Current status and future perspective of management of heart failure in japan

Current status and future perspective of management of heart failure in Japan

Hiroaki Shimokawa, MD, PhD.

Heart Failure 2015 (May 23 – 26, 2015 , Seville, Spain)

Joint Session with HFSA and JHFS- Controversial issues in drug therapy -

Chair, Department of Cardiovascular MedicineTohoku University Graduate School of Medicine

COI disclosure

Department of Evidenced-based Medicine Research grants: Daiichi Sankyo, Bayer Yakuhin,

Kyowa Hakko Kirin, Kowa Pharmaceutical Co. ,

Novartis Pharma, Dainippon Sumitomo Pharma,

Nippon Boehringer Ingelheim Co.

Hiroaki Shimokawa, MD, PhD. Lecture fees: Daiichi Sankyo, Bayer Yakuhin, Novartis Pharma.

Paradigm Shift in HF Management- From Treatment to Prevention -

Adopted from AHA/ACCF guideline 2013

Prevention Treatment

Stage-AAt high risk for HF but without

structural hearat disease of

symptoms of HF

Stage-B

Structural heart disease but

without signs or symptoms of HF

Stage-C

Structural heart disease with

prior or current symptoms of HF

Stage-D

Refractory HF requiring

specialized interventions

Neurohormonal Activation1) Renin-angiotensin-aldosterone system 4) Inflammation2) Sympathetic nervous system 5) Arginine vasopressin3) Oxidative stress 6) Endothelin

Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART) Studies

Tohoku Heart Failure AssociationFounded in 1999

ü CHART-1 (N=1,258) Study focus: Prognosis Registration:2000-2004 Follow-up: 2000-2005

ü CHART-2 (N=10,219) Study focus: Prevention, Prognosis

Registration:2006-2010Follow-up: 2006- present

Aomori

AkitaIwate

Yamagata

Miyagi

Fukushima

●Sendai

80

60

40

20

0

(%)

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

Epidemiologic Transition in Asia

CAD HT DM CAD HT DM

Japan China

2000-2004 (CHART-1)2006-2010 (CHART-2)

1993-19982003-2007

(Sakata, Shimokawa. Circ J. 2014;78:428-435.)

0

10

20

30

40

50

LVEF < 40%

LVEF > 40%

Ischemic heart disease Cardiomyopathy

50

40

30

20

10

0

P < 0.001

CHART-2 (2006-present, N=3,676)

CHART-1 (2000-2005, N=1,006)

Temporal Trends in HF Etiologies

(%)P < 0.001

(Ushigome, Shimokawa, et al. Circ J. 2015, in press)

80

70

60

50

40

30

20

10

0

P = 0.006

P < 0.001

P < 0.001

P < 0.001

P < 0.001

RAS-I β-blockers Loopdiuretics Digitalis Aldosterone

antagonists

80

70

60

50

40

30

20

10

0ICD/CRT-D

P = 0.031

(%)

CHART-2 (2006-present, N=3,676)

CHART-1 (2000-2005, N=1,006)

Temporal Trends in Treatments for Symptomatic HF


All-cause death Hospitalization for HF Cardiovascular death

(yrs.)

7563.141

5992,549

4421,771

1,0063,676

(yrs.)

Cum

ulat

ive

inci

denc

e (%

)

1,0063,676

8843,448

7392,893

5682,003

No. at riskCHART-1CHART-2

(yrs.)

8843,448

7392,893

5682,893

1,0063,676

Cum

ulat

ive

inci

denc

e (%

)

Cum

ulat

ive

inci

denc

e (%

)

CHART-2 (N=3,676)

CHART-1 (N=1,006)

CHART-2 (N=3,676)

CHART-1 (N=1,006)

CHART-2 (N=3,676)

CHART-1 (N=1,006)

HR 0.59, 95%CI 0.50-0.69; P< 0.001HR※ 0.73, 95%CI 0.59-0.88; P= 0.001

HR 0.38, 95%CI 0.31-0.46; P< 0.001HR ※ 0.45, 95%CI 0.34-0.58; P< 0.001

HR 0.51, 95%CI 0.44-0.58; P< 0.001HR ※ 0.57, 95%CI 0.47-0.68; P< 0.001

A B C

Temporal Trends in Long-term Prognosis of Symptomatic HF Patients

※： Adjusted with age, sex, hypertension, diabetes, dyslipidemia, AF, and VT


1086420

CHART2

CHART1

100%80%60%40%20%0%

Stroke death

Other cardiovascular death

Heart failure death

Sudden cardiac death

(%)0 2 4 6 8 10

P= 0.189

P= 0.285

P= 0.543

0 20 40 60 80 100 (%)

P< 0.001

AMI death

Cardiovascular death

Non-cardiovascular death

Unknown death

P< 0.001

CHART-1(2000-2005)

CHART-2(20006-present)

74%

48%

23%

36%

CHART-2 (2006-Present, N = 3,676)

CHART-1 (2000-2005, N = 1,006)

ATemporal Trends in Mode of Death in Symptomatic HF


•RAS inhibitors

•Beta blockers

•Statins

Prescription Rates of RAS inhibitors by Age

Subjects: 4,733 patients in Stage C/D patients in the CHART-2 Study

　　　　

Kaplan-Meier Curves for Composite Endpointsin the CHART-2 Study (Stage C/D)

*composite endpoints: all-cause death, HF admission, myocardial infarction and stroke.

