Publications by authors named "Marc A Pfeffer"

423 Publications

Practical Recommendations on Quantifying and Interpreting Treatment Effects in the Presence of Terminal Competing Risks: A Review.

JAMA Cardiol 2021 Dec 1. Epub 2021 Dec 1.

Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Importance: In a comparative trial, the time to a clinical event is often a key end point. However, the occurrence of a terminal event, such as death or premature study discontinuation, may preclude observation of this outcome. Although various methods for handling competing risks are available, no specific recommendations have been made for scenarios encountered in practice, especially when the terminal event profiles of the study arms are dissimilar. Moreover, appropriate methods for a desirable outcome, such as live hospital discharge, have seldom been discussed.

Observations: Several of the most commonly used methods are reviewed. The first regards the terminal event as censoring and applies standard survival analysis to the event of interest. The between-group difference is usually summarized by the cause-specific hazard ratio. This summary measure is inappropriate when the new therapy markedly prolongs time to the terminal event. Moreover, the corresponding Kaplan-Meier curve for the end point of interest is uninterpretable. The second method is to use the cumulative incidence curve, which is the probability of experiencing the event of interest by each time point, acknowledging that patients who have died will never experience the event. However, the resulting pseudo hazard ratio is difficult to interpret. With a proper alternative summary measure, this approach works well for a desirable outcome but may not for an undesirable outcome. The third method focuses on the event-free survival time by combining information from occurrences of the terminal event and the event of interest simultaneously. This clinically interpretable method naturally accounts for differences in terminal event rates when comparing treatments with respect to the time to an undesirable outcome.

Conclusions And Relevance: This article enhances our understanding of each method's advantages and shortcomings and assists practitioners in choosing appropriate methods for handling competing risk problems in practice.
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http://dx.doi.org/10.1001/jamacardio.2021.4932DOI Listing
December 2021

Mode of Death in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF Trial.

Circ Heart Fail 2021 Nov 22:CIRCHEARTFAILURE121008597. Epub 2021 Nov 22.

Cardiovascular Division, Brigham and Women's Hospital, Boston, MA. (A.S.D., M.V., B.L.C., E.B., P.F., M.A.P., S.D.S.).

Background: Patients with heart failure (HF) and preserved left ventricular ejection fraction comprise a heterogeneous group including some with mildly reduced EF. We hypothesized that mode of death differs by EF in ambulatory patients with HF and preserved left ventricular ejection fraction.

Methods: PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) compared clinical outcomes in 4796 patients with chronic HF and EF ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the mode of death in relation to baseline EF in logistic regression models and the effect of randomized treatment on cause-specific death in Cox regression models. Nonlinear relationships with continuous EF were modelled using quadratic and cubic terms.

Results: Of 691 deaths during the trial, 416 (60%) were ascribed to cardiovascular, 220 (32%) to noncardiovascular, and 55 (8%) to unknown causes. Of cardiovascular deaths, 154 (37%) were due to sudden death, 118 (28%) were due to HF, 35 (8%) to stroke, 27 (6%) to myocardial infarction, and 82 (20%) to other cardiovascular causes. Rates of all-cause, cardiovascular, and sudden death were higher in those with lower left ventricular ejection fraction (all <0.001), while rates of non-cardiovascular death were greater in patients with higher EF. Sacubitril/valsartan did not reduce overall death, cardiovascular death, or sudden death compared with valsartan, irrespective of baseline EF (all for interaction >0.30).

Conclusions: Among patients with HF and preserved left ventricular ejection fraction enrolled in PARAGON-HF, the proportion of cardiovascular and sudden death were higher in those with lower left ventricular EF, and the proportion of noncardiovascular death rose with EF. Regardless of EF, sacubitril/valsartan did not reduce death from any cause compared with valsartan.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.121.008597DOI Listing
November 2021

Impact of Chronic Obstructive Pulmonary Disease in Patients With Heart Failure With Preserved Ejection Fraction: Insights From PARAGON-HF.

J Am Heart Assoc 2021 Nov 19:e021494. Epub 2021 Nov 19.

BHF Glasgow Cardiovascular Research CentreUniversity of Glasgow United Kingdom.

Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; <0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; <0.001) and more frequent history of heart failure hospitalization (54% versus 47%; <0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 μmol/L versus 96 μmol/L) and neutrophil-to-lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25-1.83), total heart failure hospitalization 1.54 (95% CI, 1.24-1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10-1.82), and all-cause death (adjusted HR, 1.52; 95% CI, 1.25-1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without. Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
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http://dx.doi.org/10.1161/JAHA.121.021494DOI Listing
November 2021

Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction.

