Clinical outcomes in patients with atrial fibrillation treated with digoxin, according to the presence of heart failure: Insights from the MISOAC-AF trial.

BACKGROUND: Digoxin is widely used in atrial fibrillation (AF) and heart failure (HF). However, current evidence regarding its association with clinical outcomes is conflicting. AIM: To investigate the relationship between digoxin therapy and adverse outcomes in patients with AF, with or without HF, in a contemporary AF cohort. METHODS: We performed a retrospective analysis of data from 698 patients, who were followed over a median of 2.5 years. The primary outcome was all-cause mortality and the secondary outcome was all-cause hospitalization, in a time-to-event analysis. Propensity scores were used to derive matched populations, balanced on key baseline covariates. To limit potential confounding, inverse probability of treatment weighting (IPTW) analysis was performed. RESULTS: Among patients with HF, 39 (10.5%) were administered digoxin at baseline, whereas 331 (89.5%) were not. Digoxin administration was not associated with an increased risk of death (hazard ratio (HR) in the digoxin group, 1.21; 95% Confidence Interval (CI), 0.69 to 2.13, p = 0.50) or hospitalization of any cause (HR 1.15; 95% CI, 0.67 to 1.96; p = 0.60). Among patients without HF, 11 (3.5%) were administered digoxin, with neutral effects on all-cause mortality (HR: 3.25; 95% CI, 0.98 to 10.70), p = 0.06) and all-cause hospitalization (HR, 1.15; 95% CI, 0.67 to 1.96, p = 0.60). Qualitatively, consistent results were observed using IPTW. CONCLUSIONS: Among patients with AF, digoxin administration was not associated with an increased risk of death and hospitalization for any cause, irrespective of HF status.

Renal function and mortality in patients with atrial fibrillation.

AIM: The aim of this study is to examine the association of the presence of chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) values with mortality in patients with atrial fibrillation. METHODS: This posthoc analysis of a randomized controlled trial consisted of hospitalized patients with atrial fibrillation who were followed up for a median of 2.7 years after discharge. Kaplan-Meier curves, multivariate Cox-regression and spline curves were utilized to assess the association of CKD, CKD stages 2-5 according to the KDOQI guidelines, and the continuum of eGFR values with the primary outcome of all-cause death, and the secondary outcome of cardiovascular mortality. RESULTS: Out of 1064 hospitalized patients with atrial fibrillation, 465 (43.7%) had comorbid CKD. The presence of CKD was associated with an increased risk for both all-cause and cardiovascular mortality following hospitalization [adjusted hazard ratio (aHR): 1.60; 95% confidence intervals (95% CIs): 1.25-2.05 and aHR: 1.74; 95% CI: 1.30-2.33, respectively]. The aHRs for all-cause mortality in CKD stages 2-5, as compared with CKD stage 1 were 2.18, 2.62, 4.20 and 3.38, respectively (all P < 0.05). In spline curve analyses, eGFR values lower than 50 ml/min/1.73 m2 were independent predictors of higher all-cause and cardiovascular mortality. CONCLUSION: In recently hospitalized patients with atrial fibrillation, the presence of CKD was independently associated with decreased survival, which was significant across CKD stages 2-5, as compared with CKD stage 1. Values of eGFR lower than 50 ml/min/1.73 m2 were incrementally associated with worse prognosis.

Reproducibility of masked hypertension and office-based hypertension: a systematic review and meta-analysis.

