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Showing papers by "Marc A. Pfeffer published in 2020"


Journal ArticleDOI
TL;DR: RAAS Inhibitors in Patients with Covid-19 show low levels of renin–angiotensin-converting enzyme 2 levels and activity in humans, but the effects are still uncertain.
Abstract: RAAS Inhibitors in Patients with Covid-19 The effects of renin–angiotensin–aldosterone system blockers on angiotensin-converting enzyme 2 levels and activity in humans are uncertain. The authors hy...

1,687 citations


Journal ArticleDOI
TL;DR: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone–system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction.
Abstract: Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF...

291 citations


Journal ArticleDOI
TL;DR: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men, but the present study does not provide a definite mechanistic basis for this finding.
Abstract: Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, th...

207 citations


Journal ArticleDOI
TL;DR: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan.
Abstract: Background: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal...

64 citations


Journal ArticleDOI
TL;DR: Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF, and screening NT- ProBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death.
Abstract: Objectives The authors sought to evaluate the prognostic significance of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups. Background Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). Methods In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. Results Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. Conclusions Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)

59 citations


Journal ArticleDOI
TL;DR: Re recombinant human ACE2 in pre-clinical models and patients with pulmonary arterial hypertension and acute lung injury led to a prompt increase in the Ang 1-7/Ang II ratio, reflecting ACE2 action, thus providing a direct link between the tissue and systemic RAS.
Abstract: Angiotensin-converting enzyme 2 (ACE2) has emerged as the negative regulator of the renin–angiotensin system (RAS) and was more recently identified as the SARS-CoV-2 receptor responsible for the current COVID-19 pandemic. The high burden of illness and high case fatality rate in patients with COVID-19 is driven in part by the high affinity of SARS-CoV-2 for ACE2, leading to viral entry and multisystem illness with pulmonary, gut, renal, central nervous stystem, and cardiovascular manifestations. The novel dual role of ACE2 in the RAS and as the SARS-CoV-2 receptor provides a fundamental connection between viral infection, immunity, and cardiovascular disease. Direct clinical evidence came from SARS and the current COVID-19 pandemic, where there is down-regulation of tissue ACE2 through endocytosis and proteolytic processing which leads to a corresponding increase in plasma angiotensin II (Ang II) levels as seen in COVID-19 patients (linearly correlated with SARS-CoV-2 viral load), thus providing a direct link between the tissue and systemic RAS. The SARS-CoV genome was detected in postmortem autopsy heart samples of patients who succumbed to SARS infection, suggesting prompt viral infiltration of myocardial tissue during infection. These hearts had markedly decreased myocardial ACE2 expression levels with a concomitant increase in myocardial inflammation and fibrosis. The RAS is an endogenous peptide system with key physiological and pathophysiological roles in cardiovascular disease, as illustrated by the success of its pharmacological blockers [including ACE inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs)] in mitigating cardiovascular disease progression. Ang II (octapeptide) is produced through proteolytic cleavage of Ang I (decapeptide) by ACE which activates angiotensin type 1 receptors (AT1Rs), thereby mediating downstream pathophysiological effects. The ACE2/Ang 1-7 counter-regulatory axis, by removing a single C-terminus, inactivates Ang II and forms Ang 1-7. This septapeptide acts upon the Mas receptor to initiate vasodilatory and anti-inflammatory effects mediated through beneficial signalling pathways (Figure 1). ACE2 is widely expressed and, in the cardiovascular system, ACE2 is localized to cardiomyocytes, cardiac fibroblasts, pericytes, vascular endothelium, and vascular smooth cells. Various diseases including heart failure, hypertension, and diabetes are characterized by a relative ACE2-deficient state, reducing the homeostatic protective mechanism. Importantly, recombinant human ACE2 in pre-clinical models and patients with pulmonary arterial hypertension and acute lung injury led to a prompt increase in the Ang 1-7/Ang II ratio, reflecting ACE2 action. During this unprecedented time of a rapidly expanding global epidemic, both the lay and medical communities are struggling to find relevant information concerning medical therapies to mitigate the impact of COVID-19. With the current paucity of data, associations which generally would be insufficient to guide medical therapy are given more weight than would be anticipated under more usual circumstances. The coronavirus SARS-CoV-2 and COVID-19 interface with the RAS with ACE2 led to a great deal of speculation regarding the role of pharmacological inhibitors of the RAS and COVID-19 infection. Pharmacological antagonists of the RAS, such as ACE inhibitors and ARBs, protect the cardiovascular system partly by increasing ACE2 levels in disease states, thereby dampening the effects of an activated RAS. The major conundrum is that these drugs which are used to treat cardiovascular disorders may facilitate COVID-19 infection, while, on the other hand, discontinuing their use will augment

