Impact of Additive Use of Olmesartan in Patients With Chronic Heart - - PowerPoint PPT Presentation

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Impact of Additive Use of Olmesartan in Patients With Chronic Heart - - PowerPoint PPT Presentation

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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

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SLIDE 1

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 Shimokawa1,2

  • n behalf of the SUPPORT Trial Investigators

Departments of Cardiovascular Medicine1 and Evidence-based Cardiovascular Medicine2, Tohoku University Graduate School of Medicine, Sendai, Japan.

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SLIDE 2

Trial Patients ARB NYHA class Mean LVEF Endpoint Over all ACEI BB ACEI+BB Val-HeFT HF with LVEF<40% Valsartan II 6 II 62% % III 36% 27% Combined ○

○ △ ×

All-cause death

○ ○ △ ×

CHARM- Added HF with LVEF<40%, treated with ACEI Candesartan II 24% III 73% 73% 28% Combined ○ ○/△ N/A

○

On top of

Backgr grou

  • und

The SU SUPPO PPORT Trial

* : cardiac arrest with resuscitation and hospitalization for HF * * * * : cardiovascular death and hospital admission for CHF *

  • It is still controversial whether the addition of ARB to ACEI and/or

BB is beneficial in HF patients.

  • Particularly, impacts of the combination use of ARB is to be

elucidated in the contemporary HF population including HFpEF.

The preval he prevalence of nce of HFp HFpEF is i increasi ncreasing ng worl

  • rldwide.

de. 53% 53%

20 40 60 80 100

CHART CHART-1 1

(2000 00-200 2004) 4) (%)

CHART CHART-2 2

(2006 06-201 2010) 0) P<0.01

Sakata Y and Shimokawa H, Circ J 2013

Prevalence of HFpEF in Japan

There here are are no no est established t d ther herapi pies f for

  • r HFp

HFpEF. ARB, RB, ACEI CEI, o

  • r BB is

s reco recommended i d in n HFp HFpEF, ,

  • nl
  • nly for BP

BP cont control w when com hen compl plicated ed with H h HT.

50% 50% 68% 68%

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SLIDE 3

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.

Study Ob y Obje ject ctive ve

The SU SUPPO PPORT Trial

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SLIDE 4
  • Renal dysfunction (Cr >3.0 mg/dL)
  • Chronic hemodialysis
  • Drug hypersensitivity to olmesartan
  • Severe liver dysfunction
  • History of angioedema
  • History of malignant tumor or life-

threatening illness of poor prognosis

  • Pregnant or possibly pregnant patients
  • CV surgery, AMI, or PCI within 6

months

Inclu lusion ion a and d Exclu lusion ion C Crit iter eria ia

Sakata Y, Shimokawa H, et al. J Cardiol 2013;62:31-36.

The SU SUPPO PPORT Trial

Ex Exclu lusion Cr Crit iteria ia Inclusio ion Cr Crit iteria ia

  • Aged 20 – 79 years
  • CHF in NYHA class II - IV
  • History of HT or treatment with

antihypertensive medications

  • Treatment with ACEI and/or BB
  • Not treated with any ARB

* : defined according to the JNC 7 recommendation. *

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SLIDE 5

A composite of the following outcomes: ・all-cause death ・non-fatal AMI ・non-fatal stroke ・Hospitalization for HF

Endpoi points nts

Sakata Y, Shimokawa H, et al. J Cardiol 2013;62:31-36.

The SU SUPPO PPORT Trial

Pri rimar ary E Endpoi ndpoint Second econdary E Endpoi ndpoints

  • CV death
  • death due to HF
  • sudden death
  • AMI
  • stroke
  • new-onset diabetes
  • development of renal dysfunction
  • new-onset atrial fibrillation, etc
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SLIDE 6

Study dy F Flow

  • w

Hypertensive patients with Stage C/D HF (n = 1147) Randomization Cont

  • ntrol gr

group

  • up

(n = n = 569) 569) Olmesa sart rtan gr group

  • up

(n = n = 578 578) Excluded (n=1)

・lack of information (n=1)

Excluded (n=0) Cont

  • ntrol gr

group

  • up

(n = n = 568 568) Olmesa sart rtan gr group

  • up

(n = n = 578 578) Enrollment : 2006.10.1 – 2010.3.31 Annual follow-up ( 2013.3.31) ~

The SU SUPPO PPORT Trial

993 (87%) at out-patient clinics. Titrated up to 40mg/day. （clinicaltrials.gov-NCT00417222）

