Baylor Heart and Vascular Institute

Zannad, F., M. L. A. Alonso Garcia, J. S. Borer, W. G. Stough, T. Clutton-Brock, Y. Rosenberg and M. Packer (2017). “Role of payers in the development of cardiovascular therapeutics: Misalignment between approval and reimbursement.” J Am Coll Cardiol 70(22): 2822-2830.

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Regulators and payers have contrasting priorities that can lead to divergent decisions and delays in patient access to new treatments. Those involved in coverage decisions have not routinely been integrated in the drug development process. Theoretically, inclusion of payer representatives early in development could help discern discordance among stakeholder priorities; facilitate cooperation to align objectives; foster agreement on the evidence required for approval and reimbursement; improve transparency, accountability, and consistency of payer decision making; and ideally, minimize delays in patient access to new therapies. However, early participation by payers may not provide these expected benefits if payers’ decision-making processes are not evidence based or cannot be reliably predicted. This paper describes current interactions among regulatory agencies, payers, sponsors, and investigators and proposes collaboration among all stakeholders earlier in the development process. The premise that a priori discussions might facilitate the delivery of advances in cardiovascular care is a hypothesis worth testing.

Mogensen, U. M., L. Kober, P. S. Jhund, A. S. Desai, M. Senni, S. L. Kristensen, A. Dukat, C. H. Chen, F. Ramires, M. P. Lefkowitz, M. F. Prescott, V. C. Shi, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. Packer and J. J. V. McMurray (2017). “Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in paradigm-hf.” Eur J Heart Fail: 2017 Nov [Epub ahead of print].

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AIMS: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. METHODS AND RESULTS: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1-Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA >/=8.6 mg/dL) compared with Q1 (<5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m(2) ), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09-1.50), P = 0.003], cardiovascular death [1.44 (1.11-1.77), P = 0.001], HF hospitalization [1.37 (1.11-1.70), P = 0.004], and all-cause mortality [1.36 (1.13-1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17-0.32) mg/dL over 12 months (P < 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration. CONCLUSION: Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA.

Packer, M. (2017). “Early worsening of renal function after treatment with antihyperglycemic drugs: A consistent finding in large-scale trials.” Am J Med: 2017 Nov [Epub ahead of print].

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Prolonged hyperglycemia in type 2 diabetes exerts adverse structural and functional effects on the kidney, and sustained lowering of blood glucose for a decade or longer has been shown to reduce the risk of progression to end-stage renal disease. 1 However, during the first months or years of treatment with an antihyperglycemic drug, patients may experience worsening of renal function regardless of the agent used to lower blood glucose. There is minimal recognition of this phenomenon in the medical literature. The most persuasive evidence supporting the occurrence of early worsening of renal function after initiation of treatment with antidiabetic drugs is derived from randomized controlled clinical trials with different antihyperglycemic agents. Sequential changes in estimated glomerular filtration rate (or in serum creatinine) have been reported in 5 large-scale trials completed since regulatory agencies issued a new guidance on diabetes in 2008. 2

Cleland, J. G. F., K. V. Bunting, M. D. Flather, D. G. Altman, J. Holmes, A. J. S. Coats, L. Manzano, J. J. V. McMurray, F. Ruschitzka, D. J. van Veldhuisen, T. G. von Lueder, M. Bohm, B. Andersson, J. Kjekshus, M. Packer, A. S. Rigby, G. Rosano, H. Wedel, A. Hjalmarson, J. Wikstrand and D. Kotecha (2017). “Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: An individual patient-level analysis of double-blind randomized trials.” Eur Heart J: 2017 Oct [Epub ahead of print].

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Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF >/= 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 >/= 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF >/= 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF >/=50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis. Conclusion: Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.

Gonzalez-Hernandez, J., P. Prajapati, G. Ogola, V. Nguyen, N. Channabasappa and H. G. Piper (2017). “A comparison of lipid minimization strategies in children with intestinal failure.” J Pediatr Surg: 2017 Oct [Epub ahead of print].

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PURPOSE: The purpose of this study was to compare outcomes of lipid minimization with either Intralipid (IL) or Omegaven(R) in children with intestinal failure (IF) who developed intestinal failure-associated liver disease (IFALD) while receiving parenteral nutrition (PN). METHODS: A retrospective review of children with IF requiring PN who developed IFALD (direct bilirubin >2 mg/dL) while receiving IL (2009-2016) was performed. Clinical characteristics, nutritional, and laboratory values were compared between children treated with reduced IL or Omegaven(R). RESULTS: 16 children were reviewed (8 treated with IL and 8 treated with Omegaven(R) at a median dose of 1g/kg/d). Both groups had similar demographics, small bowel length, and parenteral nutritional intake during the study (82.9+/-27.1 kcal/kg/d vs. 75.9+/-16.5 kcal/kg/d, p=0.54). The mean direct bilirubin (DBili) prior to initiating treatment was 7.8+/-4.3 mg/dL and 7.5+/-3.5 mg/dL (p=0.87) in the IL and Omegaven(R) groups, respectively. The IL group took a median of 113 days to achieve a DBili <0.5 mg/dL compared to 124 days in the Omegaven(R) group (p=0.49). There were no differences in markers of liver function or growth trajectories among groups. CONCLUSIONS: Lipid minimization with either IL or Omegaven(R) has similar success in achieving a normal DBili in children with IF and IFALD without major differences in nutritional status or growth.