58 citations


Journal ArticleDOI
TL;DR: The effect of three different neurohumoral modulators in large trials which provide data on clinical outcomes in patients with HF, across the full range of LVEF is explored, incorporating the three commonly described HF phenotypes.
Abstract: Recently, the Prospective Comparison of ARNI (angiotensin receptor–neprilysin inhibitor) with ARB (angiotensin receptor blocker) Global Outcomes in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) trial suggested that women might obtain more benefit than men from sacubitril/valsartan, compared with valsartan, in heart failure with preserved ejection fraction (HFpEF).1–3 However, the picture is more complicated as there was also an interaction between left ventricular ejection fraction (LVEF) and the effect of sacubitril/valsartan.2 Patients with a LVEF at or below the median (57%) seemed to gain more benefit from sacubitril/valsartan than those with a LVEF above the median.2 To make matters more complex still, it is well known that the distribution of LVEF is different in women and men, with women, on average, having a higher LVEF than men, be it in the general population or in individuals with heart failure (HF).4–6 Despite a higher LVEF, women with HFpEF had worse systolic function, as assessed by tissue Doppler echocardiography, compared to men with HFpEF.7 To further investigate the relationship between sex, LVEF and treatment in HF, we explored the effect of three different neurohumoral modulators in large trials which provide data on clinical outcomes in patients with HF, across the full range of LVEF, incorporating the three commonly described HF phenotypes – HF with reduced ejection fraction (HFrEF, LVEF <40%), HFpEF (LVEF >50%) and HF with mid-range ejection fraction (HFmrEF, LVEF 40–50%).8 We pooled individual patient-level data from: (i) three trials using an angiotensin receptor blocker – the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) – the CHARM-Alternative and CHARM-Added trials in HFrEF and the CHARM-Preserved trial in HFmrEF/HFpEF;9 (ii) three trials using a mineralocorticoid receptor antagonist (MRA) – two HFrEF trials, the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), and one HFmrEF/HFpEF trial – the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT).10–12 Only TOPCAT patients from the Americas were included; (iii) two trials using sacubitril/valsartan – the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF trial (PARADIGM-HF) in HFrEF and PARAGON-HF in HFmrEF/HFpEF.1,13 Cox proportional hazards modelling was used to analyse (i) the primary composite outcome (first occurrence of HF hospitalization or cardiovascular death); (ii) first HF hospitalization; and (iii) cardiovascular death. Likelihood ratio tests were used to report (i) two-way interaction between treatment and sex; and (ii) three-way interaction between treatment, sex and LVEF. LVEF, modelled as a fractional polynomial, and its interaction with treatment using the best fit model for each drug category (based on the primary composite outcome) was examined with the mfpi command in Stata. Models were stratified by trial for MRAs and sacubitril/valsartan. All analyses were conducted using Stata version 16 (Stata Corp., College Station, TX, USA). This present analysis included 2400, 1938 and 4311 women and 5199, 4229 and 8884 men in the candesartan, MRA and sacubitril/valsartan trials, respectively (Table 1). Overall mean LVEF (%) was 38.9±14.9%, 35.3±16.0% and 39.7± 15.1%, respectively. Women had a higher mean LVEF, with the difference compared to men 6.3%, 9.4% and 10.3%, respectively. Women had a lower incidence of the primary composite outcome (and its components) in each of the treatment and control groups. In keeping with prior reports from the CHARM Programme and TOPCAT, as well as a recent analysis of PARADIGM-HF and PARAGON-HF, we found that treatment with an ARB, MRA or ARNI may be of benefit beyond the upper limit of LVEF eligibility used in contemporary HFrEF clinical trials (40%) and may extend to what has been termed HFmrEF (LVEF 40–49%) and even to the lower part of the LVEF range currently categorized as HFpEF.2,6,14,15 Importantly, the benefit of each treatment seemed to extend to a higher LVEF in women, compared to men (Figure 1). There was no difference in efficacy of therapy between men and women with HFrEF. Because these are post hoc analyses, they are only hypothesis generating. However, the fact that all three neurohumoral modulating therapies demonstrated the same sex-related pattern of response raises the possibility that the differential response between women and men identified in PARAGON-HF may be real rather than due to the play of chance, although interpretation of PARAGON-HF is more complex as it had an active comparator compared with a placebo control in the other trials. Despite this consistent observation in the trials examined, the biological basis for such a finding is uncertain. As detailed elsewhere, the possibilities include sex-related differences in cardiac remodelling in response to blood pressure, age and other stimuli, and differences in age-related arterial stiffening, which is more pronounced in women than men.3 Women may also have other evidence of contractile dysfunction, compared with men, for a given ejection fraction.3 Natriuretic peptide levels are lower in women with HFpEF than in men, and women may have reduced cyclic guanosine monophosphateprotein kinase G signalling compared with men, especially after the menopause.3 The possibility that women with HF might benefit from treatment to a higher level of LVEF than previously considered could be of great clinical importance. Women with HF have fewer treatment options than men with HF because HFmrEF and HFpEF are the predominant HF phenotypes in women and no therapy has been approved by regulatory authorities for either of these phenotypes.6 More research on this matter is clearly required. Conflict of interest: P.D. and A.J. report no conflicts. C.S.P.L., M.A.P., F.Z., B.P., S.D.S. and J.J.V.McM. or their institutions were paid for their participation in one or more of these trials. J.J.V.McM reports receiving fees (all fees listed paid

