AHA Scientific Sessions 2014. Clinical Science: Special Reports CS.03 Management of Cardiovascular Disease November 17, 2014, McCormick Place. Chicago, IL. Impact of Additive Use of Olmesartan in Patients With Chronic Heart Failure: The Supplemental Benefit of an Angiotensin Receptor Blocker in Hypertensive Patients With Stable Heart Failure Using Olmesartan (SUPP SUPPORT RT) Trial Yasuhiko Sakata, 1 Kotaro Nochioka, 1 Masanobu Miura, 1 Tsuyoshi Takada, 1 Soichiro Tadaki, 1 Satoshi Miyata, 2 Nobuyuki Shiba, 2 and Hiroaki Shimokawa 1,2 on behalf of the SUPPORT Trial Investigators Departments of Cardiovascular Medicine 1 and Evidence-based Cardiovascular Medicine 2 , Tohoku University Graduate School of Medicine, Sendai, Japan.
The SU SUPPO PPORT Trial Backgr grou ound • It is still controversial whether the addition of ARB to ACEI and/or ARB, RB, ACEI CEI, o or BB is s reco recommended i d in n HFp HFpEF, , There here are are no no est established t d ther herapi pies f for or HFp HFpEF. The preval he prevalence of nce of HFp HFpEF is i increasi ncreasing ng worl orldwide. de. BB is beneficial in HF patients. onl only for BP BP cont control w when com hen compl plicated ed with H h HT. Prevalence of HFpEF in Japan • Particularly, impacts of the combination use of ARB is to be (%) P<0.01 elucidated in the contemporary HF population including HFpEF. 100 On top of NYHA Mean Over 53% 53% Trial Patients ARB Endpoint 80 class LVEF all ACEI BB ACEI+BB Combined ○ ○ △ × 60 * HF with II 62% II 6 % Val-HeFT Valsartan III 36% 27% All-cause 40 LVEF<40% ○ ○ △ × 68% 68% death 50% 50% 20 HF with 73% 28% Combined ○ ○ / △ N/A CHARM- LVEF<40%, Candesartan II 24% ○ * * 0 Added treated with III 73% CHART CHART-1 1 CHART CHART-2 2 ACEI (2000 00-200 2004) 4) (2006 06-201 2010) 0) * : cardiac arrest with resuscitation and hospitalization for HF * * : cardiovascular death and hospital admission for CHF Sakata Y and Shimokawa H, Circ J 2013
The SU SUPPO PPORT Trial Study Ob y Obje ject ctive ve To examine whether an additive treatment with an ARB, olmesartan, reduces the mortality and morbidity in hypertensive patients with CHF treated with ACEI, BB, or both in the real world practice, in which the prevalence of HFpEF is increasing. Sakata Y, Shimokawa H, et al. J Cardiol 2013;62:31-36.
The SU SUPPO PPORT Trial Inclu lusion ion a and d Exclu lusion ion C Crit iter eria ia Inclusio ion Cr Crit iteria ia Ex Exclu lusion Cr Crit iteria ia • Renal dysfunction (Cr >3.0 mg/dL) • Aged 20 – 79 years • Chronic hemodialysis • CHF in NYHA class II - IV • Drug hypersensitivity to olmesartan * • History of HT or treatment with • Severe liver dysfunction antihypertensive medications • History of angioedema • Treatment with ACEI and/or BB • History of malignant tumor or life- threatening illness of poor prognosis • Not treated with any ARB • Pregnant or possibly pregnant patients • CV surgery, AMI, or PCI within 6 * : defined according to the JNC 7 months recommendation. Sakata Y, Shimokawa H, et al. J Cardiol 2013;62:31-36.
The SU SUPPO PPORT Trial Endpoi points nts Pri rimar ary E Endpoi ndpoint Second econdary E Endpoi ndpoints A composite of • CV death the following outcomes: • death due to HF • sudden death ・ all-cause death • AMI ・ non-fatal AMI • stroke ・ non-fatal stroke • new-onset diabetes ・ Hospitalization for HF • development of renal dysfunction • new-onset atrial fibrillation, etc Sakata Y, Shimokawa H, et al. J Cardiol 2013;62:31-36.
