Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure (TRUE-AHF)

Transcription

1 Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure (TRUE-AHF) Elizabeth Tien, PharmD, BCPS PGY2 Cardiology Pharmacy Resident Moses H. Cone Memorial Hospital Greensboro, NC Kristen Pogue, PharmD, BCPS-AQ Cardiology Clinical Pharmacist Specialist, Cardiology Michigan Medicine Ann Arbor, MI

2 Disclosures The speaker has nothing to disclose concerning possible financial or personal relationships with commercial entities that may have direct or indirect interest in the subject matter of this presentation.

3 TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr; Suppl: S1-S27. Acute Heart Failure

4 Ularitide Mechanism of Action Nat Rev Cardiol 2015;12:

5 Am Heart J 2005;150: 1239.e Initial Ularitide Trials

6 TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr. TRUE-AHF Objective To determine if prompt ularitide administration reduces longterm cardiovascular death risk in acute heart failure Design Randomized, double-blind, placebo-controlled trial Treatment Ularitide 15 ng/kg/min Placebo

7 TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr. Design Inclusion Acute heart failure hospitalization Worsened dyspnea at rest in previous week Heart failure evidence on chest radiograph BNP > 500 pg/ml or NT-proBNP > 2000 pg/ml Study initiation within 12 hours Systolic blood pressure mmhg Exclusion Intravenous diuretic within 2 hours Change in intravenous infusions within 2 hours Dobutamine > 5 mcg/kg/min or vasopressor use Levosimendan, milrinone, or phosphodiesterase inhibitor use within 7 days Mechanical circulatory support CrCl < 30 ml/min/1.73 m 2 Severe hepatic impairment

8 TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr. Outcomes Primary Outcomes Cardiovascular death Clinical course within first 48 hours Secondary Outcomes Length of hospitalization stay Length of intensive care unit stay Rehospitalization for heart failure Change in NT-proBNP

9 Hierarchical Clinical Composite Endpoint TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr.

10 Baseline Characteristics Characteristic Ularitide Placebo Age, yrs Male Gender (%) Nonblack race (%) Left Ventricular Ejection Fraction (%) < 40% > 40% Enrollment Region (%) Eastern Europe Blood Pressure, mmhg Systolic Diastolic NT-proBNP, pg/ml Troponin T, pg/ml Intravenous Nitrates (%) Intravenous Dobutamine (%) TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr.

11 TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr. Results Outcome Ularitide (N=1088) Placebo (N=1069) P-Value Cardiovascular Death 21.7% 21.0% 0.75 Clinical Outcome Improved Unchanged Worsened NT-proBNP Decrease (pg/ml) 48.6% 44.8% 6.6% 47.5% 44.2% 8.3% <0.001

12 TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr. Cardiovascular Events

13 TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr. In-Hospital Events

14 Blood Pressure Effects TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr; Suppl: S1-S27.

15 Conclusion Early administration of ularitide significantly decreased NT-proBNP levels No difference in clinical course or cardiovascular death

16 Critique Limitations Exclusion of patients requiring vasopressors Heart failure ejection fraction (EF) inclusion Subjective measurement of clinical improvement Evidence does not support early injury effect

17 Clinical Practice Implications Maintaining integrity of future multisite trials Variation of results by geographical region Natriuretic peptide place in therapy No benefit in early or delayed treatment Confirms lack of long-term benefits seen in previous trials

18 TRUE-AHF vs. ASCEND-AHF TRUE-AHF ASCEND-AHF Patients Enrolled 7,007 patients 2,157 patients Inclusion Treatment within 48 hours No EF exclusion Treatment within 12 hours EF < 40% Exclusion SBP < 90 mmhg SBP < 116 mmhg Dyspnea Assessment Hierarchical clinical outcome assessment 7-point Likert scale TRUE-AHF Investigators. N Engl J Med. Epub 2017 Apr. O'Connor C, Starling RC, Hernandez AF, et al. N Engl J Med 2011;365:32-43.

19 ASCEND-AHF Outcomes O'Connor C, Starling RC, Hernandez AF, et al. N Engl J Med 2011;365:32-43.

20 Current Clinical Trials Serelaxin Recombinant human relaxin-2 Mediates arterial vasodilation in pregnancy RELAX-AHF trials Pre-RELAX: reduction in dyspnea RELAX: possible cardiovascular mortality benefit RELAX-AHF Investigators. Lancet. 2013;381(9860): Teerlink JR, Metra M, Felker GM, et al. Lancet. 2009;373(9673):

21 RELAX-AHF Investigators. Lancet. 2013;381(9860): RELAX-AHF

22 Acknowledgments Kristen Pogue, PharmD, BCPS-AQ Cardiology Lisa Curran, PharmD, BCPS, CPP ACCP Cardiology PRN Journal Club Coordinators Ted Berei, PharmD, MBA Genevieve Hale, PharmD, BCPS Zachary Noel, PharmD, BCPS Thomas Szymanski, PharmD Candidate

23 Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure (TRUE-AHF) Elizabeth Tien, PharmD, BCPS PGY2 Cardiology Pharmacy Resident Moses H. Cone Memorial Hospital Greensboro, NC Kristen Pogue, PharmD, BCPS-AQ Cardiology Clinical Pharmacist Specialist, Cardiology Michigan Medicine Ann Arbor, MI