N Engl J Med 2021 11;385(20):1845-1855

From the Cardiovascular Division (M.A.P., B.C., S.D.S., K.J., E.B.) and the Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division (E.B.), Brigham and Women's Hospital and Harvard Medical School, Boston; the Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto (E.F.L.), and the Heart Failure and Preventive Cardiology Programs, Department of Veterans Affairs Greater Los Angeles, University of California, Los Angeles, Los Angeles (F.V.M.) - both in California; Duke University Medical Center, Durham, NC (C.B.G.); Rigshospitalet, Blegdamsvej, University of Copenhagen (L.K.), and the Department of Cardiology, Herlev-Gentofte University Hospital (M. Schou) - both in Copenhagen; National Association of Hospital Cardiologists Research Center, Florence (A.P.M.), and the Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo (M. Senni) - both in Italy; Washington University School of Medicine, St. Louis (D.L.M.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Montreal Heart Institute, University of Montreal, Montreal (J.-L.R.); Université de Paris, Assistance Publique-Hôpitaux de Paris, French Alliance for Cardiovascular Trials and INSERM Unité 1148, Paris (P.G.S.); Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo (O.B.); the Department of Cardiovascular Diseases, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia (M.C.); the Department of Cardiovascular Medicine, Flinders Medical Centre, Adelaide, SA, Australia (C.G.D.P.); Baylor Soltero CV Research Center, Baylor Scott and White Heart and Vascular Hospital, Dallas (C.E.); Cardiology Service, Sanatorio Modelo Quilmes, Quilmes, Argentina (A.F.); the Department of Cardiology, German Center for Cardiovascular Research Partner Site Berlin, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin (U.L.); Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (R.M.); the Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); Acibadem City Clinic Cardiovascular Center, Sofia, Bulgaria (I.P.); National Heart Center Singapore, Singapore (D.S.); the Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (P.M.); and Novartis, East Hanover, NJ (M.L., Y.Z., J.G.).

Background: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking.

Methods: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first.

Results: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group.

Conclusions: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).
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http://dx.doi.org/10.1056/NEJMoa2104508DOI Listing
November 2021

Outpatient diuretic intensification as endpoint in heart failure with preserved ejection fraction trials: an analysis from TOPCAT.

Eur J Heart Fail 2021 Nov 9. Epub 2021 Nov 9.

Inserm, Centre d'Investigations Cliniques Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Université de Lorraine, Nancy, France.

Aims: Outpatient treatment for the worsening of signs and symptoms of heart failure (HF) is usually not incorporated in the main outcomes of HF trials. Patients with HF and a preserved ejection fraction (HFpEF) may experience frequent episodes of outpatient worsening HF. The aim of this study was to evaluate the frequency, prognostic impact, and the effect of spironolactone on outpatient diuretic intensification (ODI), among 1767 patients enrolled in TOPCAT-Americas.

Methods And Results: Time-updated Cox models and win ratio analysis. ODI was defined by a post-randomization loop diuretic dose increase or new initiation. The median follow-up was 2.9 years. At baseline, 1362 (77%) patients were taking loop diuretics. During the follow-up, 685 (38.8%) patients experienced ODI, which was associated with a higher risk of subsequent cardiovascular events and death [adjusted hazard ratio (HR) for HF hospitalization or cardiovascular death 1.67, 95% confidence interval (CI) 1.36-2.04; HR for cardiovascular death 2.17, 95% CI 1.64-2.87); and HR for all-cause mortality 1.75, 95% CI 1.41-2.16] (p < 0.001 for all outcomes). Adding ODI to the composite of HF hospitalization or cardiovascular death increased the event rate by three-fold in the placebo group (from 10.4 to 29.9 events per 100 person-years). Spironolactone treatment led to a 26% relative reduction of the extended composite of ODI or HF hospitalization or cardiovascular death (HR 0.74, 95% CI 0.65-0.85; p < 0.001) compared with a 16% relative reduction of HF hospitalization or cardiovascular death (HR 0.84, 95% CI 0.70-0.99; p = 0.044). Using win ratio provided similar estimates.

Conclusion: In HFpEF, ODI was frequent and independently associated with subsequent cardiovascular events. Spironolactone significantly reduced an extended composite outcome incorporating ODI.
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http://dx.doi.org/10.1002/ejhf.2376DOI Listing
November 2021

Association of Hyper-Polypharmacy With Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

Circ Heart Fail 2021 Nov 22;14(11):e008293. Epub 2021 Oct 22.

Minneapolis VA Center for Care Delivery and Outcomes Research and University of Minnesota Medical School (O.V.).

Background: Polypharmacy is associated with a poor prognosis in the elderly, however, information on the association of polypharmacy with cardiovascular outcomes in heart failure with preserved ejection fraction is sparse. This study sought to investigate the relationship between polypharmacy and adverse cardiovascular events in patients with heart failure with preserved ejection fraction.