(+) RAS inhibitors n=3,421

(-) RAS inhibitors n=1,312

Adjusted HR 1.08 (0.93-1.25), P=0.32

　　　　

LVEF<40% LVEF40-50% LVEF>50%

Adjusted HR 1.10, P=0.56 Adjusted HR 1.31, P=0.13 Adjusted HR 0.98, P=0.83

β遮断薬あり n=383β遮断薬なし n=213

β遮断薬あり n=1,161β遮断薬なし n=1,485


Kaplan-Meier Curves for Composite Endpointsin the CHART-2 study (Stage C/D)

(+) RAS inhibitors n=563(-) RAS inhibitors n=134

(+) RAS inhibitors n=152(-) RAS inhibitors n=58

(+) RAS inhibitors n=2,166(-) RAS inhibitors n=957

The SUPPORT Trial

(Sakata, Shimokawa, et al. Eur Heart J. 2015;36:915-923.)

Study Flow

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

Randomization

Control group(n = 569)

Olmesartan group(n = 578)

Excluded (n=1)・lack of information 　　　(n=1)

Excluded (n=0)

Control group (n = 568)

Olmesartan group (n = 578)

Enrollment : 2006.10.1 – 2010.3.31

Annual follow-up ( 2013.3.31)~

The SUPPORT Trial

993 (87%) at out-patient clinics.

Titrated up to 40mg/day.

（clinicaltrials.gov-NCT00417222） (Sakata, Shimokawa, et al. Eur Heart J. 2015;36:915-923.)

　Control(n=569)

Olmesartan (n=578) P-value

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

Patient CharacteristicsThe SUPPORT Trial

　Control (n=569)

Olmesartan (n=578) P-value

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


Control 568 513 483 449 317 134 28Olmesartan 578 517 474 436 293 118 47

Cum

ulat

ive

even

t rat

e

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

Control Olmesartan

No. at risk

(%)

Primary EndpointThe SUPPORT Trial


Primary and Other EndpointsThe SUPPORT Trial

Control (n=568)

Olmesartan

(n=578) Hazard ratio

95% C.I.P-value

　 events, n (%) events, n (%) 　 lower upper

Primary endpoint 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

Secondary endpoints

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.


P=0.588 HR=1.12(0.75, 1.66)

Control 104 95 88 80 59 37 8

Olmesartan 106 101 96 90 65 43 43

P=0.118 HR=0.66(0.39, 1.12)

C. (+)ACEI, (+)BBA. (+)ACEI, (-)BB B. (-)ACEI, (+)BB

ControlOlmesartan

Cum

ulat

ive

even

t rat

e

Cum

ulat

ive

even

t rat

e

Cum

ulat

ive

even

t rat

eControlOlmesartan

ControlOlmesartan

(%)(%) (%)

Control 312 286 270 251 168 68 45

Olmesartan 299 261 233 211 140 93 30

P=0.006 HR=1.47(1.11, 1.95)

Control 148 130 124 117 96 55 7

Olmesartan 170 154 144 135 92 37 37

Number at risk

Number at risk

Number at risk

Baseline Medications and the Primary EndpointThe SUPPORT Trial


Primary Endpoint Overall

(+) ACEI, (-) BB

(-) ACEI, (+) BB

(+) ACEI, (+) BB

Olmesartanbetter worse

HR 4.03.53.02.52.01.51.00.50.0

All-cause Death Overall

(+) ACEI, (-) BB

(-) ACEI, (+) BB

(+) ACEI, (+) BB


HR4.03.53.02.52.01.51.00.50.0

Renal Dysfunction Overall

(+) ACEI, (-) BB

(-) ACEI, (+) BB

(+) ACEI, (+) BB


HR 4.03.53.02.52.01.51.00.50.0

ACEI: ACE inhibitorsBB: Beta blockers

Triple Combination and Adverse Cardiac EventsThe SUPPORT Trial


•RAS inhibitors

•Beta blockers

•Statins

Prescription of Beta-blockers in the CHART-2 Study

Carvedilol 67.5% Bisoprolol 9.0%Metoprolol 5.1%Unknown 18.4%


30歳未満 40歳以上50歳未満60歳以上70歳未満 80歳以上

0

20

40

60

80

100

30歳未満 40歳以上50歳未満60歳以上70歳未満 80歳以上

0

20

40

60

80

100

Prescription Rates of Beta-blockers by Age

0

20

40

60

80

100 (%)