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SLIDE 7

Contr

  • ntrol

(n= n=56 569) Olmesar artan an (n=578) 78) P-val alue ue Age, years 65.5 ± 10.1 65.8 ± 10.4 0.445 Males, % 427 (75.2%) 429 (74.2%) 0.71 Body mass index, kg/m2 24.6 ± 4.1 24.2 ± 4.1 0.185 NYHA functional class 0.564 II 530 (93.5%) 535 (92.6%) III 37 (6.5%) 43 (7.4%) Baseline cardiovascular disease Ischemic heart disease 262 (46.1%) 283 (49%) 0.337 Dilated cardiomyopathy 132 (23.2%) 110 (19%) 0.081 Diabetes mellitus 292 (51.4%) 283 (49%) 0.408 Hemodynamics and LV function Systolic BP, mmHg 127.1 ± 18.0 128.7 ± 18.2 0.081 Diastolic BP, mmHg 73.9 ± 11.7 74.8 ± 12.2 0.311 Heart rate, bpm 71.5 ± 14.6 71.2 ± 13.8 0.808 LVDd, mm 54.0 ± 8.7 53.3 ± 9.0 0.113 LVEF, % 53.7 ± 14.5 54.5 ± 14.9 0.277

Pat atient Ch Char aract acteristics

The SU SUPPO PPORT Trial

Contr

  • ntrol

(n=569) 69) Olmesar artan an (n=578) 78) P-val alue ue Laboratory findings Hemoglobin, g/dL 13.7 ± 1.9 13.8 ± 1.7 0.279 Blood urea nitrogen, mg/dL 18.0 ± 6.9 18.3 ± 7.5 0.556 Creatinine, mg/dL 0.95 ± 0.36 0.94 ± 0.33 0.956 Albumin, mg/dL 4.2 ± 0.4 4.2 ± 0.4 0.28 LDL-C, mg/dL 107.3 ± 30.0 108.2 ± 30.8 0.775 eGFR, mL/min/1.73 m2 70.4 ± 24.4 70.0 ± 22.6 0.887 BNP, pg,/mL 78.2 (37.8, 173.0) 84.2 (36.7, 188.8) 0.63 Baseline medication Beta-blocker 416 (73.2%) 405 (70.1%) 0.234 ACE inhibitor 460 (81.0%) 469 (81.1%) 0.946 Diuretics 322 (56.7%) 328 (56.7%) 0.984 Calcium channel blocker 212 (37.3%) 222 (38.4%) 0.705 Statin 274 (48.2%) 287 (49.7%) 0.632

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SLIDE 8

Years after randomization 1 2 3 4 5 6

Control (N) 568 544 522 495 359 151 19 Olmesartan (N) 576 548 529 503 350 150 11

mmHg

150 100 50

Blood pressure

Olmes esar artan Cont

  • ntrol

Time C e Cour urse e in B Blood

  • od P

Pres essur ure

Systolic Diastolic

The SU SUPPO PPORT Trial

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SLIDE 9

Contr

  • ntrol

568 513 483 449 317 134 28 Olmesar artan an 578 517 474 436 293 118 47

Cum umul ulative ev event ent r rat ate

29.2% vs.33.2% HR 1.18 (0.96-1.46), P=0.112 Cont ntrol

  • l

Olmes esar artan an

  • No. at
  • . at risk

isk

(%)

Prim Primary ry End ndpo point

The SU SUPPO PPORT Trial

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SLIDE 10

Primar mary a and d ot

  • ther

er e endp dpoints

The SU SUPPO PPORT Trial

Cont

  • ntrol

(N=568 568) Olmesa sart rtan (N=578 578) Hazard ratio 95% C.I. P-value

ev events, n n (%) %) ev events, n n (%) %)

lower upper 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 non-fatal stroke 26 ( 4.6 ) 34 ( 5.9 ) 1.313 0.788 2.188 0.296 hospitalization for HF 99 ( 17.4 ) 113 ( 19.6 ) 1.148 0.877 1.504 0.316

Secondar

  • ndary e

endpoi points nts

CV death 38 ( 6.7 ) 48 ( 8.3 ) 1.258 0.822 1.926 0.290 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

Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications.

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SLIDE 11

P=0.588 HR=1.12(0.75, 1.66)

Cont

  • ntrol

104 95 88 80 59 37 8 Olmes esar artan an 106 101 96 90 65 43 43

P=0.118 HR=0.66(0.39, 1.12)

  • C. (+)ACEI, (+)BB
  • A. (+)ACEI, (-)BB
  • B. (-)ACEI, (+)BB

Cont

  • ntrol
  • l

Olmes mesar artan

Cumulative event rate Cumulative event rate Cumulative event rate

Cont

  • ntrol
  • l

Olmes mesar artan Cont

  • ntrol
  • l

Olmes mesar artan

(%) (%) (%) Cont

  • ntrol

312 286 270 251 168 68 45 Olmes esar artan an 299 261 233 211 140 93 30

P=0.006 HR=1.47(1.11, 1.95)

Cont

  • ntrol

148 130 124 117 96 55 7 Olmes esar artan an 170 154 144 135 92 37 37 Number ber at ris isk Number ber at ris isk Number ber at ris isk