Methods: Baseline total number of medications was determined in 1758 patients with heart failure with preserved ejection fraction enrolled in the Americas regions of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), by 3 categories: nonpolypharmacy (<5 medications), polypharmacy (5-9), and hyper-polypharmacy (≥10). We examined the relationship of polypharmacy status with the primary outcome (cardiovascular death, HF hospitalization, or aborted cardiac arrest), hospitalizations for any reason, and serious adverse events.

Results: The proportion of patients taking 5 or more medications was 92.5% (inclusive of polypharmacy [38.7%] and hyper-polypharmacy [53.8%]). Over a 2.9-year median follow-up, compared with patients with polypharmacy, hyper-polypharmacy was associated with an increased risk for the primary outcome, hospitalization for any reason and any serious adverse events in the univariable analysis, but not significantly associated with mortality. After multivariable adjustment for demographic and comorbidities, hyper-polypharmacy remained significantly associated with an increased risk for hospitalization for any reason (hazard ratio, 1.22 [95% CI, 1.05-1.41]; =0.009) and any serious adverse events (hazard ratio, 1.23 [95% CI, 1.07-1.42]; =0.005), whereas the primary outcome was no longer statistically significant.

Conclusions: Hyper-polypharmacy was common and associated with an elevated risk of hospitalization for any reason and any serious adverse events in patients with heart failure with preserved ejection fraction. There were no significant associations between polypharmacy status and mortality.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.008293DOI Listing
November 2021

Growth differentiation factor 15 predicts poor prognosis in patients with heart failure and reduced ejection fraction and anemia: results from RED-HF.

Clin Res Cardiol 2021 Oct 5. Epub 2021 Oct 5.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Nydalen, P. B. 4950, 0424, Oslo, Norway.

Aims: We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia METHODS AND RESULTS: Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23-1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38-2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin.

Conclusions: In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients.
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http://dx.doi.org/10.1007/s00392-021-01944-6DOI Listing
October 2021

Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction.

Eur Heart J 2021 09;42(36):3741-3752

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK.

Aims: Patients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on 'apparent resistant hypertension' in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril-valsartan with valsartan.

Methods And Results: In this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). 'Apparent resistant hypertension' was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. 'Apparent mineralocorticoid receptor antagonist (MRA)-resistant' hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril-valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6-19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7-14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05-1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril-valsartan vs. valsartan in patients with apparent resistant hypertension [-4.8 (-7.0 to -2.5) and 3.9 (-6.6 to -1.3) mmHg] and apparent MRA-resistant hypertension [-8.8 (-14.0 to -3.5) and -6.3 (-12.5 to -0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril-valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30-2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18-5.89).

Conclusion: Sacubitril-valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA.

Clinical Trial Registration: PARAGON-HF: ClinicalTrials.gov Identifier NCT01920711.
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http://dx.doi.org/10.1093/eurheartj/ehab499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455346PMC
September 2021

Prognostic Value of Minimal Left Atrial Volume in Heart Failure With Preserved Ejection Fraction.

J Am Heart Assoc 2021 08 30;10(15):e019545. Epub 2021 Jul 30.

Cardiovascular Division Brigham and Women's Hospital and Harvard Medical School Boston MA.

Background Maximal left atrial (LA) volume is reported by most echocardiography laboratories and is associated with clinical outcomes in patients with heart failure (HF). Recent studies suggest that minimal LA volume may better reflect left ventricular filling pressure and may be more prognostic than maximal LA volume. This study assessed the prognostic value of indexed minimal LA volume (LAVImin) in patients with HF with preserved ejection fraction. Methods and Results We assessed the relationship of LAVImin with a primary composite end point of cardiovascular death, aborted cardiac death, or HF hospitalization in 347 patients with HF with preserved ejection fraction enrolled from the Americas region in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We compared LAVImin with indexed maximal LA volume with respect to their prognostic values. In addition, we assessed if LA functional parameters provide additional prognostic information over LAVImin. During a median follow-up of 2.5 years, 107 patients (31%) experienced a primary composite end point. LAVImin was associated with increased risk of a primary composite outcome (hazard ratio [HR], 1.35; 95% CI, 1.12-1.61) and HF hospitalization alone (HR, 1.42; 95% CI, 1.17-1.71) after adjusting for clinical confounders and ejection fraction. In contrast, indexed maximal LA volume was not related to the primary composite outcome, but related to HF alone (HR, 1.25; 95% CI, 1.02-1.54). In comparison with indexed maximal LA volume, LAVImin was significantly more prognostic for primary composite outcome ( for comparison=0.032). Both LA emptying fraction and LA strain were prognostic of primary outcome independent of LAVImin (all <0.05). Conclusions In patients with HF with preserved ejection fraction, LAVImin was more predictive of cardiovascular outcome than indexed maximal LA volume, suggesting this measure may be more physiologically relevant and might better identify patients at high risk for cardiovascular events. LA functional parameters provide prognostic information independent of LAVImin. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00094302.
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http://dx.doi.org/10.1161/JAHA.120.019545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475710PMC
August 2021

Integrating High-Sensitivity Troponin T and Sacubitril/Valsartan Treatment in HFpEF: The PARAGON-HF Trial.

