How Should Subgroup Analyses Affect Clinical Practice? Insights from the Metoprolol Succinate Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF)

CONTEXT: The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization in patients with heart failure. While none of these trials are large enough to provide definitive results in any particular subgroup, it is of interest for physicians to examine the consistency of results as regards efficacy and safety for various subgroups or risk groups. OBJECTIVE: To summarize results from both predefined as well as post-hoc subgroup analyses performed in the MERIT-HF trial, and to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. For some subgroups we performed metaanalyses with data from the CIBIS II and COPERNICUS trials in order to obtain more robust data on mortality in subgroups with a small number of deaths (e.g. for women). SETTING: MERIT-HF was run in 14 countries, and randomized a total of 3,991 patients with symptomatic systolic heart failure (NYHA class II to IV with ejection fraction < or =0.40). Treatment was initiated with a very low dose with careful titration to a maximum target dose of 200 mg metoprolol succinate controlled release/extended release (CR/XL), or highest tolerated dose. MAIN OUTCOME MEASURES: Total mortality (first primary endpoint), total mortality plus all-cause hospitalization (second primary endpoint), and total mortality plus hospitalization for heart failure (first secondary endpoint) analyzed on a time to first event basis. RESULTS: Overall, MERIT-HF demonstrated a 34% reduction in total mortality ( p = 0.00009 nominal) and a 19% reduction for mortality plus all-cause hospitalization ( p = 0.00012). The first secondary endpoint of mortality plus hospitalization for heart failure was reduced by 31% ( p = 0.0000008). The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as nearly all post-hoc subgroups. Metoprolol CR/XL has been very well tolerated, overall as well as in all subgroups analyzed. Overall 87% of the patients reached a dose of 100 mg or more of metoprolol CR/XL once daily, and 64% reached the target dose of 200 mg once daily. CONCLUSION: Our results show that when carefully titrated, metoprolol CR/XL can safely be instituted for the overwhelming majority of outpatients with clinically stable systolic heart failure, with minimal side effects or deterioration. The time has come to overcome the barriers that physicians perceive to beta-blocker treatment, and to provide it to the large number of patients with heart failure in need of this therapy, including also high risk patients like elderly patients, patients with severe heart failure, and patients with diabetes. Because of the increased risk, these are the patients in whom treatment will have the greatest impact as shown by number of lives saved and number of hospitalizations avoided. The target dose should be strived for in all patients who tolerate this dose. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups due to small sample size in subgroups and due to chance. However, we believe that the best estimate of treatment effect for any particular subgroup should be the overall effect observed in the trial.     

A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS

BACKGROUND: Recent large randomized, controlled trials (BEST [Beta-blocker Evaluation of Survival Trial], CIBIS-II [Cardiac Insufficiency Bisoprolol Trial II], COPERNICUS [Carvedilol Prospective Randomized Cumulative Survival Study], and MERIT-HF [Metoprolol Randomized Intervention Trial in Congestive Heart Failure]) have addressed the usefulness of beta-blockade in the treatment of advanced heart failure. CIBIS-II, COPERNICUS, and MERIT-HF have shown that beta-blocker treatment with bisoprolol, carvedilol, and metoprolol XL, respectively, reduce mortality in advanced heart failure patients, whereas BEST found a statistically nonsignificant trend toward reduced mortality with bucindolol. We conducted a post hoc analysis to determine whether the response to beta-blockade in BEST could be related to differences in the clinical and demographic characteristics of the study populations. We generated a sample from BEST to resemble the patient cohorts studied in CIBIS-II and MERIT-HF to find out whether the response to beta-blocker therapy was similar to that reported in the other trials. These findings are further compared with COPERNICUS, which entered patients with more severe heart failure. METHODS: To achieve conformity with the entry criteria for CIBIS-II and MERIT-HF, the BEST study population was adjusted to exclude patients with systolic blood pressure <100 mm Hg, heart rate <60 bpm, and age >80 years (exclusion criteria employed in those trials). The BEST comparison subgroup (BCG) was further modified to more closely reflect the racial demographics reported for patients enrolled in CIBIS-II and MERIT-HF. The association of beta-blocker therapy with overall survival and survival free of cardiac death, sudden cardiac death, and progressive pump failure in the BCG was assessed. RESULTS: In the BCG subgroup, bucindolol treatment was associated with significantly lower risk of death from all causes (hazard ratio (HR)=0.77 [95% CI=0.65, 0.92]), cardiovascular death (HR=0.71 [0.58, 0.86]), sudden death (HR=0.77 [0.59, 0.999]), and pump failure death (HR=0.64 [0.45, 0.91]). CONCLUSIONS: Although not excluding the possibility of differences resulting from chance alone or to different properties among beta-blockers, this study suggests the possibility that different heart failure population subgroups may have different responses to beta-blocker therapy.     

Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy.

OBJECTIVES: We studied the prognostic implications of midwall fibrosis in dilated cardiomyopathy (DCM) in a prospective longitudinal study. BACKGROUND: Risk stratification of patients with nonischemic DCM in the era of device implantation is problematic. Approximately 30% of patients with DCM have midwall fibrosis as detected by late gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR), which may increase susceptibility to arrhythmia and progression of heart failure. METHODS: Consecutive DCM patients (n = 101) with the presence or absence of midwall fibrosis were followed up prospectively for 658 +/- 355 days for events. RESULTS: Midwall fibrosis was present in 35% of patients and was associated with a higher rate of the predefined primary combined end point of all-cause death and hospitalization for a cardiovascular event (hazard ratio 3.4, p = 0.01). Multivariate analysis showed midwall fibrosis as the sole significant predictor of death or hospitalization. However, there was no significant difference in all-cause mortality between the 2 groups. Midwall fibrosis also predicted secondary outcome measures of sudden cardiac death (SCD) or ventricular tachycardia (VT) (hazard ratio 5.2, p = 0.03). Midwall fibrosis remained predictive of SCD/VT after correction for baseline differences in left ventricular ejection fraction between the 2 groups. CONCLUSIONS: In DCM, midwall fibrosis determined by CMR is a predictor of the combined end point of all-cause mortality and cardiovascular hospitalization, which is independent of ventricular remodeling. In addition, midwall fibrosis by CMR predicts SCD/VT. This suggests a potential role for CMR in the risk stratification of patients with DCM, which may have value in determining the need for device therapy.     

Modest Increase in Peak VO2 Is Related to Better Clinical Outcomes in Chronic Heart Failure Patients: Results From Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training

Background- The prognostic ability of a single measurement of peak oxygen uptake (VO(2)) is well established in patients with chronic heart failure. The relation between a change in peak VO(2) and clinical outcomes is not well defined. Methods and Results- This investigation determined whether an increase in peak VO(2) was associated with a lower risk of the primary end point of time to all-cause mortality or all-cause hospitalization and 3 secondary end points. In Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training, an exercise training trial for patients with systolic heart failure, cardiopulmonary exercise tests were performed at baseline and ≈3 months later in 1620 participants. Median peak VO(2) in the combined sample increased from 15.0 (11.9-18.0 Q1-Q3) to 15.4 (12.3-18.7 Q1-Q3) mL·kg(-1)·min(-1). Every 6% increase in peak VO(2,) adjusted for other significant predictors, was associated with a 5% lower risk of the primary end point (hazard ratio=0.95; CI=0.93-0.98; P<0.001); a 4% lower risk of the secondary end point of time to cardiovascular mortality or cardiovascular hospitalization (hazard ratio=0.96; CI=0.94-0.99; P<0.001); an 8% lower risk of cardiovascular mortality or heart failure hospitalization (hazard ratio=0.92; CI=0.88-0.96; P<0.001); and a 7% lower all-cause mortality (hazard ratio=0.93; CI=0.90-0.97; P<0.001). Conclusions- Among patients with chronic systolic heart failure, a modest increase in peak VO(2) over 3 months was associated with a more favorable outcome. Monitoring the change in peak VO(2) for such patients may have benefit in assessing prognosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.     

Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study

OBJECTIVES: This study analyzed the effect of the beta(1)-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure.BACKGROUND: There continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure.METHOD: SA subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction < 0.25 were identified (n = 795). The analysis was by intention-to-treat.RESULTS: The mean ejection fraction at baseline was 0.19, and the yearly placebo mortality during follow-up was 19.1%. Treatment with metoprolol CR/XL compared to placebo resulted in significant reductions in all predefined mortality end points including: total mortality, 45 versus 72 deaths (risk reduction 39%; 95% confidence interval 11% to 58%; p = 0.0086); sudden death, 22 vs. 39 deaths (45% [7% to 67%]; p = 0.024); and death due to worsening heart failure, 13 vs. 28 deaths (55% [13% to 77%]; p = 0.015). Metoprolol CR/XL also reduced the number of hospitalizations for worsening heart failure by 45% compared with placebo (p < 0.0001). The NYHA functional class improved in the metoprolol CR/XL group compared with placebo (p = 0.0031). Metoprolol CR/XL was well tolerated, with 31% fewer patients withdrawn from study medicine (all causes) compared with placebo (p = 0.027).CONCLUSIONS: This subgroup analysis of the MERIT-HF study shows that patients with severe heart failure receive a similar mortality benefit and a similar reduction in hospitalizations for worsening heart failure with metoprolol CR/XL treatment as those patients included in the total study.     

Resting Heart Rate as an Important Predictor of Mortality and Morbidity in Ambulatory Patients With Heart Failure: A Systematic Review and Meta-Analysis

BackgroundResting heart rate is a risk factor of adverse heart failure outcomes; however, studies have shown controversial results. This meta-analysis evaluates the association of resting heart rate with mortality and hospitalization and identifies factors influencing its effect.Methods and ResultsWe systematically searched electronic databases in February 2019 for studies published in 2005 or before that evaluated the resting heart rate as a primary predictor or covariate of multivariable models of mortality and/or hospitalization in adult ambulatory patients with heart failure. Random effects inverse variance meta-analyses were performed to calculate pooled hazard ratios. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess evidence quality. Sixty-two studies on 163,445 patients proved eligible. Median population heart rate was 74 bpm (interquartile range 72–76 bpm). A 10-bpm increase was significantly associated with increased risk of all-cause mortality (hazard ratio 1.10, 95% confidence interval 1.08–1.13, high quality). Overall, subgroup analyses related to patient characteristics showed no changes to the effect estimate; however, there was a strongly positive interaction with age showing increasing risk of all-cause mortality per 10 bpm increase in heart rate.ConclusionsHigh-quality evidence demonstrates increasing resting heart rate is a significant predictor of all-cause mortality in ambulatory patients with heart failure on optimal medical therapy, with consistent effect across most patient factors and an increased risk trending with older age.     

Influence of diabetes on cardiac resynchronization therapy with or without defibrillator in patients with advanced heart failure