50 citations


Journal ArticleDOI
TL;DR: Recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, and considering heart failure or kidney outcomes within the primary outcome.
Abstract: Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

45 citations


Journal ArticleDOI
TL;DR: This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure with preserved ejection fraction and whether sacubitril–valsartan reduces SUA and use of SUA‐related therapies.
Abstract: Aims This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies. Methods and results We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (+/- standard deviation) age of patients was 73 +/- 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37-1.90]. The treatment effect of sacubitril-valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction = 0.14). Sacubitril-valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31-0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 mg/dL vs. -0.32 mg/dL) (P-value for interaction = 0.031). Sacubitril-valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P <0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P <0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA. Conclusions Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril-valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.

27 citations


Journal ArticleDOI
TL;DR: In high‐risk patients with T2DM, NT‐proBNP by itself demonstrated discriminatory ability similar to a multivariable model in predicting both death and cardiovascular events and should be considered for risk stratification.
Abstract: Background NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) improves the discriminatory ability of risk‐prediction models in type 2 diabetes mellitus (T2DM) but is not yet used in clinical pra...

27 citations


Journal ArticleDOI
TL;DR: The average spironolactone/placebo doses provided during the TOPCAT trial, overall and within high‐risk subgroups (e.g. elderly, renal dysfunction, high potassium); discontinuation rates; and the efficacy of lower than target doses in heart failure with preserved ejection fraction are assessed.
Abstract: Aims Spironolactone up-titration may be limited by side effects that could be minimized at lower than target doses, but whether lower than target doses remain efficacious is unknown. In TOPCAT, spironolactone (or placebo) were started at 15 mg/day, and increased up to a maximum of 45 mg/day. The prognostic implications related to spironolactone dose are yet to be reported. We aimed to assess the average spironolactone/placebo doses provided during the trial, overall and within high-risk subgroups (e.g. elderly, renal dysfunction, high potassium); discontinuation rates; and the efficacy of lower than target doses in heart failure with preserved ejection fraction. Methods and results Overall, 1767 patients from 'TOPCAT-Americas' were included. Linear, logistic and Cox regressions were applied. Patients randomized to spironolactone received lower doses than placebo: 22.5 (15.0-27.5) mg/day vs. 27.5 (17.5-27.5) mg/day (P 4.5 mmol/L, received lower spironolactone doses (median ≈ 20 mg/day). This pattern of dose differences was not observed in patients taking placebo, where the between-subgroup placebo doses were similar (spironolactone-placebo by subgroup Pinteraction 0.1). Spironolactone discontinuation was associated with a two to fourfold higher risk of subsequent events. Conclusion Spironolactone (but not placebo) was used at lower doses among the elderly, those with renal dysfunction and with higher potassium levels. The effect of spironolactone was homogeneous across these subgroups. In patients unable to tolerate target doses, a low-dose strategy should be preferred to stopping treatment.

Journal ArticleDOI
TL;DR: The dal-GenE clinical outcome trial as discussed by the authors was designed to evaluate the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke.

Journal ArticleDOI
TL;DR: Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes, and the importance of primary and secondary prevention of MI in patients with HFp EF is highlighted.
Abstract: Objectives The authors investigated the relationship between past or incident myocardial infarction (MI) and cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF). Background MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain. Methods The authors pooled data from 3 trials—CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N = 8,916)—and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization. Results At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p Conclusions Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302)

Journal ArticleDOI
TL;DR: Higher baseline depressive symptoms and worsening depressive symptoms were associated with all-cause mortality and randomization to spironolactone was associated with modest reduction in depressive symptoms.
Abstract: Objectives This study analyzed changes in depressive symptoms in patients with heart failure and preserved ejection fraction (HFpEF) who were enrolled in the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. Background There are limited longitudinal data for depressive symptoms in patients with HFpEF. Methods In patients enrolled in the United States and Canada (n = 1,431), depressive symptoms were measured using Patient Health Questionnaire-9 (PHQ-9). Clinically meaningful changes in PHQ-9 scores were defined as worse (≥3-point increase) or better (≥3-point decrease). Multivariate models were used to identify predictors of change in depressive symptoms. Cox proportional hazard models were used to determine the impact of symptom changes from baseline on subsequent incident cardiovascular events. Results At 12 months, 19% of patients experienced clinically worsening depressive symptoms, 31% better, and 49% unchanged. Independent predictors of clinically meaningful improvement in depressive symptoms included higher baseline PHQ-9 scores, male sex, lack of chronic obstructive pulmonary disease, and randomization to spironolactone. After data were adjusted for cardiovascular comorbidities, higher baseline PHQ-9 was associated with all-cause mortality (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 1.02 to 1.16; p = 0.011), whereas worsening depressive symptoms at 12 months were associated with cardiovascular death (HR: 2.47; 95% CI: 1.32 to 4.63; p = 0.005) and all-cause mortality (HR: 1.82; 95% CI: 1.13 to 2.93; p = 0.014). Randomization to spironolactone was associated with modest but statistically significant reduction in depressive symptoms over the course of the trial (p = 0.014). Conclusions Higher baseline depressive symptoms and worsening depressive symptoms were associated with all-cause mortality. Randomization to spironolactone was associated with modest reduction in depressive symptoms. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302)

