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EFFECT OF THE DIRECT RENIN INHIBITOR ALISKIREN ON LEFT VENTRICULAR REMODELING FOLLOWING MYOCARDIAL INFARCTION WITH LEFT VENTRICULAR DYSFUNCTION.

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  1. EFFECT OF THE DIRECT RENIN INHIBITOR ALISKIREN ON LEFT VENTRICULAR REMODELING FOLLOWING MYOCARDIAL INFARCTION WITH LEFT VENTRICULAR DYSFUNCTION Scott D. Solomon, MD, FACC, Sung Hee Shin, MD, Amil Shah, MD, Lars Kober, MD, Aldo P. Maggioni, MD, Jean Rouleau, MD, FACC, John J. V. McMurray, MD, FACC, Roxzana Kelly, Allen Hester, Marc A. Pfeffer, MD, PhD, FACC for the Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) investigators Brigham and Women’s Hospital, Boston, MA; Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; ANMCO Research Center, Firenze, Italy; University of Montreal, Montreal, Canada; Western Infirmary, Glasgow, Scotland; Novartis Pharmaceuticals, East Hanover, NJ

  2. Disclosures • Dr. Solomon, Kober, Maggioni, Rouleau, McMurray and Pfeffer have received research support from and have consulted for Novartis. • Ms. Kelly and Dr. Hester are employees of Novartis • The ASPIRE trial was funded by Novartis.

  3. Background • Despite major therapeutic advances acute myocardial infarction (AMI) remains associated with increased morbidity and mortality • In post-MI patients, reduced left ventricular (LV) systolic function is associated with increased risk of LV remodeling, mortality and heart failure • Angiotensin converting enzyme inhibitors (ACE-i) decrease the risk of death or chronic HF in patients with AMI1,2,3 and angiotensin receptor blockers (ARB) are an established alternative to ACE-i4 1 Pfeffer et al. SAVE Invest. NEJM 1992; 2 AIRE Invest. Lancet 1993; 3 TRACE Invest. NEJM 1995 4 Pfeffer et al. VALIANT invest NEJM 2003

  4. The direct renin inhibitor Aliskiren blocks the RAAS proximally and may attenuate ACE or ARB induced compensatory rise in PRA and further RAAS activation Non-ACE Pathways(e.g., chymase) • Vasoconstriction • Cell growth • Na/H2O retention • Sympathetic activation Negative Feedback Angiotensinogen ARBs AT1 Angiotensin I renin Angiotensin II Aliskiren ACE ACE-Inhibitors AT2 Aldosterone • Vasodilation • Antiproliferation(kinins) Cough,Angioedema Benefits? InactiveFragments Bradykinin Gradman et al. Circulation, 2006; McMurray et al. Circulation, 2004

  5. Hypothesis Adding aliskiren to standard therapy, including a proven inhibitor of the RAAS, would result in greater attenuation of adverse LV remodeling in patients after high risk acute myocardial infarction.

  6. Methods • International multicenter, randomized, double-blind, placebo-controlled trial • Primary Endpoint: Change in LVESV (baseline to week 36) • 80% power, alpha=0.05, to detect 3.1mL difference in LVESV reduction: Estimated sample size ~ 800 patients • Key Secondary endpoints: • CV death, hospitalization for heart failure, or a reduction in ejection fraction greater than 6 units • CV death, hospitalization for heart failure, recurrent myocardial infarction, stroke or resuscitated sudden death • overall safety and tolerability in combination with standard therapy in patients post acute myocardial infarction. • other echocardiographic assessments of cardiac size and function

  7. Methods Inclusion criteria • >18 years-old • AMI and LV systolic dysfunction within 7-42 days • Stable doses for 2 weeks of: antiplatelet, statin, beta-blocker, ACE-i or ARB • Qualifying echo: quality, LVEF< 45%, infarct size>20% Key Exclusion criteria • On both ACE-I and ARB • Severe refractory hypertension • Cardiogenic shock • eGFR< 30ml/min/1.73m2 • K > 5.0 mEq

  8. Design and titration Background Rx: antiplatelet, statin, beta-blocker, ACE-I or ARB Aliskiren 300 mg once daily 150 mg 75 mg Placebo 300 mg once daily Randomization Qualifying MI 150 mg 75 mg 1 week 1 week 2-8 weeks Total Follow-up: 36 weeks Visit 2 Baselineecho Visit 10 finalecho Echocardiograms evaluated in core laboratory Endpoints adjudicated by blinded central committee

  9. Died (8), withdrew consent (10), Echo of insufficient quality or other (50) ASPIRE Patient Flow Patients Screened Post MI N=1074 Enrolled/Randomized N= 820 Placebo n=397 Aliskiren n=423 Received Aliskiren n=422 Died (17), withdrew consent (11), echo of insufficient quality or other (52) Paired Evaluable Echocardiograms n=329 Paired Evaluable Echocardiograms n=343

  10. Baseline Demographics

  11. Concomitant Medications at Baseline • Optimal dose of ACE-I or ARB defined as daily doses of captopril 150mg, enalapril 20mg, lisinopril 20mg, perindopril 8mg, ramipril 10mg, candesartan 32mg, valsartan 320mg, losartan 100mg, irbesartan 300mg

  12. Baseline Echo parameters

  13. Mean Sitting Blood Pressure Throughout Trial 140 Placebo 124.2 ± 14.9 Aliskiren 122.4 ± 16.3 130 120 110 Placebo 100 Blood Pressure (mm Hg) Aliskiren 90 Placebo 76.5 ± 9.4 Aliskiren 74.2 ± 9.3 80 70 60 50 40 2 4 6 8 10 Visit

  14. Primary Outcome: Left Ventricular End-Systolic Volume at Baseline and Final Echo visit Baseline and Final LVESV Delta LVESV Difference0.90 (-1.6, 3.4) P = 0.44

  15. Echocardiographic Measures

  16. Secondary Efficacy Variables: composite endpoints of echo and adjudicated outcomes

  17. Cardiovascular Outcomes No Significant between group differences

  18. Posthoc Subgroup Analysis:Difference in primary endpoint (delta LVESV) between placebo and aliskiren P for interaction 0.765 0.063 0.604 0.819 0.913 0.925 0.44 Male (n=565) Female (n=107) No DM (n=524) DM (n=148) No HTN (n=327) HTN (n=345) age<65 (n=427) age>65 (n=245) No Aldo Blockers (n=499) Aldo Blockers (n=173) LVEF<35% (n=495) LVEF>35% (n=177) Overall (n=672) -6 -4 -2 0 2 4 6 8 10 12 Difference in change in LVESV (placebo - aliskiren) placebo favors aliskiren

  19. Adverse Events + Based on Fisher’s exact test *based on MEDRA codes

  20. Biochemical abnormalities

  21. Conclusions • In high risk post-MI patients with LV systolic dysfunction, the addition of aliskiren to a standard optimal medical regimen, including an ACE-I or an ARB, did not result in benefit with respect to ventricular remodeling compared to placebo and was associated with more adverse events. • Although ASPIRE utilized a surrogate endpoint, and was not powered to assess hard clinical outcomes, these results do not provide support for testing the use of aliskiren in a morbidity and mortality trial in this population. • Ongoing outcomes trials with aliskiren in patients with heart failure and diabetic kidney disease are well underway and will further assess the role for direct renin inhibition in these populations.

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