practice and for clinical trial design

Patient profile and outcomes associated with follow-up in specialty vs. primary care in heart failure.

AIMS: Factors influencing follow-up referral decisions and their prognostic implications are poorly investigated in patients with heart failure (HF) with reduced (HFrEF), mildly reduced (HFmrEF), and preserved (HFpEF) ejection fraction (EF). We assessed (i) the proportion of, (ii) independent predictors of, and (iii) outcomes associated with follow-up in specialty vs. primary care across the EF spectrum. METHODS AND RESULTS: We analysed 75 518 patients from the large and nationwide Swedish HF registry between 2000-2018. Multivariable logistic regression models were fitted to identify the independent predictors of planned follow-up in specialty vs. primary care, and multivariable Cox models to assess the association between follow-up type and outcomes. In this nationwide registry, 48 115 (64%) patients were planned for follow-up in specialty and 27 403 (36%) in primary care. The median age was 76 [interquartile range (IQR) 67-83] years and 27 546 (36.5%) patients were female. Key independent predictors of planned follow-up in specialty care included optimized HF care, that is follow-up in a nurse-led HF clinic [odds ratio (OR) 4.60, 95% confidence interval (95% CI) 4.41-4.79], use of HF devices (OR 3.99, 95% CI 3.62-4.40), beta-blockers (OR 1.39, 95% CI 1.32-1.47), renin-angiotensin system/angiotensin-receptor-neprilysin inhibitors (OR 1.21, 95% CI 1.15-1.27), and mineralocorticoid receptor antagonists (OR 1.31, 95% CI 1.26-1.37); and more severe HF, that is higher NT-proBNP (OR 1.13, 95% CI 1.06-1.20) and NYHA class (OR 1.13, 95% CI 1.08-1.19). Factors associated with lower likelihood of follow-up in specialty care included older age (OR 0.29, 95% CI 0.28-0.30), female sex (OR 0.89, 95% CI 0.86-0.93), lower income (OR 0.79, 95% CI 0.76-0.82) and educational level (OR 0.77, 95% CI 0.73-0.81), higher EF [HFmrEF (OR 0.65, 95% CI 0.62-0.68) and HFpEF (OR 0.56, 95% CI 0.53-0.58) vs. HFrEF], and higher comorbidity burden, such as presence of kidney disease (OR 0.91, 95% CI 0.87-0.95), atrial fibrillation (OR 0.85, 95% CI 0.81-0.89), and diabetes mellitus (OR 0.92, 95% CI 0.88-0.96). A planned follow-up in specialty care was independently associated with lower risk of all-cause [hazard ratio (HR) 0.78, 95% CI 0.76-0.80] and cardiovascular death (HR 0.76, 95% CI 0.73-0.78) across the EF spectrum, but not of HF hospitalization (HR 1.06, 95% CI 1.03-1.10). CONCLUSIONS: In a large nationwide HF population, referral to specialty care was linked with male sex, younger age, lower EF, lower comorbidity burden, better socioeconomic environment and optimized HF care, and associated with better survival across the EF spectrum. Our findings highlight the need for greater and more equal access to HF specialty care and improved quality of primary care

Subtypes of atrial fibrillation with concomitant valvular heart disease derived from electronic health records: phenotypes, population prevalence, trends and prognosis

AIMS: To evaluate population-based electronic health record (EHR) definitions of atrial fibrillation (AF) and valvular heart disease (VHD) subtypes, time trends in prevalence and prognosis. METHODS AND RESULTS: A total of 76 019 individuals with AF were identified in England in 1998-2010 in the CALIBER resource, linking primary and secondary care EHR. An algorithm was created, implemented, and refined to identify 18 VHD subtypes using 406 diagnosis, procedure, and prescription codes. Cox models were used to investigate associations with a composite endpoint of incident stroke (ischaemic, haemorrhagic, and unspecified), systemic embolism (SSE), and all-cause mortality. Among individuals with AF, the prevalence of AF with concomitant VHD increased from 11.4% (527/4613) in 1998 to 17.6% (7014/39 868) in 2010 and also in individuals aged over 65 years. Those with mechanical valves, mitral stenosis (MS), or aortic stenosis had highest risk of clinical events compared to AF patients with no VHD, in relative [hazard ratio (95% confidence interval): 1.13 (1.02-1.24), 1.20 (1.05-1.36), and 1.27 (1.19-1.37), respectively] and absolute (excess risk: 2.04, 4.20, and 6.37 per 100 person-years, respectively) terms. Of the 95.2% of individuals with indication for warfarin (men and women with CHA2DS2-VASc ≥1 and ≥2, respectively), only 21.8% had a prescription 90 days prior to the study. CONCLUSION: Prevalence of VHD among individuals with AF increased from 1998 to 2010. Atrial fibrillation associated with aortic stenosis, MS, or mechanical valves (compared to AF without VHD) was associated with an excess absolute risk of stroke, SSE, and mortality, but anticoagulation was underused in the pre-direct oral anticoagulant (DOAC) era, highlighting need for urgent clarity regarding DOACs in AF and concomitant VHD