ObjectivesWe performed a post hoc analysis to determine the influence of cardiac resynchronization therapy with a defibrillator (CRT-D) or without a defibrillator (CRT-P) on outcomes among diabetic patients with advanced heart failure (HF).BackgroundIn patients with systolic HF, diabetes is an independent predictor of morbidity and mortality. No data are available on its impact on CRT-D or CRT-P in advanced HF.MethodsThe database of the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure trial was examined to determine the influence of CRT (CRT-D and CRT-P) on outcomes among diabetic patients. All-cause mortality or hospitalization, all-cause mortality or cardiovascular hospitalization, all-cause mortality or HF hospitalization, and all-cause mortality were analyzed among diabetic patients (n = 622). A Cox proportional hazard model, adjusting for age, gender, New York Heart Association, ischemic status, body mass index, left ventricular ejection fraction, heart rate, QRS, left or right bundle branch block, blood pressure, comorbidities (renal failure, carotid artery disease, peripheral vascular disease, hypertension, coronary artery bypass grafting, and atrial fibrillation), medications, and device (with or without defibrillator), was used to estimate hazard ratios (HRs) and significance.ResultsThe overall outcome of diabetic patients was similar to that of nondiabetic patients in the optimal pharmacologic therapy arm. With CRT, diabetic patients experienced a substantial reduction in all-cause mortality or all-cause hospitalization (HR = 0.77, 95% confidence interval [CI] 62–0.97), all-cause mortality or cardiovascular hospitalization (HR = 0.67, 95% CI 0.53–0.85), all-cause mortality or HF hospitalization (HR = 0.52, 95% CI 0.40–0.69), and all-cause mortality (HR = 0.67, 95% CI 0.45–0.99) compared with optimal pharmacologic therapy. Procedure-related complications and length of stay were identical in diabetic and nondiabetic patients.ConclusionIn diabetic patients with advanced HF, there is a substantial benefit from device therapy with significant improvement in all end points.     

Prevalence of dyssynchrony and relation with long-term outcome in patients after acute myocardial infarction

The impact of left ventricular (LV) dyssynchrony on the long-term outcomes of patients with acute myocardial infarction (AMI) remains unknown. The purpose of the present study was to evaluate the prevalence of LV dyssynchrony after AMI and the potential relation with adverse events. A total of 976 consecutive patients admitted with AMI treated with primary percutaneous coronary intervention were evaluated. Two-dimensional echocardiography was performed <48 hours after admission. LV dyssynchrony was assessed with speckle-tracking imaging and calculated as the time difference between the earliest and latest activated segments. Patients were followed up for the occurrence of all-cause mortality (the primary end point) or the composite secondary end point (heart failure hospitalization and all-cause mortality). Within 48 hours of admission for the index infarction, mean LV dyssynchrony was 61 ± 79 ms, and 14% of the patients demonstrated a ≥130-ms time difference, defined as significant LV dyssynchrony. During a mean follow-up period of 40 ± 17 months, 82 patients (8%) reached the primary end point. In addition, 36 patients (4%) were hospitalized for heart failure. The presence of LV dyssynchrony was associated with an increased risk for all-cause mortality and hospitalization for heart failure during long-term follow-up (adjusted hazard ratio 1.06, 95% confidence interval 1.05 to 1.08, p <0.001, per 10-ms increase). Moreover, LV dyssynchrony provided incremental value over known clinical and echocardiographic risk factors for the prediction of adverse outcomes. In conclusion, LV dyssynchrony is a strong predictor of long-term mortality and hospitalization for heart failure in a population of patients admitted with ST-segment elevation AMI treated with primary percutaneous coronary intervention.     

Chronic heart failure – Impact of the condition on patients and the healthcare system in the Czech Republic: A retrospective cost-of-illness analysis