JACC Heart Fail 2021 09 7;9(9):627-635. Epub 2021 Jul 7.

Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address:

Objectives: This study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF).

Background: hs-TnT is a marker of myocardial injury in HF.

Methods: The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT.

Results: hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07).

Conclusions: Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan.
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http://dx.doi.org/10.1016/j.jchf.2021.04.009DOI Listing
September 2021

Influence of study discontinuation during the run-in period on the estimated efficacy of sacubitril/valsartan in the PARAGON-HF trial.

Eur J Heart Fail 2021 Jun 11. Epub 2021 Jun 11.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Aims: The 4822 patients randomized in the PARAGON-HF trial were a subset of 5746 initially eligible patients who entered sequential run-in periods. We identified patient factors associated with study discontinuation during the run-in period and estimated the implications of these discontinuations for the overall study result.

Methods And Results: We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run-in period. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion. A total of 924 (16.1%) subjects failed to complete the run-in period. In multivariable models, non-completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (HF) hospitalization, and lack of prior use of renin-angiotensin system inhibitors or beta-blocker. In repeat analysis of the effect of randomized treatment in PARAGON-HF giving greater weight to participants resembling those who failed to complete the run-in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio 0.86; 95% confidence interval 0.74-1.00).

Conclusion: Patients with more advanced HF were at higher risk for non-completion of the run-in period in PARAGON-HF. Re-analysis of study outcomes accounting for the effect of run-in non-completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan.
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http://dx.doi.org/10.1002/ejhf.2262DOI Listing
June 2021

NT-proBNP versus routine clinical risk factors as a predictor of cardiovascular events or death in people with dysglycemia - A brief report from the ORIGIN trial.

J Diabetes Complications 2021 07 16;35(7):107928. Epub 2021 Apr 16.

The Population Health Research Institute and the Department of Medicine, McMaster University and Hamilton Health Sciences, Hamilton, Canada.

In patients with diabetes and cardiovascular or renal comorbidities, circulating levels of the N-terminal fragment of prohormone B-type natriuretic peptide (NT-proBNP) have similar discriminatory ability as multivariate models for prediction of cardiovascular events or death. We validated this finding in patients with dysglycemia not selected for co-existing cardiorenal diseases.
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http://dx.doi.org/10.1016/j.jdiacomp.2021.107928DOI Listing
July 2021

Incidence and Outcomes of Pneumonia in Patients With Heart Failure.

J Am Coll Cardiol 2021 04;77(16):1961-1973

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Background: The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).

Objectives: This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials.

Methods: The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide).

Results: In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58).

Conclusions: The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711).
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http://dx.doi.org/10.1016/j.jacc.2021.03.001DOI Listing
April 2021

Global Differences in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

Circ Heart Fail 2021 04 19;14(4):e007901. Epub 2021 Apr 19.

National Heart Centre Singapore (J.T., C.S.P.L.).

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial.

Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region.

Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction >0.05).

Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007901DOI Listing
April 2021

Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): design and baseline characteristics.

Eur J Heart Fail 2021 06 22;23(6):1040-1048. Epub 2021 Apr 22.

TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

Aims: Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial.

Methods And Results: PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate <60 mL/min/1.73 m , diabetes, prior myocardial infarction, atrial fibrillation, LVEF <30%, Killip class ≥III, ST-elevation myocardial infarction without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints (cardiovascular death, HF hospitalization or outpatient development of HF). Randomization of 5669 patients occurred 4.3 ± 1.8 days from presentation with index AMI. The mean age was 64 ± 12 years, 24% were women. The majority (76%) qualified with ST-segment elevation myocardial infarction; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were in Killip class ≥II.

Conclusions: Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and cardiovascular death following AMI.
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http://dx.doi.org/10.1002/ejhf.2191DOI Listing
June 2021

Worsening Heart Failure Episodes Outside a Hospital Setting in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

JACC Heart Fail 2021 05 7;9(5):374-382. Epub 2021 Apr 7.

Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objectives: This study sought to evaluate the frequency and prognostic implications of urgent heart failure (HF) visits in a large global clinical trial of HF with preserved ejection fraction (HFpEF).