Blood pressure (BP) phenotypes have a prognostic significance for target organ damage in long-term studies. However, it remains uncertain whether a single baseline phenotype classification is reproducible over time and represents accurately the patients' BP status. The aim of this study was to systematically investigate the reproducibility of masked hypertension and office-based hypertension either with ambulatory BP monitoring (ABPM) or home BP monitoring (HBPM). PubMed, Cochrane Library and Web of Science were searched to identify studies with paired baseline office BP and ABPM or HBPM measurements at two timepoints. The outcome of the analysis was the individual phenotype reproducibility between the baseline and follow-up timepoints. The used effect measure was Cohen's kappa coefficient. We found 15 studies eligible for the meta-analysis enrolling a total of 5729 patients. The reproducibility of masked hypertension was better with ABPM, kappa reliability test: 0.41 [95% confidence interval (CI): 0.32-0.49], than with HBPM, kappa reliability test: 0.26 (95% CI: 0.10-0.40). The reproducibility of office-based hypertension with both methods was low, indicating slight agreement. Kappa reliability test was slightly better with ABPM (κ: 0.27, 95% CI: 0.12-0.41) than with HBPM (κ: 0.18, 95% CI: 0.08-0.27). This systematic review and meta-analysis show a slight to fair reproducibility of masked hypertension and office-based hypertension assessed through ABPM and HBPM. Considering that poor reproducibility may be a result of office BP measurements, an ABPM/HBPM-based strategy should be established for the evaluation and treatment of patients with masked hypertension or office-based hypertension.

Rhythm control versus rate control in patients with atrial fibrillation and heart failure across the left ventricular ejection fraction spectrum.

BACKGROUND: Rhythm control and rate control are both employed commonly in patients with atrial fibrillation (AF) and heart failure (HF), but limited real-world data exist on them. We aimed to compare outcomes between these two strategies across the left ventricular ejection fraction (LVEF) spectrum. MATERIALS AND METHODS: This retrospective cohort study used data from the randomized MISOAC-AF trial, including from patients with AF and coexistent HF who were hospitalized and followed up after discharge. At baseline, the patients were classified into pharmaceutical (or electrical cardioversion) rhythm control strategy or rate control treatment (b-blocker, digoxin, calcium channel blockers) groups. The primary outcome was all-cause mortality. Kaplan-Meier curves and multivariable-adjusted Cox regression were utilized to compare the two strategies. Spline curve models were used to demonstrate the results across the LVEF stratified spectrum. RESULTS: In total, 199 AF patients with HF were studied (mean age, 77 years). At discharge, 73 (36.7%) patients received rhythm control and 126 (63.3%) rate control treatment. After a median follow-up period of 31 months, 26 (35.6%) patients in the rhythm-control group died, as compared to 43 (33.3%) in the rate-control group (aHR: 1.29; 95% CI: 0.78-2.14; p = 0.31). The spline curves also revealed no difference in all-cause mortality favoring either strategy in any HF subtype across the nominally classified LVEF. CONCLUSION: The use of a pharmacological rhythm-control strategy was not associated with a survival advantage compared to the rate control strategy in recently hospitalized patients with AF and comorbid HF. More randomized trials and large studies are needed in the future to explore these results in each subgroup of HF patients.

Associations of Atrial Fibrillation Patterns With Mortality and Cardiovascular Events: Implications of the MISOAC-AF Trial.

AIM: This retrospective cohort study aimed to evaluate the prognostic implications of the distinct atrial fibrillation (AF) temporal patterns: first diagnosed, paroxysmal, and persistent or permanent AF. METHODS: In this post hoc analysis of the MISOAC-AF trial (NCT02941978), a total of 1052 patients with AF (median age 76 years), discharged from the cardiology ward between 2015 and 2018, were analyzed. Kaplan-Meier and Cox-regression analyses were performed to compare the primary outcome of all-cause mortality, the secondary outcomes of stroke, major bleeding and the composite outcome of cardiovascular (CV) mortality or hospitalization among AF patterns. RESULTS: Of patients, 121 (11.2%) had first diagnosed, 356 (33%) paroxysmal, and 575 (53.2%) persistent or permanent AF. During a median follow-up of 31 months (interquartile range 10 to 52 months), 37.3% of patients died. Compared with paroxysmal AF, patients with persistent or permanent AF had higher mortality rates (adjusted hazard ratio (aHR), 1.37; 95% confidence interval [CI], 1.08-1.74, P = .009), but similar CV mortality or hospitalization rates (aHR, 1.09; 95% CI, 0.91-1.31, P = .35). Compared with first diagnosed AF, patients with persistent or permanent AF had similar mortality (aHR, 1.26; 95% CI, 0.87-1.82, P = .24), but higher CV mortality or hospitalization rates (aHR, 1.35; 95% CI, 1.01-1.8, P = .04). Stroke and major bleeding events did not differ across AF patterns (all P > .05). CONCLUSIONS: In conclusion, in recently hospitalized patients with comorbid AF, the presence of persistent or permanent AF was associated with a higher incidence of mortality and morbidity compared with paroxysmal and first diagnosed AF.