Baseline Medications and the Primary Endpoint

The SU SUPPO PPORT Trial

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SLIDE 12

Primary Endpoi dpoint nt

Overall (+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB Olmesartan

better worse

HR

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Al All-caus use e Death

Overall (+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB Olmesartan

better worse

HR

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Renal enal Dysfun unction Overall (+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB Olmesartan

better worse

HR

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

ACEI: Angi ngioten ensin n conv

  • nverting

ng enz enzyme i inhi nhibi bitors BB: BB: Bet eta a bl bloc

  • cker

ers

Triple combination and adversecardiac events

The SU SUPPO PPORT Trial

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SLIDE 13

Limi mitations

The SU SUPPO PPORT Trial

  • 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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SLIDE 14

Di Discussion

The SU SUPPO PPORT Trial

Trial Patients ARB NYHA class Mean LVEF Endpoint Overall ACEI BB ACEI+BB SUPPORT HT with CHF Olmesartan II 9 II 93% III 7% 54% 54% Combined

△ △ △ ×

All-cause death

△ △ ○ ×

Val-HeFT HF with LVEF<40% Valsartan II 6 II 62% % III 36% 27% Combined

○ ○ △ ×

All-cause death

○ ○ △ ×

CHARM- Added HF with LVEF<40%, treated with ACEI Candesartan II 24% III 73% 73% 28% Combined

○ ○/△ N/A ○

* : cardiac arrest with resuscitation and hospitalization for HF * * * * * * * * : cardiovascular death and hospital admission for CHF * * * : all-cause death, non-fatal AMI, non-fatal stroke and hospitalization for HF

Impact of ARB on top of ACEI and/or BB is still controversial in HF.

On top of

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SLIDE 15
  • Additive use of olmesartan did not improve

clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications.

  • Particularly, the triple combination therapy

with olmesartan, ACE inhibitors and beta- blockers was associated with increased adverse cardiac events.

Co Conc nclusion

  • ns

The SU SUPPO PPORT Trial

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SLIDE 16

Exec ecut utive e Committe ttee

  • H. Shimokawa (principal investigator), M. Fukuchi, T. Goto, T. Hiramoto, K.

Inoue, A. Kato, T. Komaru, M. Ohe, N. Sekiguchi, N. Shiba, T. Shinozaki, M. Sugi, K. Tamaki. Steer eering C ng Committee ee

  • T. Hiramoto, K. Inoue, A. Kato, M. Ogata, S. Sato, M. Sugi.

Endpoi dpoint nt E Eval aluat uation C

  • n Committee

ee

  • N. Ishide, S. Ibayashi, Y. Maruyama.

Ethics C Committe ttee

  • I. Ohno, K. Tamaki.

Data S a Safet ety M Monitor

  • ring B

ng Boar ard

  • H. Ogawa, M. Kitakaze.

Statist stica cal A Analys ysis B s Board

  • I. Tsuji, T. Watanabe.

Collabor aborat ating H ng Hospi pital als a and A Active e Inves estigat gator

  • rs b

by Pref efec ectur ure Aomor

  • ri P

Pref efec ectur ure

  • S. Oyama (Towada City Hospital).

Iwat ate P e Prefec ectur ure

  • E. Nozaki, A. Nakamura, T. Takahashi, H. Endo, S. Fukui, S. Nakajima

(Iwate Prefectural Central Hospital).

  • M. Nakagawa, T. Nozaki, T. Yagi (Iwate Prefectural Isawa Hospital).

Akita P a Pref efec ectur ure

  • S. Horiguchi, E. Fushimi, Y. Sugai, S. Takeda, K. Fukahori, K. Aizawa

(Hiraka General Hospital). Yamagat agata P a Pref efec ectur ure

  • M. Ohe, T. Tashima, K. Sakurai, T. Kobayashi (Kojirakawa Shiseido

Hospital).

  • T. Goto, M. Matsui, Y. Tamada, T. Yahagi,
  • A. Fukui, K. Takahashi, K. Takahashi, Y. Kikuchi (Yamagata Prefectural

Central Hospital). Miyagi agi Prefe fectu ture

  • A. Sugimura, J. Ohashi (Sendai Red Cross Hospital).
  • H. Kanno, J. Kaneko (Katta General Hospital).
  • S. Suzuki, K. Takahashi (KKR Tohoku Kosai Hospital).
  • K. Akai (Kurihara Central Hospital).
  • D. Katayose (Miyagi Rifu Ekisaikai Hospital).
  • S. Onodera, T. Hiramoto, S. Komatsu, M. Chida, K. Iwabuchi, M. Takeuchi,
  • H. Yahagi, N. Takahashi (Osaki Citizen Hospital).
  • K. Otsuka, Y. Koseki, M. Morita (Saito Hospital).
  • T. Shinozaki, T. Ishizuka, N. Onoue, N. Yamaguchi, H. Fujita (Sendai

Medical Center).