Background: Episodes of worsening HF managed without hospitalization are common and prognostically important in HF with reduced ejection fraction (EF). The significance of these ambulatory worsening HF events in HFpEF is uncertain.

Methods: PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) randomly assigned 4,796 patients with HFpEF (≥45%) to treatment with sacubitril/valsartan vs. valsartan with a primary composite endpoint of total HF hospitalizations and cardiovascular death. Urgent ambulatory HF visits requiring intravenous diuretic treatment were prospectively collected and adjudicated by a blinded committee. We examined the effect of study treatment on a prespecified expanded composite of cardiovascular death and worsening HF events (including HF hospitalizations and urgent HF visits) and the effect of each type of HF event on subsequent mortality.

Results: Of 884 first worsening HF events, 66 (7.5%) were urgent HF visits. Patients whose first episode of worsening HF event was an urgent visit had similar age, comorbidities, baseline N-terminal prohormone of B-type natriuretic peptide, and Meta-Analysis Global Group in Chronic Heart Failure risk scores to those in whom the first HF event was a hospitalization (all comparisons p > 0.05). Regardless of the treatment setting, patients with a first episode of worsening HF had higher rates of subsequent death (19.2 per 100 patient-years; 95% confidence interval [CI]: 16.9 to 21.8 for HF hospitalization and 10.1 per 100 patients-years; 95% CI: 5.4 to 18.7 for urgent HF visit) compared with those who did not experience worsening HF (death rate 4.0 per 100 patient-years; 95% CI: 3.6 to 4.4). Including total urgent HF visits in the composite study endpoint added 95 total events and would have shortened the trial duration needed for event accrual. The addition of urgent HF visits in a prespecified composite endpoint reinforced the treatment efficacy of sacubitril/valsartan compared with valsartan (rate ratio 0.86; 95% CI: 0.75 to 0.99; p = 0.040).

Conclusions: Like HF hospitalizations, worsening HF events treated in the ambulatory setting are prognostically important in HFpEF. Inclusion of these events in the composite primary endpoint underscores the benefit of sacubitril/valsartan compared with valsartan in PARAGON-HF. (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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http://dx.doi.org/10.1016/j.jchf.2021.01.014DOI Listing
May 2021

Role of Adenylate Cyclase 9 in the Pharmacogenomic Response to Dalcetrapib: Clinical Paradigm and Molecular Mechanisms in Precision Cardiovascular Medicine.

Circ Genom Precis Med 2021 04 2;14(2):e003219. Epub 2021 Apr 2.

Montreal Heart Institute (D.R., M.R.B., M.-P.D., J.-C.T.).

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 () gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.
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http://dx.doi.org/10.1161/CIRCGEN.121.003219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284386PMC
April 2021

Burden of Heart Failure Signs and Symptoms, Prognosis, and Response to Therapy: The PARAGON-HF Trial.

JACC Heart Fail 2021 05 10;9(5):386-397. Epub 2021 Mar 10.

Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objectives: This study investigated the prognostic importance of heart failure (HF) signs and symptoms in patients with heart failure and preserved ejection fraction (HFpEF), and the effect of sacubitril/valsartan on HF signs and symptoms.

Background: In patients with HFpEF, worsening of HF symptoms, as a marker of cardiac decompensation, is frequently the reason for hospitalization. In this heterogenous disease entity, the prognostic value of HF signs and symptoms with regard to cardiovascular (CV) outcomes is poorly defined.

Methods: The authors examined the association between baseline HF signs and symptoms (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, and third heart sound) as well as burden of these HF signs and symptoms (classified as ≤2 and ≥3 HF signs and symptoms) and the primary composite of total HF hospitalizations and CV death, its components, and all-cause death in 4,725 patients enrolled in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HFpEF) with available signs and symptoms at randomization. Response to sacubitril/valsartan on the basis of the presence of signs and symptoms was evaluated. Effects of sacubitril/valsartan on signs and symptoms over time were assessed using binary repeated-measures logistic regression.