Effects of Major Antihypertensive Drug Classes on Erectile Function: a Network Meta-analysis.

PURPOSE: To determine the effect of major antihypertensive classes on erectile function (EF) in patients with or at high risk of cardiovascular disease. METHODS: We performed a systematic review and frequentist network meta-analysis of randomized controlled trials assessing the effect of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, calcium channel blockers, and thiazide diuretics on EF compared to each other and to placebo (PROSPERO: CRD42020189529). Similarly, we performed a network meta-analysis to explore the effect of different ß-blockers on erectile function (nebivolol, other vasodilating and non-vasodilating ß-blockers, placebo). Records were identified through search of PubMed, Cochrane Library, and Scopus databases and sources of grey literature until September 2020. RESULTS: We included 25 studies (7784 patients) in the qualitative and 16 studies in the quantitative synthesis. The risk of bias was concerning or high in the majority of studies, and inconsistency was also high. No significant differences in EF were demonstrated in the pairwise comparisons between major antihypertensive classes. Similarly, when placebo was set as the reference treatment group, no treatment strategy yielded significant effects on EF. In the ß-blockers analysis, nebivolol contributed a beneficial effect on EF only when compared to non-vasodilatory ß-blockers (OR 2.92, 95%CI 1.3-6.5) and not when compared to placebo (OR 2.87, 95%CI 0.75-11.04) or to other vasodilatory ß-blockers (OR 2.15, 95%CI 0.6-7.77). CONCLUSION: All antihypertensive medication classes seem to exert neutral or insignificant effects on EF. Further high-quality studies are needed to better explore the effects of antihypertensive medication on EF.

Atrial High-Rate Episodes in Patients with Devices Without a History of Atrial Fibrillation: a Systematic Review and Meta-analysis.

PURPOSE: Atrial high-rate episodes (AHREs) recorded with cardiac implantable electronic devices (CIEDs) have been associated with the development of clinical atrial fibrillation (AF) and increase in stroke and death risk. We sought to perform a systematic review with a meta-analysis to evaluate the prevalence of AHREs detected by CIEDs, their association with stroke risk, development of clinical AF, and mortality among patients without a documented history of AF. METHODS: We searched several databases, ClinicalTrials.gov, references of reviews, and meeting abstract books without any language restrictions up to 9 September 2020. We studied patients with CIEDs in whom AHREs were detected. Exclusion criterion was AF history. Our primary outcome was the risk of ischemic stroke in patients with AHREs. RESULTS: We deemed eligible eight studies for the meta-analysis enrolling a total of 4322 patients with CIED and without a documented AF history. The overall AHRE incidence ratio was estimated to be 17.56 (95% CI, 8.61 to 35.79) cases per 100 person-years. Evidence of moderate certainty suggests that patients with documented AHREs were 4.45 times (95% CI 2.87-6.91) more likely to develop clinical AF. Evidence of low confidence suggests that AHREs were associated with a 1.90-fold increased stroke risk (95% CI 1.19-3.05). AHREs were not associated with a statistically significant increased mortality risk. CONCLUSION: The present systematic review and meta-analysis demonstrated that among patients without a documented history of AF, the detection of AHREs by CIEDs was associated with significant increased risk of clinical AF and stroke. REGISTRATION NUMBER (DOI): Available in https://doi.org/10.17605/OSF.IO/ZRF6M .