0

20

40

60

80

100 (%)

CHART-1 (N=1,006) CHART-2 (N=3,673)

<30 30-39 40-49 50-59 60-69 70-79 80< <30 30-39 40-49 50-59 60-69 70-79 80<

Age Age

Dose of Carvedilol in the CHART-2 Study

30歳未満30歳以上40歳未満40歳以上50歳未満50歳以上60歳未満60歳以上70歳未満70歳以上80歳未満80歳以上

0

2

4

6

8

10

12

0

2

4

6

8

10

(mg)12

全体男性女性

0

2

4

6

8

10

12

0

2

4

6

8

10

(mg)12

All Male Female <30 30-39 40-49 50-59 60-69 70-79 80<

Age


　　　　

(+) Beta blockers n=2,009(-) Beta blockers n=1,900

(%)

　Time (Year)

0 1 2 3 4

Kaplan-Meier Curves for All-cause Deathin the CHART-2 Study (Stage C/D)

Adjusted HR 0.80 (0.72-0.90), P<0.001

100

60

80

20

40

0

Sur

viva

l rat

e

　　　　

LVEF<40% LVEF40-50% LVEF>50%

Adjusted HR 0.48, P<0.001 Adjusted HR 0.80, P=0.15 Adjusted HR 1.01, P=0.86

(%)

100

80

60

40

20

0

(%)

100

80

60

40

20

0

(%)

100

80

60

40

20

0


β遮断薬あり n=1,161β遮断薬なし n=1,485


0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Kaplan-Meier Curves for All-cause Deathin the CHART-2 study (Stage C/D)

(+) Beta-blockers n=465(-) Beta-blockers n=202

　Time (Year)

Sur

viva

l rat

e

　Time (Year) 　Time (Year)(+) Beta-blockers n=383(-) Beta-blockers n=213

(+) Beta-blockers n=1,161(-) Beta-blockers n=1,485

Prognostic Impacts of Beta-blockers in Stage C/D Patients with Sinus Rhythm

HFrEF(N=885)

HFpEF(N=1,803)

(Takada, Shimokawa, et al. Eur J Heart Fail. 2014;16:309-316.)

Beta-blockersbetter worse

HR

Beta-blockersbetter worse

HR

All-cause death Hospitalization for HF

CHART-1 (n=306)

Log-rank P= 0.010

CHART-2 (n=710)

(years)

Log-rank P= 0.015

(years)

CHART-1 (n=306)

CHART-2 (n=710)

(%) (%)

Sur

viva

l rat

e

Hos

pita

lizat

ion-

free

rate

306710

281666

247570

189406

306710

245611

209496

156346

HR 0.60, 95%CI 0.49-0.81; P= 0.011

HR 0.69, 95%CI 0.51-0.93;P= 0.015



DCM: Kaplan-Meier Survival Curves

(Ushigome R, Shimokawa H, et al. Circ J. 2015;79:1332-1341.)

6

Stroke death

Other death

Heart failure death

Sudden cardiac death


100%80%60%40%20%0%

51.6 84.1

37.1 11.4

（%）

CHART-1

CHART-2

Cardiovascular death


Unknown death

CHART-1

CHART-2

0 1 2 3 4 5

P= 0.526

P= 0.107

P= 0.257

0 20 40 60 80 100 (%)

P< 0.001

P= 0.062

84%

52%

DCM: Mode of Death


(%)

Surv

ival

rate

CHART-1 (n=147)

CHART-2 (n=567)

(years)

(%)

Surv

ival

rate

Log-rank P= 0.851

CHART-1 (n=159)

CHART-2 (n=143)

HR 0.94, 95%CI 0.53-1.71; P= 0.850

(years)

159143

147133

131109

11584


147567

135534

116468

79343


(+) Beta-blocker(-) Beta-blocker

Beta-blockers in DCM Patients

Log-rank P= 0.017

HR 0.53, 95%CI 0.31-0.90;P= 0.019


•RAS inhibitors

•Beta blockers

•Statins

Selection of HFpEF Populations

Total cohort

Matched cohort

Required past or current symptoms of HF

(Nochioka, Shimokawa, et al. Circ J. 2015;79:574-582.)