Results: Patients with high (≥3) burden of HF signs and symptoms (n = 1,772 [38%]) were more commonly women, had slightly lower left ventricular ejection fractions, higher body mass index, and more advanced New York Heart Association functional class compared with patients with low (≤2) burden (n = 2,953 [62%]) (p < 0.001 for all). Levels of N-terminal pro-B-type natriuretic peptide did not differ significantly between groups (p = 0.14). Greater burden of signs and symptoms was associated with higher risk for total HF hospitalizations and CV death (rate ratio [RR]: 1.50; 95% confidence interval [CI]: 1.30 to 1.74) and all-cause death (RR: 1.41; 95% CI: 1.21 to 1.65). Among individual signs and symptoms, orthopnea (RR: 1.29; 95% CI: 1.04 to 1.61) and rales (RR: 1.52; 95% CI: 1.10 to 2.10) were most predictive of the primary endpoint. Treatment response to sacubitril/valsartan was not significantly modified by burden of HF signs and symptoms (p for interaction = 0.08), though patients with orthopnea appeared to derive greater benefit from sacubitril/valsartan (RR: 0.67; 95% CI: 0.49 to 0.90) than those without orthopnea (RR: 0.97; 95% CI: 0.82 to 1.14; p for interaction = 0.04). Compared with valsartan, sacubitril/valsartan did not significantly decrease overall burden of HF signs and symptoms over time (odds ratio: 0.84; 95% CI: 0.67 to 1.07) but did reduce exertional dyspnea (odds ratio: 0.76; 95% CI: 0.63 to 0.93).

Conclusions: High burden of HF signs and symptoms, particularly the presence of orthopnea and rales, portends a higher risk for adverse CV events in patients with HF with preserved ejection fraction. Sacubitril/valsartan did not significantly decrease the burden of HF signs and symptoms over time but did reduce exertional dyspnea relative to valsartan. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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http://dx.doi.org/10.1016/j.jchf.2021.01.011DOI Listing
May 2021

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

Circ Heart Fail 2021 03 12;14(3):e008052. Epub 2021 Mar 12.

Division of Cardiovascular, Brigham and Women's Hospital, Boston, MA (L.E.R., B.L.C., M.A.P., A.S.D., S.D.S.).

Background: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction.

Methods: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality.

Results: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], <0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], <0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction <0.05 for both outcomes).

Conclusions: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.008052DOI Listing
March 2021

Spironolactone in Patients With Heart Failure, Preserved Ejection Fraction, and Worsening Renal Function.

J Am Coll Cardiol 2021 03;77(9):1211-1221

Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address:

Background: Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood.

Objectives: The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF.

Methods: In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term.

Results: WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF.

Conclusions: Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF.
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http://dx.doi.org/10.1016/j.jacc.2020.12.057DOI Listing
March 2021

Non-fatal cardiovascular events preceding sudden cardiac death in patients with an acute myocardial infarction complicated by heart failure: insights from the high-risk myocardial infarction database.

Eur Heart J Acute Cardiovasc Care 2021 Apr;10(2):127-131

National Institute of Health and Medical Research Center for Clinical Multidisciplinary Research, INSERM U1116, Université de Lorraine, Inserm, Centre d'Investigations cliniques-plurithématique 1433, Inserm U1116; CHRU Nancy; F-CRIN INI-CRCT network, Nancy, France.

Aims: Among patients with acute myocardial infarction (AMI) complicated by heart failure [HF; clinical HF or left ventricular (LV) systolic dysfunction], we explored the probability of subsequent non-fatal cardiovascular (CV) events and sudden cardiac death (SCD).

Methods And Results: The high-risk myocardial infarction (HRMI) database contains 28 771 patients with signs of HF or reduced LV ejection fraction (<40%) after AMI. We evaluated the temporal association between SCD with preceding non-fatal CV event [HF hospitalization, recurrent myocardial infarction (MI), or stroke]. Median follow-up was 1.9 years. Mean age was 65.0 ± 11.5 years and 70% were male. The incidence of CV death was 7.9 per 100 patient-years and for SCD was 3.1 per patient-years (40% of CV deaths). The incidence of SCD preceded by HF hospitalization was greater than SCD without preceding HF hospitalization (P < 0.05). However, overall, SCD was less likely to be preceded by a non-fatal CV event compared to other causes of death: 9.6% of SCD events were preceded by an MI (vs. 46.6% for non-sudden CV death); 17.0% of SCD events were preceded with an HF hospitalization (vs. 25.4% for non-sudden CV death); and 2.7% of SCD events were preceded by stroke (vs.12.9% for non-sudden CV death).

Conclusion: Among patients with AMI complicated by HF, SCD, compared with other causes of death, was less likely to be preceded by a non-fatal CV event. As patients are less likely to have preceding non-fatal CV events to alert the healthcare team of a possible impending SCD event, additional strategies for risk stratification for SCD are needed.
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http://dx.doi.org/10.1093/ehjacc/zuaa012DOI Listing
April 2021

Serum potassium and outcomes in heart failure with preserved ejection fraction: a post-hoc analysis of the PARAGON-HF trial.

Eur J Heart Fail 2021 05 8;23(5):776-784. Epub 2021 Mar 8.

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan.

Methods And Results: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up.

Conclusions: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.
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http://dx.doi.org/10.1002/ejhf.2134DOI Listing
May 2021

Impact of diabetes on serum biomarkers in heart failure with preserved ejection fraction: insights from the TOPCAT trial.