BackgroundThe number of patients with heart failure is steadily increasing, as are the costs of their treatment. Nearly 70% of the costs associated with the treatment of heart failure are direct medical costs, and 70–80% of these are spent on hospitalizations. The aim of our study is to describe the all-cause hospitalization costs of patients with chronic heart failure (chronic HF) from the perspective of the healthcare system in the Czech Republic.MethodsIn total, 1274 consecutively collected patients discharged in a stable condition from hospitalization for acute heart failure (= index hospitalization) from 2006 to 2012 were followed-up for 2 years. Their all-cause mortality and all-cause hospitalizations were retrospectively evaluated. The in-patient costs were calculated based on the relative weights of DRG codes for particular hospitalization events and on the basic DRG tariff for 2013 (CZK 28,898).ResultsAt the end of the 2-year follow-up, a total of 1511 hospitalizations were recorded. A total of 31.8% of patients survived without any hospitalization, 32.1% of patients survived with at least one hospitalization, and 36.1% of patients died. Re-hospitalizations for acute heart failure accounted for 31.2% of all cases. The average cost for one chronic HF patient hospitalized for any reason was CZK 85,414; the cost for acute heart failure re-hospitalization was CZK 31,320 during the 2-year follow-up period. The cost of all-cause hospitalizations within the first year after the index hospitalization was higher compared to the cost during the second year (CZK 58,528/year vs. CZK 23,082/year). As the estimated number of chronic HF patients is 230,000 (data from the Institute of Health Information and Statistics of the Czech Republic), we can calculate the total cost of all-cause hospitalizations of chronic HF patients to be approximately CZK 7.98 billion per year in the Czech Republic.ConclusionThe data from clinical practice confirm that patients with chronic HF discharged from acute heart failure hospitalization are at high risk of death and/or subsequent hospitalization. The average annual costs for all-cause hospitalizations of CHS patients within the first and second years are CZK 58,528 and CZK 23,082 per patient, respectively. The costs attributed to all-cause hospitalization care of chronic HF patients can be estimated as approximately 7.7% of all annual inpatient expenses of health insurance companies and 2.7% of total healthcare expenditures in the Czech Republic.     

Economic implications of extended-release metoprolol succinate for heart failure in the MERIT-HF trial: a US perspective of the MERIT-HF trial

BACKGROUND: The MERIT-HF trial demonstrated improved survival and fewer hospitalizations for worsening heart failure with extended-release (ER) metoprolol succinate in patients with heart failure. This study sought to estimate the economic implications of this trial from a US perspective. METHODS AND RESULTS: A discrete event simulation was developed to examine the course of patients with heart failure. Characteristics of the population modeled, probabilities of hospitalization and death with standard therapy, and risk reductions with ER metoprolol succinate were obtained from Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) and evaluated in weekly cycles. Direct medical costs were estimated from US databases in 2001 US dollars. Uncertainty in inputs was incorporated and analyses were carried out to estimate events prevented total and net costs. The model predicts that ER metoprolol succinate will prevent approximately 7 deaths and 15 hospitalizations from heart failure per 100 patients over 2 years. Compared with standard therapy alone, this translates to a cost reduction between $395 and $1112 per patient, depending on whether the costs of hospitalizations for other causes are included. Savings were maintained in 90% of the simulations. CONCLUSION: This analysis predicts that the positive effect of ER metoprolol succinate on mortality and morbidity demonstrated in MERIT-HF leads to substantial savings.     

Beta-blocker treatment of chronic systolic heart failure improves prognosis even in patients meeting one or more exclusion criteria of the MERIT-HF study.

AIMS: Improved prognosis of patients with chronic systolic heart failure by treatment with beta-blockers has been shown in several randomized controlled multicentre trials. However, in clinical practice only a part of heart failure patients meet the inclusion criteria of these trials. The present study evaluates whether reduction of mortality by beta-blockers also can be achieved in patients presenting one or more exclusion criteria of the MERIT-HF trial. METHODS AND RESULTS: From the Ludwigshafen Heart Failure Registry 675 patients with chronic systolic heart failure consecutively enrolled between January 1995 and June 2004 were divided in two groups either meeting the inclusion criteria of the MERIT-HF trial ('trial patients': n = 278, 60% treated with beta-blockers) or not ('non-trial patients': n = 397; 51% treated with beta-blockers). The distribution of the MERIT-HF exclusion criteria in the group of 'non-trial patients' was as follows: acute myocardial infarction 9.6%; systolic blood pressure <100 mmHg 7.5%; chronic obstructive lung disease 33.2%; other serious diseases potentially limiting prognosis 16.9%; acutely performed or planned ICD, bypass surgery, PCI, heart transplantation: 17.1, 15.9, 7.8, and 4.8%, respectively. Median follow-up was 31.3 months (upper/lower quartile 16.3/50.0 months). All-cause mortality was significantly reduced by beta-blocker treatment not only in 'trial patients' (adjusted hazard ratio 0.57, 95% CI 0.38-0.86) but also in 'non-trial patients' (adjusted hazard ratio 0.72, 95% CI 0.53-0.97). CONCLUSION: In clinical practice only the smaller part of the population to be treated for chronic systolic heart failure meets the inclusion criteria of the MERIT-HF study. However, beta-blocker treatment is associated with a significantly reduced long-term mortality even in patients meeting one or more exclusion criteria of the MERIT-HF study.     