Study dy F Flow ow The SU SUPPO PPORT Trial Hypertensive patients with Stage C/D HF (n = 1147) Enrollment : 2006.10.1 – 2010.3.31 Randomization 993 (87%) at out-patient clinics. Cont ontrol gr group oup Olmesa sart rtan gr group oup Titrated (n = n = 569) 569) (n = n = 578 578) up to 40mg/day. Excluded (n=1) ・ lack of information Excluded (n=0) (n=1) Cont ontrol gr group oup Olmesa sart rtan gr group oup (n = n = 568 568) (n = n = 578 578) Annual follow-up ( 2013.3.31) ~ （ clinicaltrials.gov-NCT00417222 ）
The SU SUPPO PPORT Trial Pat atient Ch Char aract acteristics Contr ontrol Olmesar artan an Contr ontrol Olmesar artan an P-val alue ue P-val alue ue (n= n=56 569) (n=578) 78) (n=569) 69) (n=578) 78) Age, years 65.5 ± 10.1 65.8 ± 10.4 0.445 Laboratory findings Males, % 427 (75.2%) 429 (74.2%) 0.71 Hemoglobin, g/dL 13.7 ± 1.9 13.8 ± 1.7 0.279 Body mass index, kg/m2 24.6 ± 4.1 24.2 ± 4.1 0.185 Blood urea nitrogen, mg/dL 18.0 ± 6.9 18.3 ± 7.5 0.556 NYHA functional class 0.564 Creatinine, mg/dL 0.95 ± 0.36 0.94 ± 0.33 0.956 II 530 (93.5%) 535 (92.6%) Albumin, mg/dL 4.2 ± 0.4 4.2 ± 0.4 0.28 III 37 (6.5%) 43 (7.4%) LDL-C, mg/dL 107.3 ± 30.0 108.2 ± 30.8 0.775 Baseline cardiovascular disease eGFR, mL/min/1.73 m 2 Ischemic heart disease 262 (46.1%) 70.4 ± 24.4 70.0 ± 22.6 283 (49%) 0.887 0.337 Dilated cardiomyopathy 132 (23.2%) 110 (19%) 0.081 BNP, pg,/mL 78.2 (37.8, 173.0) 84.2 (36.7, 188.8) 0.63 Diabetes mellitus 292 (51.4%) 283 (49%) 0.408 Baseline medication Hemodynamics and LV function Beta-blocker 416 (73.2%) 405 (70.1%) 0.234 Systolic BP, mmHg 127.1 ± 18.0 128.7 ± 18.2 0.081 ACE inhibitor 460 (81.0%) 469 (81.1%) 0.946 Diastolic BP, mmHg 73.9 ± 11.7 74.8 ± 12.2 0.311 Diuretics 322 (56.7%) 328 (56.7%) 0.984 Heart rate, bpm 71.5 ± 14.6 71.2 ± 13.8 0.808 Calcium channel blocker 212 (37.3%) 222 (38.4%) 0.705 LVDd, mm 54.0 ± 8.7 53.3 ± 9.0 0.113 Statin 274 (48.2%) 287 (49.7%) 0.632 LVEF, % 53.7 ± 14.5 54.5 ± 14.9 0.277
The SU SUPPO PPORT Trial Time C e Cour urse e in B Blood ood P Pres essur ure mmHg Systolic 150 Blood pressure Olmes esar artan 100 Cont ontrol 50 Diastolic 0 Years after 0 1 2 3 4 5 6 randomization Control (N) 568 544 522 495 359 151 19 Olmesartan (N) 576 548 529 503 350 150 11
The SU SUPPO PPORT Trial Primary Prim ry End ndpo point (%) ate Cont ntrol ol rat ent r Olmes esar artan an event ulative ev umul Cum 29.2% vs.33.2% HR 1.18 (0.96-1.46), P=0.112 No. at o. at risk isk Contr ontrol 568 513 483 449 317 134 28 Olmesar artan an 578 517 474 436 293 118 47