ESC Heart Fail 2021 04 12;8(2):1130-1138. Epub 2021 Jan 12.

Division of Cardiology, Montreal Heart Institute and Université de Montréal, 5000 rue Bélanger, Montreal, QC, H1T 1C8, Canada.

Aims: Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non-diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs. no diabetes (non-DM) and the impact of spironolactone on these biomarkers. This study aims to address such gaps in the literature.

Methods And Results: Biomarkers were measured at randomization and at 12 months in 248 patients enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist's North American cohort. At baseline, DM patients had significantly lower estimated glomerular filtration rate and higher high-sensitivity C-reactive protein, pro-collagen type III amino-terminal peptide, tissue inhibitor of metalloproteinase 1 (TIMP-1), and galectin-3 levels than those without diabetes. There was a significantly larger 12 month increase in levels of high-sensitivity troponin T (hs-TnT), a marker of myocyte death, in DM patients. Elevated pro-collagen type III amino-terminal peptide and galectin-3 levels were associated with an increased risk of the primary outcome (cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization) in DM patients, but not in those without diabetes. A statistically significant interaction between spironolactone and diabetes status was observed for hs-TnT and for TIMP-1, with greater biomarker reductions among those with diabetes treated with spironolactone.

Conclusions: The presence of diabetes is associated with higher levels of cardiac, profibrotic, and proinflammatory biomarkers in HFpEF. Spironolactone appears to alter the determinants of extracellular matrix remodelling in an anti-fibrotic fashion in patients with diabetes, reflected by changes in hs-TnT and TIMP-1 levels over time.
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http://dx.doi.org/10.1002/ehf2.13153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006665PMC
April 2021

Pulse Pressure, Prognosis, and Influence of Sacubitril/Valsartan in Heart Failure With Preserved Ejection Fraction.

Hypertension 2021 02 28;77(2):546-556. Epub 2020 Dec 28.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (K.S., B.C., M.M., M.A.P., S.D.S.).

Arterial stiffness is increased with increasing age, and pulse pressure (PP), a marker of arterial stiffness, is a predictor of incident cardiovascular disease and mortality. However, the prognostic relevance of PP in heart failure (HF) with preserved ejection fraction has not been fully understood. We studied 4796 patients with HF with preserved ejection fraction from the PARAGON-HF trial. All patients underwent sequential run-in phases of valsartan and sacubitril/valsartan before randomization. We categorized patients by PP quartile and evaluated the influence of baseline PP on the PARAGON-HF primary end point (total HF hospitalizations and cardiovascular death). At screening, the median PP was 58 mm Hg (interquartile range, 50-69 mm Hg). There was a nonlinear, J-shaped association between PP and outcomes. Multivariable Cox proportional hazards models showed that patients in the highest PP quartile had a higher risk of the primary end point (adjusted hazard ratio, 1.39 [95% CI, 1.14-1.69]; =0.001), total HF hospitalizations (adjusted hazard ratio, 1.43 [95% CI, 1.15-1.79]; =0.001), and myocardial infarction (adjusted hazard ratio, 1.54 [95% CI, 1.06-2.23]; =0.022) compared with those in the second (lowest risk) PP quartile. Reductions in PP during sacubitril/valsartan run-in were associated with a decreased risk of the primary end point and total HF hospitalizations. One year after randomization, PP was significantly lower in the sacubitril/valsartan group compared with the valsartan group (3.0 mm Hg decrease [95% CI, 2.4-3.5]; <0.001). In conclusion, PP was an independent predictor of cardiovascular events in patients with HF with preserved ejection fraction enrolled in PARAGON-HF. Sacubitril/valsartan lowered PP compared with valsartan.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16277DOI Listing
February 2021

Developing and validating models to predict sudden death and pump failure death in patients with heart failure and preserved ejection fraction.

Clin Res Cardiol 2021 Aug 10;110(8):1234-1248. Epub 2020 Dec 10.

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK.

Background: Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF.

Methods: Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials.

Results: The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.71 (95% CI 0.68-0.75) and 0.78 (95% CI 0.75-0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination.

Conclusions: The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials.

Clinical Trial Registration: I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712.
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http://dx.doi.org/10.1007/s00392-020-01786-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318942PMC
August 2021

Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF.

JACC Heart Fail 2021 01 11;9(1):13-24. Epub 2020 Nov 11.

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objectives: This study sought to evaluate the efficacy and safety of sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF) according to background mineralocorticoid receptor antagonist (MRA) therapy.

Background: Current guidelines recommend consideration of MRAs in selected patients with HFpEF. This study assessed cardiovascular outcomes, renal outcomes, and safety of sacubitril/valsartan compared with valsartan in patients with HFpEF according to background MRA treatment.