Effects of sodium-glucose co-transporter-2 inhibitors by background cardiovascular medications: A systematic review and meta-analysis

Aim

To explore whether the beneficial cardiovascular (CV) effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease.

Methods

We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs).

Results

We included 12 trials comprising 83 804 patients. SGLT-2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), b-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b-blocker plus MRA, or an ARNI plus b-blocker plus MRA (HRs ranged from 0.61 to 0.83; P > .1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all-cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate.

Conclusions

The benefit of SGLT-2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified.     

Digoxin use and heart failure outcomes: results from the Valsartan Heart Failure Trial (Val-HeFT)

Several retrospective studies have raised concerns regarding digoxin therapy in select subgroups of heart failure patients. To assess the impact of digoxin therapy on outcomes in the current era of heart failure therapy, the authors analyzed data representing 5010 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) to examine the relationship of baseline digoxin use and all-cause mortality, first morbid event, and heart failure hospitalizations. At baseline, 3374 patients (67%) were receiving digoxin therapy and 1636 (33%) were not. Patients receiving digoxin had features of worse heart failure with higher New York Heart Association class and lower blood pressure, ejection fraction, and β-blocker use (32.1% vs 40.8%). Digoxin use was associated with worse mortality (21.1 vs 15.0%, P<.001), first morbid event (34.6 vs 21.7, P<.001), and HF hospitalization rate (19.1 vs 10.1%, P<.001). After adjustment for baseline group differences including medical therapy and baseline rhythm, patients receiving digoxin remained at a higher risk for all-cause mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.05-1.57), first morbid event (HR, 1.35; 95% CI, 1.15-1.59), and heart failure hospitalization (HR, 1.41; 95% CI, 1.12-1.78). These results remained materially unchanged with propensity matched analysis. No benefit with digoxin use was observed in this study, underscoring the need to reassess the role of digoxin in the contemporary management of heart failure.     

Glomerular filtration rate and N-terminal pro-brain natriuretic peptide as predictors of cardiovascular mortality in vascular patients.

OBJECTIVES: The purpose of this work was to assess the prognostic role of glomerular filtration rate (GFR) and NT-terminal pro-B-type natriuretic peptide (NT-proBNP) for mortality end points in the vascular population. BACKGROUND: The GFR and NT-proBNP have been shown to predict mortality end points in free-living and limited vascular populations, independent of traditional risk factors. However, their prognostic power in an unrestricted vascular population is poorly understood. METHODS: A total of 412 subjects from a vascular cohort with a history of either peripheral arterial disease (PAD) and/or other cardiovascular disease (CVD) were included in this prospective cohort analysis and followed for an average of 6.7 years. Outcome variables were all-cause mortality, ischemic heart disease (IHD) mortality, and any cardiovascular mortality. The prognostic roles of GFR and NT-proBNP levels were determined using multivariate survival analysis. RESULTS: Higher GFR (per 10 ml/min/1.73 m2) was significantly protective for all-cause mortality (hazard ratio [HR] 0.81, p < 0.001), IHD mortality (HR 0.82, p = 0.008), and CVD mortality (HR 0.84, p = 0.005). Conversely, NT-proBNP was not a significant predictor of any mortality end point. The GFR showed the strongest association in subjects with a history of other CVD. Although NT-proBNP did not demonstrate a significant prognostic role in any of the subgroups, the data were suggestive for patients with PAD alone. CONCLUSIONS: Glomerular filtration rate was a robust predictor of all-cause, IHD, and cardiovascular mortality in the vascular population, particularly in those with a history of other CVD, while NT-proBNP showed a suggestive association limited to the group with PAD only. These findings suggest that these markers must be selectively applied in the vascular population for greatest clinical utility.     

