Cardiology

Shutze, W., Gable, D., Ogola, G., Yasin, T., Madhukar, N., Kamma, B., Alniem, Y. and Eidt, J. (2021). “Sex, Age, and Other Barriers for Prosthetics Referral Following Amputation and the Impact on Survival.” J Vasc Surg May 31;S0741-5214(21)00839-9. [Epub ahead of print].

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BACKGROUND: Despite advances in peripheral vascular disease treatment, lower extremity amputation continues to be necessary in a significant number of patients. Up to 80% of amputees are not referred for prosthetic fitting. The factors contributing to referral decisions have not been adequately investigated, nor has the impact of prosthetic referral on survival. We characterized differences between patients who were successfully referred to our in-house prosthetists compared to those that were not, and identified factors associated with prosthetic referral and predictive of survival. METHODS: This was a retrospective analysis of all patients that underwent lower-extremity amputation by surgeons in our practice from January 1, 2010 to June 30, 2017. Age, sex, race, body mass index (BMI), diabetes, hypertension, hyperlipidemia, end stage renal disease, prior coronary artery bypass graft surgery, congestive heart failure, tobacco use, American Society of Anesthesiologists (ASA) score, previous arterial procedure, chronic obstructive pulmonary disease, statin use, postoperative ambulatory status, level of amputation, stump revision, and referral for prosthesis were collected. Survival was determined from a combination of sources, including the Social Security Death Master Index, multiple genealogic registries, and internet searches. Multivariable logistic regression was used to determine risk factors associated with prosthesis referral. Multivariable Cox proportional hazard regression with time dependent covariates was performed to assess risk factors associated with 5-year mortality. RESULTS: There were 293 patients included in this study. Mean age was 66 years and mean body mass index 27 kg/m(2). The majority of patients were male (69%), white (53%), with diabetes (65.4%) and hypertension (77.5%), and underwent below-the-knee amputation (BKA) (73%), . Prosthetic referral occurred in 123 (42.0%). Overall 5-year survival was 61.7% (95%CI, 55.9%-68.1%) (BKA 64.7% [95%CI, 57.9%-72.3%], above-the-knee amputation 53.8 % [95%CI, 43.4%-66.6%]). On multivariate analysis age >70 years, female sex, diabetes, ASA score 4 or 5, and current tobacco use were associated with no referral for prosthetic fitting. Patients with BMI 25-30, a previous arterial procedure, BKA, and history of stump revision were more likely to be referred. Factors associated with decreased survival were: increasing age, higher ASA class, Black race, and BMI; prosthetics referral was seen to be protective. CONCLUSION: We identified multiple patient factors associated with prosthetic referral, as well as several characteristics predictive of reduced survival after amputation. Being referred for prosthetic fitting was associated with improved survival not explained by patient characteristics and comorbidities. Further research is needed to determine whether the factors identified as associated with non-referral are markers for patient characteristics that make them clinically unsuitable for prosthetic fitting or if they are symptoms of unconscious bias or of patient’s access to care.

Selvaraj, S., Claggett, B.L., Packer, M., Zannad, F., Anand, I.S., Pieske, B., Zhao, Z., Shi, V.C., Lefkowitz, M.P., McMurray, J.J.V. and Solomon, S.D. (2021). “Effects of Sacubitril/Valsartan on Serum Lipids in Heart Failure with Preserved Ejection Fraction.” J Am Heart Assoc May 16;e022069. [Epub ahead of print]. e022069.

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Background Dyslipidemia is common in heart failure with preserved ejection fraction (HFpEF). Sacubitril/valsartan improves insulin sensitivity and augments natriuretic peptide (NP) signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking. Methods and Results We analyzed 4,744 participants from PARAGON-HF with available screening lipids. During follow-up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16-week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A1c and urinary cyclic guanosine monophosphate (cGMP)/creatinine [a biomarker of NP activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides -5.0% (-6.6%, -3.5%), increased high-density lipoprotein cholesterol (HDL-c) +2.6% (+1.7%, +3.4%), and increased low-density lipoprotein cholesterol (LDL-c) +1.7% (+0.4%, +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (p-interaction<0.001), and at 16-weeks by -13.0% (-18.1%, -7.6%), or -29.9 (-44.3, -15.5) mg/dL, in this group. Adjusting for the change in urinary cGMP/creatinine significantly attenuated treatment effects on triglycerides and HDL-c, but not LDL-c, while adjusting for other biomarkers did not significantly alter the treatment effects. Conclusions Sacubitril/valsartan significantly reduces triglycerides compared with valsartan, an effect that was substantially stronger in those with elevated baseline triglycerides. Modest increases in HDL-c and LDL-c cholesterol were also observed with therapy. The underlying mechanism(s) of changes in HDL-c and triglycerides are related to sacubitril/valsartan's effects on NP activity.

Packer, M., Januzzi, J.L., Jr., Ferreira, J.P., Anker, S.D., Butler, J., Filippatos, G., Pocock, S.J., Brueckmann, M., Jamal, W., Cotton, D., Iwata, T. and Zannad, F. (2021). “Concentration-Dependent Clinical and Prognostic Importance of High-Sensitivity Cardiac Troponin T in Heart Failure and a Reduced Ejection Fraction and the Influence of Empagliflozin: the EMPEROR-Reduced Trial.” Eur J Heart Fail May 30. [Epub ahead of print].