Τhe association of heart failure across left ventricular ejection fraction with mortality in atrial fibrillation.

AIMS: The aim of this study is to investigate the prognostic implications of the presence of heart failure (HF) across the range of left ventricular ejection fraction (LVEF) in patients with comorbid atrial fibrillation (AF). METHODS AND RESULTS: We conducted a retrospective cohort study of 1063 patients (median age 76 years), discharged from the cardiology ward with a primary or secondary diagnosis of AF between 2015 and 2018. We used Cox proportional-hazards and spline models to examine the association of the presence of HF, across the range of LVEF, with the primary outcome of all-cause mortality. HF was documented in 52.9% of patients at baseline. During a median follow-up of 31 months (interquartile range 10 to 52 months), 37.3% of patients died. The presence of HF was associated with a significantly higher risk of mortality [adjusted hazard ratio (aHR) 2.17; 95% confidence interval (CI), 1.70 to 2.77; P < 0.001], which was evident across HF with reduced (aHR 3.03; 95% CI 2.41 to 4.52), mid-range (aHR 2.08; 95% CI 1.47 to 2.94), and preserved LVEF (aHR 1.94; 95% CI 1.47 to 2.55). Among patients with HF, the spline curve depicted a non-linear association between LVEF and the risk of death, in which there was a steep and progressive increase in mortality for every 5% reduction in LVEF below 25% (aHR 1.97, 95% CI 1.04 to 3.73, P = 0.04). CONCLUSIONS: In patients with AF who were discharged from the hospital, the presence of HF at baseline was independently associated with a twofold risk of death, which was significant across LVEF-classified HF subtypes. Among patients with AF and HF, the risk of death rose significantly as LVEF was reduced below 25%.

Prognostic significance of diabetes mellitus in patients with atrial fibrillation.

BACKGROUND: There are limited data on the association of diabetes mellitus (DM) and levels of glycated hemoglobin (HbA1c) with outcomes in patients with atrial fibrillation (AF). METHODS: This retrospective cohort study included patients who were recently hospitalized with a primary or secondary diagnosis of AF from December 2015 through June 2018. Kaplan-Meier curves and Cox-regression adjusted hazard ratios (aHR) were calculated for the primary outcome of all-cause mortality and for the secondary outcomes of cardiovascular (CV) mortality and the composite outcome of CV death or hospitalization. Competing-risk regression analyses were performed to calculate the cumulative risk of stroke, major bleeding, AF- or HF-hospitalizations adjusted for the competing risk of all-cause death. Spline curve models were fitted to investigate associations of HbA1c values and mortality among patients with AF and DM. RESULTS: In total 1109 AF patients were included, of whom 373 (33.6%) had DM. During a median follow-up of 2.6 years, 414 (37.3%) patients died. The presence of DM was associated with a higher risk of all-cause mortality (aHR = 1.40 95% confidence intervals [CI] 1.11-1.75), CV mortality (aHR = 1.39, 95% CI 1.07-1.81), sudden cardiac death (aHR = 1.73, 95% CI 1.19-2.52), stroke (aHR = 1.87, 95% CI 1.01-3.45) and the composite outcome of hospitalization or CV death (aHR = 1.27, 95% CI 1.06-1.53). In AF patients with comorbid DM, the spline curves showed a positive linear association between HbA1c levels and outcomes, with values 7.6-8.2% being independent predictors of increased all-cause mortality, and values < 6.2% predicting significantly decreased all-cause and CV mortality. CONCLUSIONS: The presence of DM on top of AF was associated with substantially increased risk for all-cause or CV mortality, sudden cardiac death and excess morbidity. HbA1c levels lower than 6.2% were independently related to better survival rates suggesting that optimal DM control could be associated with better clinical outcomes in AF patients with DM.