Effect of hormone therapy on mortality rates among women with heart failure and coronary artery disease

Randomized, controlled trial data from the Heart and Estrogen-progestin Replacement Study were used to evaluate the effect of estrogen plus progestin use on all-cause mortality in women with heart failure and coronary disease. Over the 4.1-year follow-up, estrogen plus progestin use had no effect on all-cause mortality (hazard ratio 1.0, 95% confidence interval 0.7 to 1.4, p = 0.8) in women with heart failure and coronary disease.     

Adverse Events After Initiating Angiotensin-Converting Enzyme Inhibitor/Angiotensin II Receptor Blocker Therapy in Individuals with Heart Failure and Multimorbidity

BackgroundCurrent clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. However, evidence is lacking on whether routine follow-up testing reduces therapy-related adverse events in adults with heart failure and if multimorbidity influences the association between laboratory testing and these adverse events.MethodsWe conducted a retrospective cohort study among adults with heart failure from 4 US integrated health care delivery systems. Multimorbidity was defined using counts of chronic conditions. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACEI or ARB therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression.ResultsWe identified 3629 matched adults with heart failure initiating ACEI or ARB therapy between January 1, 2005, and December 31, 2012. Follow-up testing was not significantly associated with 30-day all-cause mortality (adjusted hazard ratio [aHR] 0.45, 95% confidence interval [CI] 0.14; 1.39) and hospitalization with hyperkalemia (aHR 0.73, 95% CI, 0.33; 1.61). However, follow-up testing was significantly associated with hospitalization with acute kidney injury (aHR, 1.40, 95% CI, 1.01; 1.94). Interaction between multimorbidity burden and follow-up testing was not statistically significant in any of the outcome models examined.ConclusionsRoutine laboratory monitoring after ACEI or ARB therapy initiation was not associated with risk of 30-day all-cause mortality or hospitalization with hyperkalemia across the spectrum of multimorbidity burden in a cohort of patients with heart failure.     

Digoxin Benefit Varies by Risk of Heart Failure Hospitalization: Applying the Tufts MC HF Risk Model

Background

Digoxin has been shown to reduce heart failure hospitalizations with a neutral effect on mortality. It is unknown whether there is heterogeneity of treatment effect for digitalis therapy according to predicted risk of heart failure hospitalization.

The Influence of Renal Function on Clinical Outcome and Response to β-Blockade in Systolic Heart Failure: Insights From Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF)

BackgroundLimited information is available on the risk and impact of renal dysfunction on the response to β-blockade and mode of death in systolic heart failure (HF).Methods and ResultsRenal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR_MDRD > 60 (n = 2496), eGFR_MDRD 45 to 60 (n = 976), and eGFR_MDRD < 45 mL/min per 1.73m² body surface area (n = 493). Hazard ratio (HR) was estimated with Cox proportional hazards models adjusted for prespecified risk factors. Placebo patients with eGFR < 45 had significantly higher risk than those with eGFR > 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR < 45 and eGFR > 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR < 45. For total mortality, metoprolol CR/XL vs placebo: HR, 0.41 (95% CI. 0.25 to 0.68; P < .001) in those with eGFR < 45 compared with HR, 0.71 (95% CI, 0.54 to 0.95; P < .021) for those with eGFR > 60; corresponding data for the combined end point was HR, 0.44 (95% CI, 0.31 to 0.63; P < .0001) and HR, 0.75 (0.62 to 0.92; P = .005, respectively; P = .095 for interaction by treatment for total mortality; P = .011 for combined end point). Metoprolol CR/XL was well tolerated in all 3 renal function subgroups.ConclusionsRenal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR < 45 as in those with eGFR > 60.