Research Spotlight

Posted February 15th 2020

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

Milton Packer M.D.
Milton Packer M.D.

McMurray, J. J. V., A. M. Jackson, C. S. P. Lam, M. M. Redfield, I. S. Anand, J. Ge, M. P. Lefkowitz, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, A. R. Rizkala, S. V. Sabarwal, A. M. Shah, S. J. Shah, V. C. Shi, D. J. van Veldhuisen, F. Zannad, M. R. Zile, M. Cikes, E. Goncalvesova, T. Katova, A. Kosztin, M. Lelonek, N. Sweitzer, O. Vardeny, B. Claggett, P. S. Jhund and S. D. Solomon (2020). “Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.” Circulation 141(5): 338-351.

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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, there is a greater heart failure therapeutic deficit in women compared with men. METHODS: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. RESULTS: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. CONCLUSIONS: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.


Posted February 15th 2020

Impaired systemic venous capacitance: the neglected mechanism in patients with heart failure and a preserved ejection fraction?

Milton Packer M.D.
Milton Packer M.D.

Maurer, M. S. and M. Packer (2020). “Impaired systemic venous capacitance: the neglected mechanism in patients with heart failure and a preserved ejection fraction?” Eur J Heart Fail Jan 16. [Epub ahead of print].

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The cardinal feature of HFpEF is an increase in LV filling pressure in the face of a LV ejection fraction that is not meaningfully reduced. In patients with a hypertrophic or infiltrative cardiomyopathy, the increase in LV filling pressures is primarily driven by an upward and leftward shift of the LV end‐diastolic pressure–volume relation. In contrast, in inflammatory‐metabolic HFpEF, LV end‐diastolic volumes (when indexed for age and sex) are not reduced; there is little evidence for a consistent shift in the end‐diastolic pressure–volume relation; and LV filling pressures are increased because the left ventricle is overfilled. The mechanisms leading to the increase in LV filling pressures and central blood volume in HFpEF have not been fully elucidated. Sodium retention and plasma volume expansion often play a role and can be ameliorated with diuretics. However, abnormalities of systemic venous capacitance likely play a critical (and unappreciated) role in driving an increase in central blood volume in HFpEF, explaining why diuretics are typically insufficient to ameliorate the increase in LV filling pressures. Mineralocorticoid receptor antagonists and neprilysin inhibitors may exert favourable effects on systemic venous capacitance, thus contributing to their action to lower LV filling pressures and wall stress in HFpEF. Additionally, treatments that block sympathetically‐mediated vasoconstriction of the splanchnic venous bed may also alleviate pulmonary congestion in patients with decompensated heart failure, a finding that also might be applicable to patients with HFpEF. Admittedly, the assessment of the effects of drugs on systemic venous capacitance is challenging, since it is extremely difficult to reliably evaluate the function of the splanchnic venous system in the clinical setting. Despite its potential importance, little work has been dedicated to understanding the role of changes in the functions of the systemic venous system in HFpEF. In the 1970s, the systemic venous system was the focus of considerable work in understanding the pathogenesis of HFrEF. It is time that we understood that, as in the case of HFrEF, HFpEF is a disorder of the entire circulation, inclusive of the peripheral circulation, and not simply a disorder of LV structure and function. (Excerpt from text, p. 3; no abstract available.)


Posted February 15th 2020

Tildrakizumab efficacy and safety are not altered by metabolic syndrome status in patients with psoriasis: Post hoc analysis of 2 phase 3 randomized controlled studies (reSURFACE 1 and reSURFACE 2).

Alan M. Menter M.D.
Alan M. Menter M.D.

Lebwohl, M. G., C. L. Leonardi, N. N. Mehta, A. B. Gottlieb, A. M. Mendelsohn, J. Parno, S. J. Rozzo and A. Menter (2020). “Tildrakizumab efficacy and safety are not altered by metabolic syndrome status in patients with psoriasis: Post hoc analysis of 2 phase 3 randomized controlled studies (reSURFACE 1 and reSURFACE 2).” J Am Acad Dermatol 82(2): 519-522.