Methods: PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction) randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. In a pre-specified subgroup analysis, the effect of sacubitril/valsartan versus valsartan was evaluated according to baseline MRA use on the primary study composite of total heart failure hospitalizations and cardiovascular death using semiparametric proportional rates methods, as well as the renal composite of ≥50% decrease in estimated glomerular filtration rate, development of end-stage renal disease, or death from renal causes using Cox proportional hazards regression models. Annual decline in estimated glomerular filtration rate was analyzed with repeated-measures mixed-effect models. Key safety outcomes included incidence of hypotension, hyperkalemia, and elevations in serum creatinine above predefined thresholds.

Results: Patients treated with MRAs at baseline (n = 1,239, 26%), compared with MRA nonusers (n = 3,557, 74%), were younger (72 vs. 73 years), more often male (52% vs. 47%), had lower left ventricular ejection fraction (57% vs. 58%), and a higher proportion of prior HF hospitalization (59% vs. 44%) (all p < 0.001). Efficacy of sacubitril/valsartan compared with valsartan with regard to the primary cardiovascular (for MRA users: rate ratio: 0.73; 95% confidence interval [CI]: 0.56 to 0.95; vs. for MRA nonusers: rate ratio: 0.94; 95% CI: 0.79 to 1.11; p = 0.11) and renal endpoints (for MRA users: hazard ratio: 0.31; 95% CI: 0.13 to 0.76; vs. for MRA non-users: HR: 0.59; 95% CI: 0.36 to 0.95; p = 0.21) did not significantly vary by baseline MRA use. The incidence of key safety outcomes including hypotension and severe hyperkalemia (K > 6.0 mmol/l) did not vary by baseline MRA use. However, annual decline in estimated glomerular filtration rate was less with the combination of MRA and sacubitril/valsartan (for MRA users: absolute difference favoring sacubitril/valsartan: +1.2 ml/min/1.73 m per year; 95% CI: 0.6 to 1.7; vs. for MRA nonusers: +0.4; 95% CI: 0.1 to 0.7; p = 0.01).

Conclusions: Clinical efficacy of sacubitril/valsartan compared with valsartan with regard to predefined cardiorenal composite outcomes in PARAGON-HF was consistent in patients treated and not treated with MRA at baseline. Addition of sacubitril/valsartan rather than valsartan alone to MRA appears to be associated with a lesser decline in renal function and no increase in severe hyperkalemia. These data support possible added value of combination treatment with sacubitril/valsartan and MRA in patients with HFpEF. (Prospective Comparison of ARNI [angiotensin receptor -neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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http://dx.doi.org/10.1016/j.jchf.2020.08.014DOI Listing
January 2021

Blood pressure and mortality in patients with type 2 diabetes and a recent coronary event in the ELIXA trial.

Cardiovasc Diabetol 2020 10 12;19(1):175. Epub 2020 Oct 12.

Cardiovascular Division, Brigham & Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

Background: The relationship between blood pressure and mortality in type 2 diabetes (T2DM) is controversial, with concern for increased risk associated with excessively lowered blood pressure.

Methods: We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline blood pressure and all-cause mortality in 5852 patients with T2DM and a recent acute coronary syndrome (ACS) who participated in the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial. Risk of death was assessed in Cox models adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, brain natriuretic peptide (BNP), urine albumin/creatinine ratio, treatment allocation and prior coronary revascularization.

Results: Although overall there was no significant association between systolic blood pressure (SBP) and mortality (hazard ratio per 10 mmHg lower SBP 1.05 (95% CI 0.99-1.12) P = 0.10), lower SBP was significantly associated with higher risk of death (hazard ratio per 10 mmHg lower SBP 1.13 (95% CI 1.04-1.22) P = 0.002) in 2325 patients with additional CVD (index ACS+ at least one of the following prior to randomization: myocardial infarction other than the index ACS, stroke or heart failure). In 3527 patients with only the index ACS no significant association was observed (hazard ratio per 10 mmHg lower SBP 0.95 (0.86-1.04) P = 0.26; P for interaction 0.005).

Conclusions: The association between blood pressure and mortality was modified by additional CVD history in patients with type 2 diabetes and a recent coronary event. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration. Trial registration ClinicalTrials.gov number NCT01147250, first posted June 22, 2010.
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http://dx.doi.org/10.1186/s12933-020-01150-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552471PMC
October 2020

Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.

Hypertension 2020 11 28;76(5):1350-1367. Epub 2020 Sep 28.

Division of Nephrology and Hypertension (K.A.N., V.D.G.), Mayo Clinic College of Medicine, Rochester, MN.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685174PMC
November 2020
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