Journal ArticleDOI
TL;DR: This study evaluated whether A1C influences a composite outcome of either HF hospitalization or CV death differently along the spectrum of LVEF.
Abstract: Aims: Chronic hyperglycaemia, assessed by elevated glycated haemoglobin (A1C), is a known risk factor for heart failure (HF) and cardiovascular (CV) death among subjects with diabetes. Whether this risk varies with left ventricular ejection fraction (LVEF) is unknown. This study evaluated whether A1C influences a composite outcome of either HF hospitalization or CV death differently along the spectrum of LVEF. Methods and results: We assessed the relationships of baseline A1C and LVEF with a composite outcome of either CV death or HF hospitalization in the 4091 patients with type 2 diabetes and a recent acute coronary syndrome enrolled in the ELIXA trial who had available LVEF. We assessed for interaction between A1C and LVEF as continuous variables with respect to this outcome. During a median follow‐up of 25.7 months, 343 patients (8.4%) had HF hospitalization or died of CV causes. In a multivariable model, A1C and LVEF were each associated with an increased risk of HF hospitalization or CV death [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01–1.21 per 1% higher A1C, and adjusted HR 1.39, 95% CI 1.27–1.51 per 10% lower in LVEF]. Both A1C and LVEF were independently and incrementally associated with risk without evidence of interaction (P for interaction = 0.31). Patients with A1C ≥ 8% and LVEF <40% were at threefold higher risk than those with A1C < 7% and LVEF ≥50% (adjusted HR 3.18, 95% CI 2.03–4.98, P < 0.001). Conclusion: In a contemporary cohort of patients with type 2 diabetes and acute coronary syndrome, baseline chronic hyperglycaemia was associated with an increased risk of HF hospitalization or CV death independently of LVEF.

Journal ArticleDOI
TL;DR: PA was associated with a reduced risk of CVD events and all-cause mortality among KTRs, and these observed associations in a large, international sample, even when controlling for traditional CVD risk factors, indicate the potential importance of PA in reducing CVD and death among K TRs.
Abstract: BACKGROUND Insufficient physical activity (PA) may increase the risk of all-cause mortality and cardiovascular disease (CVD) morbidity and mortality among kidney transplant recipients (KTRs), but limited research is available. We examine the relationship between PA and the development of CVD events, CVD death and all-cause mortality among KTRs. METHODS A total of 3050 KTRs enrolled in an international homocysteine-lowering randomized controlled trial were examined (38% female; mean age 51.8 ± 9.4 years; 75% white; 20% with prevalent CVD). PA was measured at baseline using a modified Yale Physical Activity Survey, divided into tertiles (T1, T2 and T3) from lowest to highest PA. Kaplan-Meier survival curves were used to graph the risk of events; Cox proportional hazards regression models examined the association of baseline PA levels with CVD events (e.g. stroke, myocardial infarction), CVD mortality and all-cause mortality over time. RESULTS Participants were followed up to 2500 days (mean 3.7 ± 1.6 years). The cohort experienced 426 CVD events and 357 deaths. Fully adjusted models revealed that, compared to the lowest tertile of PA, the highest tertile experienced a significantly lower risk of CVD events {hazard ratio [HR] 0.76 [95% confidence interval (CI) 0.59-0.98]}, CVD mortality [HR 0.58 (95% CI 0.35-0.96)] and all-cause mortality [HR 0.76 (95% CI 0.59-0.98)]. Results were similar in unadjusted models. CONCLUSIONS PA was associated with a reduced risk of CVD events and all-cause mortality among KTRs. These observed associations in a large, international sample, even when controlling for traditional CVD risk factors, indicate the potential importance of PA in reducing CVD and death among KTRs.