The SU SUPPO PPORT Trial Primar mary a and d ot other er e endp dpoints Cont ontrol Olmesa sart rtan 95% C.I. Hazard (N=568 568) (N=578 578) P-value ratio lower upper events, n ev n (%) %) ev events, n n (%) %) Primar ary e endpoi point nt 166 ( 29.2 ) 192 ( 33.2 ) 1.183 0.961 1.457 0.112 all-cause death 85 ( 15.0 ) 98 ( 17.0 ) 1.152 0.862 1.541 0.338 non-fatal AMI 8 ( 1.4 ) 12 ( 2.1 ) 1.479 0.604 3.617 0.391 Additive use of olmesartan did not improve non-fatal stroke 26 ( 4.6 ) 34 ( 5.9 ) 1.313 0.788 2.188 0.296 clinical outcomes but worsened renal hospitalization for HF 99 ( 17.4 ) 113 ( 19.6 ) 1.148 0.877 1.504 0.316 Secondar ondary e endpoi points nts function in hypertensive CHF patients treated CV death 38 ( 6.7 ) 48 ( 8.3 ) 1.258 0.822 1.926 0.290 with evidence-based medications. HF death 18 ( 3.2 ) 10 ( 1.7 ) 0.556 0.257 1.205 0.137 sudden death 8 ( 1.4 ) 18 ( 3.1 ) 2.238 0.973 5.148 0.058 fatal arrythmia 29 ( 5.1 ) 30 ( 5.2 ) 1.017 0.611 1.695 0.947 new-onset DM 60 ( 10.6 ) 70 ( 12.1 ) 1.169 0.828 1.650 0.376 renal dysfunction 61 ( 10.7 ) 97 ( 16.8 ) 1.638 1.189 2.257 0.003 new-onset AF 31 ( 5.5 ) 21 ( 3.6 ) 0.665 0.382 1.157 0.149
The SU SUPPO PPORT Trial Baseline Medications and the Primary Endpoint A. (+)ACEI, (-)BB B. (-)ACEI, (+)BB C. (+)ACEI, (+)BB (%) (%) (%) Cont ontrol ol Cont ontrol ol Cont ontrol ol Olmes mesar artan Cumulative event rate Cumulative event rate Cumulative event rate Olmes mesar artan Olmes mesar artan P=0.588 P=0.118 P=0.006 HR=1.12(0.75, 1.66) HR=0.66(0.39, 1.12) HR=1.47(1.11, 1.95) Number ber Number ber Number ber at ris isk at ris isk at ris isk Cont ontrol Cont ontrol Cont ontrol 148 130 124 117 96 55 7 104 95 88 80 59 37 8 312 286 270 251 168 68 45 Olmes esar artan an Olmes esar artan an Olmes esar artan an 170 154 144 135 92 37 37 106 101 96 90 65 43 43 299 261 233 211 140 93 30
The SU SUPPO PPORT Trial Triple combination and adversecardiac events Al All-caus use e Death Primary Endpoi dpoint nt Overall Overall (+) ACEI, (-) BB (+) ACEI, (-) BB (-) ACEI, (+) BB (-) ACEI, (+) BB (+) ACEI, (+) BB (+) ACEI, (+) BB HR HR 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Olmesartan Olmesartan better worse better worse Renal enal Dysfun unction Overall ACEI: Angi ngioten ensin n conv onverting ng (+) ACEI, (-) BB enzyme i enz inhi nhibi bitors (-) ACEI, (+) BB BB: BB: Bet eta a bl bloc ocker ers (+) ACEI, (+) BB HR 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Olmesartan better worse
The SU SUPPO PPORT Trial Limi mitations • Prospective, randomized, open-label blinded endpoint (PROBE) design • Well-controlled BP levels at baseline a128/74mmHg at the assignment • Stably treated, mildly symptomatic HF a aNHYA class II in 93%, median BNP levels of 80pg/ml • Relatively small sample size for patients with reduced ejection fraction aLVEF>50% in 62%, LVEF<50% in 38%
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