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This post hoc analysis evaluated tildrakizumab efficacy, durability of response, and safety in patients with moderate to severe chronic psoriasis with vs without metabolic syndrome (MetS) using pooled data from 2 phase 3, double-blind, randomized, placebo-controlled studies, reSURFACE 1 and reSURFACE 2. Patients with vs without MetS had higher prevalence of pre-existing cardiovascular disease and diabetes and higher median baseline weight and body mass index. Six patients (4.1%) with MetS (n = 5 tildrakizumab 100 mg; n = 1 tildrakizumab 200 mg) and 25 patients (4.5%) without MetS (n = 12 tildrakizumab 100 mg; n = 13 tildrakizumab 200 mg) did not complete the study. Percentages of patients with ≥75% improvement on the Psoriasis Area and Severity Index (PASI 75 responders) at weeks 12 and 52 were comparable between patients with and without MetS for both tildrakizumab doses. Percentages of PASI 90 and PASI 100 responders through week 52 were similar regardless of MetS status for both tildrakizumab doses. Tildrakizumab efficacy through week 52 was maintained comparably in patients with and without MetS. Reductions in mean PASI from baseline were similar regardless of MetS status for both tildrakizumab doses. Percentages of patients with ≥1 serious adverse event (AE) and those with ≥1 serious infection were similar in patients with and without MetS. The most common serious AEs for patients with vs without MetS were gastrointestinal and cardiac disorders after tildrakizumab 100 mg and injury/procedural complications and nervous system disorders after tildrakizumab 200 mg. Fatal AEs occurred in 2 patients with MetS (both tildrakizumab 100 mg) and 2 patients without MetS (1 per tildrakizumab dose). Infection was the most commonly reported treatment-emergent AE. Incidence was similar in patients with and without MetS receiving tildrakizumab 100 mg and numerically higher in patients with and without MetS receiving tildrakizumab 200 mg. The incidence of cardiovascular events did not vary by MetS status, and there were no reports of diabetes worsening after treatment. Weight increases through week 28 were limited (∼1 kg on average) in patients with and without MetS across both tildrakizumab doses. Exposure-adjusted rates of tier 1 treatment-emergent AEs were comparable across doses regardless of MetS status. These post hoc analyses were not powered for statistical analyses based on MetS status, and populations were not matched for smoking history and other potential cofactors. Although abdominal obesity is more highly correlated with MetS risk factors relative to body mass index, 2 the latter was used because abdominal obesity data were not collected. Sample sizes for patients with MetS were relatively small. Further evaluation of the effect of weight only on treatment efficacy and safety was not feasible because only 25 patients with a body mass index of <30 kg/m 2 met ≥3 criteria for MetS. Despite limitations, these results suggest efficacy, safety, and drug survival of tildrakizumab are comparable in patients with psoriasis regardless of MetS status. (Excerpts from text, p. 519-521; no abstract available; full text contains links to supplemental data.)


Posted February 15th 2020

Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial.

Milton Packer M.D.
Milton Packer M.D.

Lam, P. H., M. Packer, G. C. Fonarow, C. Faselis, R. M. Allman, C. J. Morgan, S. N. Singh, B. Pitt and A. Ahmed (2020). “Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial.” Am J Med 133(2): e25-e31.

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BACKGROUND: In the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by postrandomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril. METHODS: There were 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (ejection fraction less-than-or-equal-to 35%) randomized to receive starting doses (5-10 mg/day) of placebo (n = 1284) or enalapril (n = 1285). At day 14, both study drugs were blindly up-titrated to the target dose (20 mg/day). Overall, 96% (2458/2569) of the patients returned for dose up-titration, which was achieved in 59% (1444/2458), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated. RESULTS: HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14 days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06), respectively. Corresponding HRs (95% CIs) at 30 days were 0.82 (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68), respectively. The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose. CONCLUSION: These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug.


Posted February 15th 2020

Impact of microbial contamination of the islet product during total pancreatectomy with islet autotransplantation.

Bashoo Naziruddin Ph.D.
Bashoo Naziruddin Ph.D.

Kumano, K., M. Takita, S. Vasu, C. Darden, M. Lawrence, E. Beecherl, A. Gupta, N. Onaca and B. Naziruddin (2020). “Impact of microbial contamination of the islet product during total pancreatectomy with islet autotransplantation.” J Hepatobiliary Pancreat Sci Jan 16. [Epub ahead of print].

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BACKGROUND: The combined use of interleukin-1beta and tumor necrosis factor-alpha blockers in the peritransplant period has improved outcomes of total pancreatectomy with islet autotransplantation (TPIAT). However, these drugs may suppress the immune system, resulting in severe infection. METHODS: We retrospectively investigated the impact of microbial-contaminated islet product on posttransplant complications and metabolic outcomes of TPIAT patients receiving the IL-1 and TNF-blockade treatment at our center. RESULTS: Among 108 TPIAT patients, 37 patients (34%) received contaminated products. Preoperative stent treatment and fibrosis score were independent risk factors for the contamination. There were no significant differences between the contaminated and noncontaminated product groups in posttransplant infectious complication rate, length of hospitalization, or readmission rate. However, islet equivalents (P < 0.0001) and insulin independence rate (P = 0.036) at 6 months were significantly lower for patients receiving contaminated product. CONCLUSIONS: These results suggest that combined anti-inflammatory drug use is safe and well tolerated in TPIAT patients who receive contaminated islet product and does not increase the rate of infectious complications; however, contaminated islet product is associated with poor metabolic outcomes.