Journal ArticleDOI
TL;DR: To develop a risk model for sudden cardiac death (SCD) in high‐risk acute myocardial infarction (AMI) survivors, a chiral model was developed.
Abstract: Aims To develop a risk model for sudden cardiac death (SCD) in high‐risk acute myocardial infarction (AMI) survivors. Methods and results Data from the Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left Ventricular Dysfunction trial (CAPRICORN) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT) were used to create a SCD risk model (with non‐SCD as a competing risk) in 13 202 patients. The risk model was validated in the Eplerenone Post‐AMI Heart Failure Efficacy and Survival Study (EPHESUS). The rate of SCD was 3.3 (95% confidence interval 3.0–3.5) per 100 person‐years over a median follow‐up of 2.0 years. Independent predictors of SCD included age > 70 years; heart rate ≥ 70 bpm; smoking; Killip class III/IV; left ventricular ejection fraction ≤30%; atrial fibrillation; history of prior myocardial infarction, heart failure or diabetes; estimated glomerular filtration rate < 60 mL/min/1.73 m2; and no coronary reperfusion or revascularisation therapy for index AMI. The model was well calibrated and showed good discrimination (C‐statistic = 0.72), including in the early period after AMI. The observed 2‐year event rates increased steeply with each quintile of risk score (1.9%, 3.6%, 6.2%, 9.0%, 13.4%, respectively). Conclusion An easy to use SCD risk score developed from routinely collected clinical variables in patients with heart failure, left ventricular systolic dysfunction or both, early after AMI was superior to left ventricular ejection fraction. This score might be useful in identifying patients for future trials testing treatments to prevent SCD early after AMI.

Journal ArticleDOI
TL;DR: Spironolactone has been demonstrated to reduce heart failure (HF) hospitalization in patients with preserved ejection fraction in the Americas region of the TOPCAT trial (Treatm....
Abstract: Background: Spironolactone has been demonstrated to reduce heart failure (HF) hospitalization in patients with HF with preserved ejection fraction in the Americas region of the TOPCAT trial (Treatm...