Kaplan-Meier Curves for All-cause Death in HFpEF


No. at risk Matched cohort No statin use Statin use Total cohort No statin use Statin use

207207

555863

Cum

ulat

ive

Inci

denc

e (%

)

193194

529769

163166

451648

106119

320441

00

No statin use in total HFrEF cohort

No statin use in matched HFrEF cohort

Statin use in total HFrEF cohort

Statin use in matched HFrEF cohort

P=0.970 for matched HFrEF cohort

P=0.001 for total HFrEF cohort

10

20

30

1 2 3 Years

Kaplan-Meier Curves for All-cause Death in HFrEF

Statin use was not associated

with improved mortality in the PS-matched HFrEF population.


　

Statin use in the total cohort

PTotal Yes No

n=3,124 n=1,163 n=1,961 HR 95%CIAll-cause death 440 113 327 0.72 0.63-0.82 <0.001 Cardiovascular 210 64 146 1.01 0.83-1.22 0.960 Heart failure 97 28 69 1.16 0.88-1.53 0.288 Sudden death 40 12 28 0.59 0.36-0.98 0.041 Stroke 25 11 14 1.25 0.72-2.15 0.426 MI 11 3 8 0.61 0.27-1.38 0.234 Other cardiovascular 37 10 27 1.07 0.68-1.64 0.758 Non-cardiovascular 206 47 159 0.53 0.62-0.82 <0.001 Cancer 75 22 53 0.74 0.53-1.03 0.078 Infection 67 14 53 0.53 0.36-0.77 0.001 Renal failure 18 5 13 0.73 0.36-1.47 0.371 Gastrointestinal bleeding 4 0 4 0.00 - - Other non-cardiovascular 42 6 36 0.21 0.11-0.39 <0.001 Unknown cause 24 2 22 0.17 0.01-0.42 <0.001

*P value is the results of the Cox hazard models adjusted by IPTW.

Mode of death in HFpEF


HR 95% CI P value

β-blockers CHART-1 0.96 ( 0.63 - 1.44 ) 0.829 CHART-2 0.82 ( 0.68 - 1.00 ) 0.055

RAS-I CHART-1 0.79 ( 0.55 - 1.14 ) 0.208 CHART-2 0.94 ( 0.76 - 1.15 ) 0.534

Aldosterone antagonists

CHART-1 1.36 ( 0.89 - 2.07 ) 0.154 CHART-2 1.14 ( 0.93 - 1.39 ) 0.223

Loop diuretics CHART-1 1.72 ( 1.03 - 2.87 ) 0.038 CHART-2 1.29 ( 1.05 - 1.59 ) 0.017

Digitalis CHART-1 0.97 ( 0.69 - 1.38 ) 0.875 CHART-2 1.06 ( 0.87 - 1.31 ) 0.555

CCB CHART-1 1.32 ( 0.92 - 1.90 ) 0.135 CHART-2 0.91 ( 0.75 - 1.12 ) 0.376

Statin CHART-1 NA NA NACHART-2 0.81 ( 0.65 - 1.02 ) 0.068

Effects of Medications in Symptomatic HF Patients

All patients, All-cause death


HR 95% CI P value


RAS-I CHART-1 0.67 ( 0.40 - 1.12 ) 0.128 CHART-2 0.83 ( 0.60 - 1.15 ) 0.252


CHART-1 1.39 ( 0.80 - 2.43 ) 0.247 CHART-2 1.23 ( 0.91 - 1.66 ) 0.172



CCB CHART-1 1.40 ( 0.82 - 2.38 ) 0.213 CHART-2 1.09 ( 0.77 - 1.54 ) 0.618

Statin CHART-1 NA NA NA CHART-2 0.84 ( 0.60 - 1.17 ) 0.299

Effects of Medications in Symptomatic HFrEF Patients

HFrEF, All-cause death


HR 95% CI P value


RAS-I CHART-1 0.86 ( 0.51 - 1.47 ) 0.592 CHART-2 1.01 ( 0.77 - 1.32 ) 0.924


CHART-1 1.32 ( 0.67 - 2.61 ) 0.423 CHART-2 0.96 ( 0.72 - 1.29 ) 0.808



CCB CHART-1 1.31 ( 0.77 - 2.24 ) 0.321 CHART-2 0.84 ( 0.65 - 1.08 ) 0.173

Statin CHART-1 NA NA NACHART-2 0.72 ( 0.53 - 0.98 ) 0.035

HFpEF, All-cause death

Effects of Medications in Symptomatic HFpEF Patients


Conclusions

1. Along with implementation of evidence-based medications, 3-year incidences of all-cause death, cardiovascular death and HF admission have been decreased in patients with HF in Japan.

2. Better implementation of beta-blockers and statins appears to have contributed to this prognostic improvement in patients with HFrEF and those with HFpEF, respectively.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine

Acknowledgements

Tohoku Heart Failure Society

Healthcare

Current status and future perspective of management of heart failure in japan