A novel prognostic tool to predict mortality in patients with atrial fibrillation: The BASIC-AF risk score.

BACKGROUND: This study sought to develop and validate a risk score to predict mortality in patients with atrial fibrillation (AF) after a hospitalization for cardiac reasons. METHODS: The new risk score was derived from a prospective cohort of hospitalized patients with concurrent AF. The outcome measures were all-cause and cardiovascular mortality. Random forest was used for variable selection. A risk points model with predictor variables was developed by weighted Cox regression coefficients and was internally validated by bootstrapping. RESULTS: In total, 1130 patients with AF were included. During a median follow-up of 2 years, 346 (30.6%) patients died and 250 patients had a cardiovascular cause of death. N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin-T were the most important predictors of mortality, followed by indexed left atrial volume, history and type of heart failure, age, history of diabetes mellitus, and intraventricular conduction delay, all forming the BASIC-AF risk score (Biomarkers, Age, ultraSound, Intraventricular conduction delay, and Clinical history). The score had good discrimination for all-cause (c-index = 0.85 and 95% CI 0.82-0.88) and cardiovascular death (c-index = 0.84 and 95% CI 0.81-0.87). The predicted probability of mortality varied more than 50-fold across deciles and adjusted well to observed mortality rates. A decision curve analysis revealed a significant net benefit of using the BASIC-AF risk score to predict the risk of death, when compared with other existing risk schemes. CONCLUSIONS: We developed and internally validated a well-performing novel risk score for predicting death in patients with AF. The BASIC-AF risk score included routinely assessed parameters, selected through machine-learning algorithms, and may assist in tailored risk stratification and management of these patients.

Estimated Arterial Stiffness and Prediction of Vascular Aging: The Rising of a New Era.

Arterial stiffness has been associated with cardiovascular events and correlated with cardiovascular risk factors. In the new guidelines of the European Society of Hypertension, the evaluation of arterial stiffness, and specifically carotid-femoral pulse wave velocity (c-f PWV), was taken into account for the detailed screening of the hypertensive population. Despite the importance of arterial stiffness as a target organ damage, the measurement is time-consuming, not practical, needs expensive equipment and experienced staff. For all these reasons, c-f PWV is not recommended for the everyday clinical practice and its current use is restricted for research purposes. The importance of arterial properties in clinical practice and cardiovascular prevention is well known. Hence, the estimation of arterial stiffness and vascular health based on parameters that affect arterial stiffness, but without the use of a machine, is a new promising field. Furthermore, the relationship between age-related MRI abnormalities as well as ultrafast ultrasound with vascular effect gives a new promise for future vascular aging assessment.

The flipside of hydralazine in pregnancy: A systematic review and meta-analysis.

The present systematic review and meta-analysis investigated the effects of hydralazine compared with other antihypertensive drugs in maternal, perinatal and neonatal outcomes of pregnant women with hypertensive disorders. Twenty studies with 1283 participants were included. Of them, 626 received hydralazine and 657 other antihypertensive treatments, such as labetalol, nifedipine, ketanserin, diazoxide, urapidil, isradipine and epoprostenol. Women receiving hydralazine had higher heart rate (WMD: 13.4, 95%CI: 0.1 to 26.8 beats/min), increased number of adverse effects (RR: 1.21, 95%CI: 1.01 to 1.45) and gave birth to neonates of lower birthweight (WMD: 13.4, 95%CI: 0.1 to 26.8 beats/min) compared with other antihypertensive treatments at the end of follow-up. When studies, which used antihypertensive agents that are no longer indicated for hypertension in pregnancy, were excluded in the sensitivity analyses, hydralazine found not to have a statistically significant difference compared with labetalol and nifedipine regarding the reduction of maternal blood pressure (WMD: 1.72, 95%CI: -1.47 to 4.9 mmHg for systolic, WMD: 0.26, 95%CI: -1.75 to 2.28 mmHg for diastolic), maternal heart rate (WMD: 13.56, 95%CI: -5.62 to 32.74 beats/min), low birthweight (WMD: -88.62, 95%CI: -243.24 to 66 beats/min) and adverse events (RR: 1.19, 95%CI: 0.99 to 1.43). Hydralazine seems not to be inferior compared to labetalol and nifedipine for safety and efficacy.