Journal ArticleDOI
TL;DR: This study investigated the influence of milder obstructive lung disease – defined as the absence of use of steroids or supplemental O2 – on cardiovascular (CV) outcomes among patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial in the Americas.
Abstract: Chronic obstructive pulmonary disease (COPD) is highly prevalent and predictive of worse outcomes in heart failure (HF) with preserved ejection fraction (HFpEF).1,2 Severe COPD can result in cor pulmonale3 and worse outcomes in HF,2 while less severe obstructive lung disease is associated with impaired left ventricular filling and lower cardiac output despite preserved left ventricular ejection fraction (LVEF).4 We investigated the influence of milder obstructive lung disease – defined as the absence of use of steroids or supplemental O2 – on cardiovascular (CV) outcomes among patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial in the Americas. TOPCAT was a multicentre, randomized, double-blind, placebo-controlled trial that tested the efficacy of spironolactone to reduce CV morbidity and mortality in 3445 adults ≥50 years of age with HFpEF (LVEF ≥45%).5 Key exclusion criteria relevant to this analysis included severe lung disease requiring home O2 or systemic steroid therapy, moderate or severe pulmonary hypertension, and directed therapy or biologics for lung disease. Given the significant differences in population characteristics and outcomes by region,6 we studied the 1767 patients recruited in the Americas. All patients provided written informed consent, and the study was approved by local institutional review boards. Outcomes included the composite of CV death, aborted sudden death, or HF hospitalization (the TOPCAT primary outcome), the individual components of this composite, all-cause mortality, non-CV mortality, and all-cause hospitalization.5 Pulmonary disease was based on the report by the site investigator of any diagnosis of COPD or asthma at enrolment. Of 1765 patients enrolled in the Americas and with data on pulmonary disease status, 653 (37%) were included in the TOPCAT echocardiographic study.7 Multivariable Cox proportional hazards models were employed to relate pulmonary disease at baseline to each outcome, adjusted for age, female gender, white race, treatment group, enrolment strata, percutaneous coronary intervention, use of beta-blockers, smoking status, body mass index, and heart rate. We further adjusted for New York Heart Association (NYHA) class in separate models. Interaction between pulmonary disease and randomized treatment assignment (spironolactone vs. placebo) on clinical outcomes was assessed using a multiplicative interaction term. The mean age was 72± 10 years, 50% were women, and 22% were non-white. The prevalence of COPD or asthma was 24%. Patients with prevalent lung disease were younger and more frequently non-white, had higher prevalence of current smoking, obesity, prior percutaneous coronary intervention, and NYHA III/IV functional class, and lower prevalence of beta-blocker use (online supplementary Table S1). At a median follow-up of 2.4 years, the primary composite outcome occurred in 522 (30%), CV death in 223 (13%), HF hospitalization in 400 (23%), all-cause mortality in 385 (22%), and all-cause hospitalization in 1059 (60%). Prevalent pulmonary disease was associated with a higher risk of the primary composite endpoint, related to higher risk of HF hospitalization but not of CV death (Table 1). After adjustment for demographics and co-morbidities, associations