Cardiology

Russo, M.J., Thourani, V.H., Cohen, D.J., Malaisrie, S.C., Szeto, W.Y., George, I., Kodali, S.K., Makkar, R., Lu, M., Williams, M., Nguyen, T., Aldea, G., Genereux, P., Fang, H.K., Alu, M.C., Rogers, E., Okoh, A., Herrmann, H.C., Kapadia, S., Webb, J.G., Smith, C.R., Leon, M.B. and Mack, M.J. (2021). “Minimally Invasive versus Full Sternotomy for Isolated Aortic Valve Replacement in Low-risk Patients.” Ann Thorac Surg Dec 24;S0003-4975(21)02134-2. [Epub ahead of print].

Full text of this article.

BACKGROUND: Surgical aortic valve replacement can be performed either through a minimally invasive (MI) or full sternotomy (FS) approach. The present study compared outcomes of MI versus FS for isolated surgery among patients enrolled in the PARTNER 3 low-risk trial. METHODS: Patients with severe, symptomatic aortic stenosis at low surgical risk with anatomy suitable for transfemoral access were eligible for PARTNER 3 enrollment. The primary outcome was the composite endpoint of death, stroke, or rehospitalization (valve-, procedure-, or heart-failure-related) at 1 year. Secondary outcomes included the individual components of the primary endpoint as well as patient-reported health status at 30 days and 1 year. RESULTS: In the PARTNER 3 study, 358 patients underwent isolated surgery at 68 centers through an MI (n=107) or FS (n=251) approach (8 patients were converted from MI to FS). Mean age and Society of Thoracic Surgeons score were similar between groups. The Kaplan-Meier estimate of the primary outcome was similar in the MI versus FS groups (16.9% versus 14.9%; hazard ratio [95% CI]: 1.15 [0.66 – 2.03]; P=0.618). There were no significant differences in the 1-year rates of all-cause death (2.8% versus 2.8%), all stroke (1.9% versus 3.6%), or rehospitalization (13.3% versus 10.6%, P > 0.05 for all). Quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire score at 30 days or 1 year was comparable in both groups. CONCLUSIONS: For patients at low risk for isolated surgery, MI and FS approaches were associated with similar in-hospital and 1-year outcomes.

Mc Causland, F.R., Lefkowitz, M.P., Claggett, B., Packer, M., Senni, M., Gori, M., Jhund, P.S., McGrath, M.M., Rouleau, J.L., Shi, V., Swedberg, K., Vaduganathan, M., Zannad, F., Pfeffer, M.A., Zile, M., McMurray, J.J.V. and Solomon, S.D. (2022). “Angiotensin-Neprilysin Inhibition and Renal Outcomes Across the Spectrum of Ejection Fraction in Heart Failure.” Eur J Heart Fail Jan 5. [Epub ahead of print].

Full text of this article.

AIMS: Patients with heart failure are at higher risk of progression to end-stage renal disease (ESRD), regardless of ejection fraction (EF). We assessed the renal effects of angiotensin/neprilysin inhibition in a pooled anlaysis of 13 195 patients with heart failure with reduced and preserved EF. METHODS AND RESULTS: We combined data from PARADIGM-HF (LVEF ≤40%; n = 8399) and PARAGON-HF (LVEF ≥45%; n = 4796) in a prespecified pooled analysis. We assessed the effect of treatment (sacubitril/valsartan vs. enalapril or valsartan) on a composite of either ≥50% reduction in eGFR, ESRD, or death from renal causes, in addition to changes in eGFR slope. We assessed whether baseline renal function, diabetes or EF modified the effect of therapy on renal outcomes. At randomization, eGFR was 68 ± 20 mL/min/1.73m(2) in PARADIGM-HF and 63 ± 19 mL/min/1.73m(2) in PARAGON-HF. The composite renal outcome occurred in 70 of 6594 patients (1.1%) in the sacubitril/valsartan group and 123 of 6601 patients (1.9%) in the valsartan or enalapril group (HR 0.56, 95%CI 0.42-0.75; P < 0.001). The mean eGFR change was -1.8 (95%CI -1.9 to -1.7) ml/min/1.73m(2) /year for the sacubitril/valsartan group, compared with -2.4 (95%CI -2.5 to -2.2) ml/min/1.73m(2) /year for the valsartan or enalapril group. The treatment effect on the composite renal endpoint was not modified by categories of baseline eGFR (P-interaction = 0.64), but was most pronounced in those with baseline EF between 30%-60% (P-interaction = 0.001). CONCLUSIONS: In patients with heart failure, sacubitril/valsartan reduced the risk of serious adverse renal outcomes, and slowed decline in eGFR, compared with valsartan or enalapril, independent of baseline renal function.

Khan, M.S., Bakris, G.L., Packer, M., Shahid, I., Anker, S.D., Fonarow, G.C., Wanner, C., Weir, M.R., Zannad, F. and Butler, J. (2021). “Kidney function assessment and endpoint ascertainment in clinical trials.” Eur Heart J Dec 30;ehab832. [Epub ahead of print].

Full text of this article.

Heterogeneity in the reporting of kidney function, kidney outcomes, and definitions for kidney endpoints in clinical trials makes it challenging to compare results and gauge incremental benefit of interventions across trials. We conducted a systematic review of the ascertainment of baseline kidney variables, reporting of kidney endpoints, and definitions used to characterize these endpoints in type 2 diabetes mellitus (T2DM), kidney, and heart failure (HF) trials. Medline, Scopus, and ClinicalTrials.gov were searched from January 2014 through January 2021 for large (>1000 participants) T2DM, HF, and kidney disease trials and their secondary analyses. Trial publication and supplementary appendices were searched to abstract relevant data. Thirty-three trials (16 T2DM; 10 HF; 7 kidney diseases) were included. Thirteen trials did not include patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and for trials that did, representation of this cohort ranged from 0.1% to 15%. Reporting of baseline kidney function and albuminuria remained low, especially in HF trials. Variability was observed in the definition of chronic kidney disease, sustained decline in eGFR, end-stage kidney disease, kidney death, and kidney composite endpoint across trials. eGFR slope was reported in less than half trials, with differences observed in statistical models, definition of acute or chronic slope, and follow-up duration across trials. Significant heterogeneity in reporting of kidney function and kidney outcomes in large T2DM, kidney, and HF trials underscores the need for future stakeholders to draft a consensus solution. Detailed profiling of patients at baseline, accrual of more patients with advanced kidney disease, and standardization of definitions in trials may improve the ability to compare the results across trials.

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].

Full text of this article.

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.

Full text of this article.

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.