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

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Presentation on theme: "EFFECT OF THE DIRECT RENIN INHIBITOR ALISKIREN ON LEFT VENTRICULAR REMODELING FOLLOWING MYOCARDIAL INFARCTION WITH LEFT VENTRICULAR DYSFUNCTION Scott D."— Presentation transcript:

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 AMI 1,2,3 and angiotensin receptor blockers (ARB) are an established alternative to ACE-i 4 1 Pfeffer et al. SAVE Invest. NEJM 1992; 2 AIRE Invest. Lancet 1993; 3 TRACE Invest. NEJM 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 Angiotensinogen Non-ACE Pathways (e.g., chymase)  Vasoconstriction  Cell growth  Na/H 2 O retention  Sympathetic activation renin Angiotensin I Angiotensin II ACE Cough, Angioedema Benefits?  Bradykinin Inactive Fragments  Vasodilation  Antiproliferation (kinins) Aldosterone AT 2 AT 1 Aliskiren ACE-Inhibitors ARBs Gradman et al. Circulation, 2006; McMurray et al. Circulation, 2004 Negative Feedback

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

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

10 Baseline Demographics Characteristic Placebo N=397 Aliskiren N=423P value Male Gender (% )85%81%0.22 Age (Years ± SD)59 ± 1261 ± Age ≥65 years34%40%0.13 Baseline eGFR (mL/min/1.73m^2) 81 ± 1980 ± eGFR< 6013%17%0.17 Diabetes22%23%0.93 Hypertension50%55%0.27 Prior MI18%22%0.27 Prior HF4%6%0.23 Q wave MI71%68% 0.36 Anterior MI 79% 0.91 Killip Class ≥ 2 42%45%0.85

11 Concomitant Medications at Baseline Baseline Meds Placebo N=397 Aliskiren N=423P value Anti-platelet agents 98% 0.72 ACE-i 91%89%0.62 ARB 9%10%0.17 “Optimal” dose ACE-i or ARB* 43%44%0.72 Beta-Blocker 95%96%0.45 Statin 98%97%0.57 Aldosterone Blocker 24%29%0.12 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 Placebo N=374 Aliskiren N=403 P value LVESV (mL)86.1 ± ± LVEDV (mL)135.7 ± ± LVEF (%)37.5 ± ± Infarct Length (%) 25.0 ± ± WMSI1.8 ±

13 Mean Sitting Blood Pressure Throughout Trial Blood Pressure (mm Hg) Visit Placebo Aliskiren Placebo ± 14.9 Aliskiren ± 16.3 Placebo 76.5 ± 9.4 Aliskiren 74.2 ± 9.3

14 Primary Outcome: Left Ventricular End-Systolic Volume at Baseline and Final Echo visit Baseline and Final LVESV Delta LVESV Difference 0.90 (-1.6, 3.4) P = 0.44

15 Echocardiographic Measures Placebo N= 329 Aliskiren N=343 P BaselineChangeBaselineChange LVESV(mL) 84.2 ± ± ± ± LVEDV (mL) ± ± ± ± LVEF (%) 37.8 ± ± ± ± Infarct Length (%) 24.5 ± ± ± ± EF drop > 6% 2 (0.6%)6 (1.8%) 0.1 7

16 Secondary Efficacy Variables: composite endpoints of echo and adjudicated outcomes Secondary endpoints Placebo N=397 n (%) Aliskiren N=423 n (%) HR95% CI P-value Composite of CV death, hospitalization for HF, LVEF reduction by>6 units 24 (6%)29 (7%)1.06(0.60, 1.8)0.85 Composite of CV death, hospitalization for HF, recurrent MI, stroke, resuscitated sudden death 34 (9%)39 (9%)1.01(0.62, 1.63)0.98 All cause death 8 (2%)17 (4%)1.83(0.79, 4.3)0.16

17 Cardiovascular Outcomes Endpoint Placebo n=397 n (%) Aliskiren n=423 n (%) CV Death6 (1.5)13 (3.1) Resuscitated Sudden Death 4 (1.0)1 (0.2) HF Hospitalization17 (4.3)12 (2.8) Myocardial Infarction16 (4.0)11 (2.6) Stroke2 (0.5)7 (1.7) Any of the above34 (8.6)39 (9.2) No Significant between group differences

18 Posthoc Subgroup Analysis: Difference in primary endpoint (delta LVESV) between placebo and aliskiren placebofavors aliskiren P for interaction Overall (n=672) LVEF>35% (n=177) LVEF<35% (n=495) Aldo Blockers (n=173) No Aldo Blockers (n=499) age>65 (n=245) age<65 (n=427) HTN (n=345) No HTN (n=327) DM (n=148) No DM (n=524) Female (n=107) Male (n=565) Difference in change in LVESV (placebo - aliskiren)

19 Adverse Events Placebo (n = 397)Aliskiren (n = 422) p-value+ Total AEs and SAEs AEs 268 (67.5)316 (74.9) 0.02 SAEs92 (23.2)107 (25.4)0.51 Renal Dysfunction AEs 3 (0.8)10 (2.4) 0.09 SAEs 1 (0.3)2 (0.5) >0.99 Hypotension AEs 18 (4.5)37 (8.8) 0.02 SAEs3 (0.8)1 (0.2)0.36 Hyperkalemia* AEs 5 (1.3)22 (5.2) SAEs0 (0) - + Based on Fisher’s exact test *based on MEDRA codes

20 Biochemical abnormalities Placebo n=397 n (%) Aliskiren n=422 n (%) Urea  > 14.3 mmol/L (40mg/dL) 18 (4.5)52 (12.3) Creatinine  > 176 & 2 & < 3 mg/dL)  > 265  mol/L (3 mg/dL) 4 (1.0) 1 (0.3) 13 (3.1) 2 (0.5) Potassium  < 3.5 mmol/L  >5.5 &< 6.0 mmol/L  ≥ 6.0 mmol/L 11 (2.8) 16 (4.0) 10 (2.5) 10 (2.4) 32 (7.6) 23 (5.5)

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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