Milton Packer M.D.

Jackson, A.M., Rørth, R., Liu, J., Kristensen, S.L., Anand, I.S., Claggett, B.L., Cleland, J.G.F., Chopra, V.K., Desai, A.S., Ge, J., Gong, J., Lam, C.S.P., Lefkowitz, M.P., Maggioni, A.P., Martinez, F., Packer, M., Pfeffer, M.A., Pieske, B., Redfield, M.M., Rizkala, A.R., Rouleau, J.L., Seferović, P.M., Tromp, J., Van Veldhuisen, D.J., Yilmaz, M.B., Zannad, F., Zile, M.R., Køber, L., Petrie, M.C., Jhund, P.S., Solomon, S.D. and McMurray, J.J.V. (2021). “Diabetes and pre-diabetes in patients with heart failure and preserved ejection fraction.” Eur J Heart Fail Dec 17. [Epub ahead of print].

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AIM: There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre-diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre-diabetes in PARAGON-HF. METHODS AND RESULTS: Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre-diabetes, 6.0%-6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre-diabetes. Compared to patients with normal HbA1c, patients with pre-diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT-proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35-1.88), total HFH (RR 1.67, 95% CI 1.39-2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07-1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre-diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00-1.60) and HFH (HR 1.35, 95% CI 1.03-1.77), but not of CV death (HR 1.02, 95% CI 0.75-1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with 'lean diabetes' had similar mortality rates to those with a higher body mass index, but lower rates of HFH. CONCLUSION: Pre-diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01920711.

Ferreira, J.P., Anker, S.D., Butler, J., Filippatos, G., Iwata, T., Salsali, A., Zeller, C., Pocock, S.J., Zannad, F. and Packer, M. (2021). “Impact of anaemia and the effect of empagliflozin in heart failure with reduced ejection fraction: findings from EMPEROR-Reduced.” Eur J Heart Fail.

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AIMS: Anaemia is frequent among patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with poor outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) increase haematocrit and may correct anaemia. This study aims to investigate the impact of empagliflozin on haematocrit and anaemia, and whether anaemia influenced the effect of empagliflozin in EMPEROR-Reduced. METHODS AND RESULTS: Mixed-effects models and survival analysis. A total of 3726 patients (out of 3730) had baseline haematocrit values, 3013 (81%) had no anaemia and 713 (19%) had anaemia. Patients with anaemia were older (70.4 vs. 66.0 years), had lower body mass index (26.6 vs. 28.2 kg/m(2) ), lower estimated glomerular filtration rate (54.2 vs. 63.9 ml/min/1.73 m(2) ), and higher N-terminal pro-B-type natriuretic peptide (2362 vs. 1800 pg/ml). Compared to patients without anaemia, those with anaemia had 1.5 to 2.5-fold higher rates of cardiovascular and all-cause mortality, total HF hospitalizations, and kidney composite outcomes. The effect of empagliflozin to reduce the primary composite outcome of cardiovascular death or HF hospitalizations, total HF hospitalizations, and kidney composite outcome was not modified by baseline anaemia status (interaction p > 0.1 for all). Compared to placebo, empagliflozin rapidly (as early as week 4) increased haematocrit and haemoglobin and reduced the rates of new-onset anaemia throughout the follow-up (22.6% in placebo vs. 12.3% in empagliflozin; hazard ratio 0.49, 95% confidence interval 0.41-0.59; p < 0.001). CONCLUSIONS: Anaemia was associated with poor outcomes. Empagliflozin reduced new-onset anaemia throughout the follow-up and improved HF and kidney outcomes irrespective of anaemia status at baseline.

Curtain, J.P., Jackson, A., Shen, L., Jhund, P.S., Docherty, K.F., Petrie, M.C., Castagno, D., Desai, A.S., Rohde, L.E., Lefkowitz, M.P., Rouleau, J.L., Zile, M.R., Solomon, S.D., Swedberg, K., Packer, M. and McMurray, J.J.V. (2021). “Effect of sacubitril/valsartan on investigator-reported ventricular arrhythmias in PARADIGM-HF.” Eur J Heart Fail Dec 30. [Epub ahead of print].