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BACKGROUND: Circulating troponin is an important measure of risk in patients with heart failure, but it has not been used to determine if disease severity influences the responses to drug treatments in randomized controlled trials. METHODS: In the EMPEROR-Reduced trial, patients with class II-IV heart failure and a reduced ejection fraction were randomly assigned to placebo or empagliflozin 10 mg daily and followed for the occurrence of serious heart failure and renal events. High-sensitivity cardiac troponin T (hs-cTnT) was measured in 3636 patients (> 97%) at baseline, and patients were divided into four groups based on the degree of troponin elevation. RESULTS: With increasing concentrations of hs-cTnT, patients were progressively more likely to have diabetes and atrial fibrillation, to have New York Heart Association class III-IV symptoms and been hospitalized for heart failure within the prior year, and to have elevated levels of natriuretic peptides and worse renal function (P-trend <0.0001 for all comparisons), but importantly, the troponin groups did not differ with respect to ejection fraction. A linear relationship was observed between the logarithm of hs-cTnT and the combined risk of cardiovascular death or hospitalization for heart failure (P = 0.0015). When treated with placebo, patients with the highest levels of hs-cTnT had risks of cardiovascular death and hospitalization for heart failure that were 3-5 fold greater than those with values in the normal range. Patients with higher levels of hs-cTnT were also more likely to experience worsening of renal function and serious adverse renal events and show the least improvement in health status (as measured by the Kansas City Cardiomyopathy questionnaire). When compared with placebo, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure, regardless of the baseline level of hs-cTnT, whether the effects of treatment were analyzed as hazard ratios or absolute risk reductions (Graphical Abstract).. CONCLUSIONS: Elevations in hs-cTnT reflect the clinical severity, stability and prognosis of patients with heart failure and a reduced ejection fraction, with biomarkers, comorbidities, clinical course and risks that are proportional to the magnitude of hs-cTnT elevation. Empagliflozin exerted favorable effects on heart failure and renal outcomes, regardless of the baseline concentration of hs-cTnT.

Ferreira, J.P., Konstam, M.A., McMurray, J.J.V., Butler, J., Girerd, N., Rossignol, P., Sharma, A., Voors, A.A., Lam, C.S.P., Packer, M. and Zannad, F. (2021). “Dosing of losartan in men vs. women with HFrEF: the HEAAL trial.” Eur J Heart Fail May 29. [Epub ahead of print].

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BACKGROUND: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit. METHODS: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and Machine Learning algorithms. RESULTS: The mean age was 66 years and 30% of the patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses: HR (95%CI) comparing high- vs- low-dose losartan for the composite outcome of all-cause death or all-cause hospitalisation was 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women, interaction P=0.018. Female sex clustered along with older age, ischemic HF, NYHA III/IV, and eGFR<60 ml/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe HF symptoms. CONCLUSIONS: Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g., kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders.

Swolinsky, J.S., Nerger, N.P., Leistner, D.M., Edelmann, F., Knebel, F., Tuvshinbat, E., Lemke, C., Roehle, R., Haase, M., Costanzo, M.R., Rauch, G., Mitrovic, V., Gasanin, E., Meier, D., McCullough, P.A., Eckardt, K.U., Molitoris, B.A. and Schmidt-Ott, K.M. (2021). “Serum creatinine and cystatin C-based estimates of glomerular filtration rate are misleading in acute heart failure.” ESC Heart Fail May 6. [Epub ahead of print].

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AIMS: We aimed to test whether the endogenous filtration markers serum creatinine or cystatin C and equation-based estimates of glomerular filtration rate (GFR) based on these markers appropriately reflect changes of measured GFR in patients with acute heart failure. METHODS: In this prospective cohort study of 50 hospitalized acute heart failure patients undergoing decongestive therapy, we applied an intravenous visible fluorescent injectate (VFI), consisting of a low molecular weight component to measure GFR and a high molecular weight component to correct for measured plasma volume. Thirty-eight patients had two sequential GFR measurements 48 h apart. The co-primary endpoints of the study were safety of VFI and plasma stability of the high molecular weight component. A key secondary endpoint was to compare changes in measured GFR (mGFR) to changes of serum creatinine, cystatin C and estimated GFR. RESULTS: VFI-based GFR measurements were safe and consistent with plasma stability of the high molecular weight component and glomerular filtration of the low molecular weight component. Filtration marker-based point estimates of GFR, when compared with mGFR, provided only moderate correlation (Pearson’s r, range 0.80-0.88, depending on equation used), precision (r(2) , range 0.65-0.78) and accuracy (56%-74% of estimates scored within 30% of mGFR). Correlations of 48-h changes GFR estimates and changes of mGFR were significant (P < 0.05) but weak (Pearson's r, range 0.35-0.39). Observed decreases of eGFR by more than 15% had a low sensitivity (range 38%-46%, depending on equation used) in detecting true worsening mGFR, defined by a >15% decrease in mGFR. CONCLUSIONS: In patients hospitalized for acute heart failure, serum creatinine- and cystatin C-based predictions performed poorly in detecting actual changes of GFR. These data challenge current clinical strategies to evaluate dynamics of kidney function in acute heart failure.