  • A. Katoh, S. Namiuchi, T. Sugie, K. Saji, T. Takii, (Sendai Open Hospital).
  • M. Fukuchi, M. Ogata, T. Tanikawa, O. Kitamukai (Sendai Tokushukai

Hospital).

  • Y. Matsumoto (Shizugawa Public Hospital).
  • K. Inoue, J. Koyama, T. Tomioka, H. Shioiri, Y. Ito (South Miyagi Medical

Center).

  • H. Kato, C. Takahashi, A. Kawana (Tohoku Rosai Hospital).
  • Y. Sakata, K. Ito, M. Nakayama, K. Fukuda, J. Takahashi, S. Miyata, K.

Sugimura, K. Sato, Y. Matsumoto, M. Nakano, T. Shiroto, R. Tsuburaya, K. Nochioka, H. Yamamoto, T. Aoki, K. Hao, M. Miura, M. Kondo, S. Tatebe, S. Yamamoto, H. Suzuki, Y. Hasebe, K. Nishimiya, N. Yaoita (Tohoku University Hospital). Fuku kush shima P Prefect cture

  • M. Sugi, Y. Yamamoto, S. Toda, Y. Minatoya, Y. Takagi (Iwaki Kyouritsu

Hospital).

  • K. Fukuda (Watanabe Hospital).

4.

  • 4. Hea

ead O Office and C and Coor

  • ordinating C

Cent enter

  • Y. Sakata, J. Takahashi, S. Miyata, K. Nochioka, M. Miura, S. Tadaki, R.

Ushigome, T. Yamauchi, K. Sato, K. Tsuji, T. Onose, R. Abe, C. Saga, J. Suenaga, Y. Yamada, J. Kimura, H. Ogino, I. Oikawa, S. Watanabe, M. Saga, M. Washio, K. Nagasawa, S. Nagasawa, S. Kotaka, W. Komatsu, R. Hashimoto, Y. Ikeno, T. Suzuki, H. Hamada (Tohoku University Hospital)

The S he SUPPORT T Trial al Inv Investigato tors

Acknow

  • wledgem

ement

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SLIDE 17

Subgroup

Number Hazard 95% C.I. P value P-value for interaction Event/Total Ratio lower upper

Age, y.o.

< 65 97 / 435 1.401 0.937 2.097 0.101

0.331

> 65 261 / 711 1.111 0.872 1.417 0.394

Gender

Male 277 / 856 1.220 0.963 1.546 0.099

0.590

Female 81 / 290 1.070 0.692 1.655 0.760

SBP, mmHg

<130 203 / 599 1.399 1.061 1.843 0.017

0.097

>130 154 / 545 0.990 0.721 1.359 0.951

DBP, mmHg

< 85 313 / 938 1.214 0.972 1.516 0.087

0.669

> 85 44 / 206 1.075 0.594 1.947 0.811

LVEF, %

< 50 179 / 429 1.164 0.868 1.561 0.310

0.854

> 50 179 / 709 1.215 0.905 1.631 0.196

eGFR, mL/min/1.73 m2

< 60 170 / 461 1.424 1.050 1.932 0.023

0.113

> 60 187 / 683 1.017 0.763 1.355 0.908

BNP, pg/mL

< 100 119 / 635 0.930 0.649 1.332 0.692

0.076

> 100 234 / 492 1.385 1.069 1.795 0.014

hsCRP, mg/L

< 1 182 / 662 1.017 0.76 1.36 0.912

0.075

> 1 169 / 463 1.485 1.096 2.010 0.011

Spironolactone

Yes 113 / 305 1.414 0.975 2.052 0.068

0.286

No 245 / 841 1.104 0.859 1.418 0.441

Subgr bgrou

  • up A

p Analy alysis is ( (1)

The SU SUPPO PPORT Trial

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SLIDE 18

Subgr bgrou

  • up A

p Analy alysis is ( (2)

Olmesartan better worse HR Olmesartan better worse HR

(+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB (+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB

eGFR

< 130mmHg > 130mmHg < 60 mL/min /1.73 m2 > 60 mL/min /1.73 m2

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 3.5 4.0

(+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB (+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB

SBP

The SU SUPPO PPORT Trial

slide-19
SLIDE 19

Olmesartan better worse HR Olmesartan better worse HR

BNP hsCRP

< 100pg/mL > 100pg/mL < 1.0 mg/L > 1.0 mg/L

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 3.5 4.0

(+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB (+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB (+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB (+) ACEI, (-) BB (-) ACEI, (+) BB (+) ACEI, (+) BB

Subgr bgrou

  • up A

p Analy alysis is ( (3)

The SU SUPPO PPORT Trial