persisted with the primary composite endpoint, HF hospitalization and all-cause hospitalization (Table 1). In a post hoc exploratory analysis, pulmonary disease at enrolment modified the relationship between treatment with spironolactone and subsequent CV mortality (interaction P = 0.01) and all-cause mortality (interaction P = 0.02), such that the risk reduction associated with spironolactone was greater among patients compared to those without pulmonary disease (Table 1). No significant effect modification was observed for the primary endpoint, HF hospitalization, or all-cause hospitalization. Among patients with pulmonary disease, those randomized to spironolactone demonstrated a lower prevalence of prior myocardial infarction and higher prevalence of beta-blocker use (online supplementary Table S2). Results remained unchanged in models adjusting for randomization strata, and further adjusting for prior myocardial infarction and beta-blocker use (online supplementary Table S3). Among 653 patients in the echocardiographic study, 159 (24%) had pulmonary disease (online supplementary Table S4). Pulmonary disease was associated with greater left ventricular wall thickness and left ventricular hypertrophy prevalence, higher LVEF and tissue Doppler imaging s’, and smaller left atrial volume index in unadjusted analysis. Only associations with LVEF, tissue Doppler imaging s’, and left atrial volume index persisted after accounting for age, sex, and race (online supplementary Table S5). In this analysis of HFpEF patients enrolled in TOPCAT in the Americas, obstructive lung disease was independently associated with a heightened risk of the primary composite outcome, HF hospitalization alone, and allcause hospitalization. Despite this, pulmonary disease was associated with higher LVEF and smaller left atrial volume index, without differences in right ventricular function or pulmonary pressure, suggesting an important role for extracardiac factors in mediating the observed increase in risk. In an exploratory post hoc analysis, obstructive lung disease modified the relationship of randomized treatment with all-cause and CV mortality, but not with the TOPCAT primary endpoint. Similar findings were observed in the I-PRESERVE trial, where COPD prevalence was an independent predictor of HF death or hospitalization.8 Potential mechanisms linking COPD to increased risk of HF hospitalization in HFpEF include misdiagnosis of less severe COPD as a HF exacerbation due to overlapping signs and symptoms,1 or to lower cardiopulmonary reserve in patients with combined HFpEF and obstructive pulmonary disease leading to a lower threshold for HF or respiratory decompensation resulting in an increased likelihood of hospitalization. One possible explanation for the finding of effect modification of baseline pulmonary disease on treatment effect for CV and allcause mortality is chance, given the post hoc nature of this analysis. However, pulmonary



Journal ArticleDOI
TL;DR: The association between 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.
Abstract: 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. 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. 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). 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

Journal ArticleDOI
TL;DR: Patients with heart failure and preserved left ventricular ejection fraction (HFpEF) comprise a heterogeneous group including some with mildly reduced EF, and it is hypothesized that mode of death differs by EF in HFpEF.