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BACKGROUND: Sudden death is a leading cause of mortality in HFrEF. In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyze the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias. METHODS: Adverse event reports related to ventricular arrhythmias were examined in PARADIGM-HF. The effect of randomized treatment on two arrhythmia outcomes was analyzed: ventricular arrhythmias and the composite of a ventricular arrhythmia, ICD shock or resuscitated cardiac arrest. The risk of death related to a ventricular arrhythmia was examined in time-updated models. The interaction between heart failure aetiology, or baseline ICD/CRT-D use, and the effect of sacubitril/valsartan was analyzed. RESULTS: Of the 8399 participants, 333 (4.0%) reported a ventricular arrhythmia and 372 (4.4%) the composite arrhythmia outcome. Ventricular arrhythmias were associated with higher mortality. Compared with enalapril, sacubitril/valsartan reduced the risk of a ventricular arrhythmia [HR 0.76 (0.62-0.95); p = 0.015] and the composite arrhythmia outcome [HR 0.79 (0.65-0.97); p = 0.025]. The treatment effect was maintained after adjustment and accounting for the competing risk of death. Baseline ICD/CRT-D use did not modify effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (0.71-1.21) versus 0.53 (0.37-0.78) in those without an ischaemic aetiology (p for interaction = 0.020). CONCLUSIONS: Sacubitril/valsartan reduced the incidence of investigator-reported ventricular arrhythmias in patients with HFrEF. This effect may have been greater in patients with a non-ischaemic aetiology.

Verma, S., Dhingra, N.K., Butler, J., Anker, S.D., Ferreira, J.P., Filippatos, G., Januzzi, J.L., Lam, C.S.P., Sattar, N., Peil, B., Nordaby, M., Brueckmann, M., Pocock, S.J., Zannad, F. and Packer, M. (2021). “Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): a post-hoc analysis of a randomised, double-blind trial.” Lancet Diabetes Endocrinol Nov 30;S2213-8587(21)00292-8. [Epub ahead of print].

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BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy.

Pocock, S.J., Ferreira, J.P., Gregson, J., Anker, S.D., Butler, J., Filippatos, G., Gollop, N.D., Iwata, T., Brueckmann, M., Januzzi, J.L., Voors, A.A., Zannad, F. and Packer, M. (2021). “Novel biomarker-driven prognostic models to predict morbidity and mortality in chronic heart failure: the EMPEROR-Reduced trial.” Eur Heart J 42(43): 4455-4464.

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AIMS: The aim of this study was to generate a biomarker-driven prognostic tool for patients with chronic HFrEF. Circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) each have a marked positive relationship with adverse outcomes in heart failure with reduced ejection fraction (HFrEF). A risk model incorporating biomarkers and clinical variables has not been validated in contemporary heart failure (HF) trials. METHODS AND RESULTS: In EMPEROR-Reduced, 33 candidate variables were pre-selected. Multivariable Cox regression models were developed using stepwise selection for: (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, and (iii) cardiovascular mortality. A total of 3730 patients were followed up for a median of 16 months, 823 (22%) patients had a primary outcome and 515 (14%) patients died, of whom 389 (10%) died from a cardiovascular cause. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last HF hospitalization, longer time since HF diagnosis, lower systolic blood pressure, New York Heart Association (NYHA) Class III or IV, higher heart rate and peripheral oedema were key predictors (eight variables in total, all P < 0.001). The primary outcome risk score discriminated well (c-statistic = 0.73), with patients in the top 10th of risk having an event rate >9 times higher than those in the bottom 10th. Empagliflozin benefitted patients across risk levels for the primary outcome. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality, followed by NYHA Class III or IV and ischaemic aetiology (four variables in total, all P < 0.001). The mortality risk model presented good event discrimination for all-cause and cardiovascular mortality (c-statistic = 0.69 for both). These simple models were externally validated in the BIOSTAT-CHF study, achieving similar c-statistics. CONCLUSIONS: The combination of NT-proBNP and hs-cTnT with a small number of readily available clinical variables provides prognostic assessment for patients with HFrEF. This predictive tool kit can be easily implemented for routine clinical use.