Non-vitamin K oral anticoagulants in nonvalvular atrial fibrillation: a network meta-analysis.

OBJECTIVES: We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) including the comparison of non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin for patients with atrial fibrillation (AF). DESIGN: Network meta-analysis. Two authors independently extracted data. All authors evaluated overall confidence in the evidence. RESULTS: Eighteen RCTs included in our review, a total of 78,796 patients with AF, with sample sizes from 90 to 21,105 patients. Apixaban 5 mg (OR: 0.79, 95% CI: 0.66 to 0.95), dabigatran 110 mg (0.91, 0.74-1.12), dabigatran 150 mg (0.66, 0.53-0.82), edoxaban 60 mg (0.87, 0.74-1.02), and rivaroxaban 20 mg (0.88, 0.74-1.03) reduced the risk of stroke or systemic embolism compared with warfarin. Dabigatran 150 mg had the highest P-score for reducing stroke or systemic embolic events. The risk of haemorhagic stroke and all-cause mortality was lower with all NOACs than with warfarin. Apixaban 5 mg (0.69, 0.60-0.80), dabigatran 110 mg (0.80, 0.69-0.93), dabigatran 150 mg (0.93, 0.80-1.08), edoxaban 30 mg (0.46, 0.40-0.54), and edoxaban 60 mg (0.78, 0.69-0.90) reduced the risk of major bleeding compared with warfarin. Edoxaban 30 mg had the highest P-score for reducing major bleeding. The plots of P-scores rank showed that apixaban offered the most favorable balance of efficacy and safety. CONCLUSIONS: This study adds an attempt for treatment ranking of both efficacy and safety outcomes. Future trials comparing directly NOACs are needed in order to provide conclusive proofs for these results and not only circumstantial evidence offered by a network meta-analysis.

A systematic review and network meta-analysis of the comparative efficacy of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in hypertension.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are drugs commonly used for the treatment of hypertension. However, studies on their comparative efficacy have not been extensively investigated. The current systematic review and network meta-analysis studied the comparative efficacy of the two antihypertensive treatment categories in reducing blood pressure, mortality, and morbidity in essential hypertension patients. A literature search was carried out in Medline and Cochrane Central Register of Controlled Trials for placebo- and active-controlled, double-blind randomized clinical trials, which had reported blood pressure effects, mortality, and/or morbidity. Blood pressure results were found in 30 studies with 7370 participants and 8 studies with 25,158 participants with mortality/morbidity results included in the analysis. The two drug classes had similar effectiveness in lowering systolic (weighted mean difference (WMD): 0.59, 95% CI: -0.21 to 1.38) and diastolic blood pressure (WMD: 0.62, 95% CI: -0.06 to 1.30), all-cause mortality (risk ratio (RR)): 0.96, 95% CI 0.80 to 1.14), cardiovascular mortality (RR: 0.87, 95% CI 0.67 to 1.14), fatal and non-fatal myocardial infarction (RR: 1.02, 95% CI 0.75 to 1.37) and stroke (RR: 1.13, 95% CI 0.87 to 1.46). Angiotensin-converting enzyme inhibitors were more helpful in the prevention and/or the hospitalization for heart failure than angiotensin receptor blockers (RR: 0.71, 95% CI 0.54 to 0.93). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were similarly effective in decreasing blood pressure, mortality, and morbidity in essential hypertension. Angiotensin-converting enzyme inhibitors were more protective in the advancement and/or hospitalization of the hypertensive patient for heart failure than angiotensin receptor blockers.