Surgical Treatment for IschemicSurgical Treatment for IschemicHeart Failure (STICH) Trial:Heart Failure (STICH) Trial:CABG versus CABG + SVRCABG versus CABG + SVR

LORENZO A. MENICANTILORENZO A. MENICANTIIrccs Policlinico San DonatoIrccs Policlinico San Donato

Surgical Treatment for IschemicSurgical Treatment for IschemicHeart Failure (STICH) Trial:Heart Failure (STICH) Trial:CABG versus CABG + SVRCABG versus CABG + SVR

LORENZO A. MENICANTILORENZO A. MENICANTIIrccs Policlinico San DonatoIrccs Policlinico San Donato

Core STICH Study OrganizationCore STICH Study Organization

Principal Investigator: Robert H. JonesPrincipal Investigator: Robert H. Jones

Co-Principal investigator: Eric VelazquezCo-Principal investigator: Eric Velazquez

DCC Principal Investigator: Kerry L. LeeDCC Principal Investigator: Kerry L. Lee

Study Chair: Jean L. RouleauStudy Chair: Jean L. Rouleau

Executive Committee: Robert H. Jones, Eric Velazquez, Kerry Executive Committee: Robert H. Jones, Eric Velazquez, Kerry L. Lee, Jean L. Rouleau, Patrice Desvigne-Nickens, George L. Lee, Jean L. Rouleau, Patrice Desvigne-Nickens, George Sopko, Christopher O’Connor, Robert Michler, Jae OhSopko, Christopher O’Connor, Robert Michler, Jae Oh

DSMB chair: Sidney GoldsteinDSMB chair: Sidney Goldstein

Policy and Publication Committee chair: James HillPolicy and Publication Committee chair: James Hill

Clinical Endpoints Committee chair: Peter CarsonClinical Endpoints Committee chair: Peter Carson

Hypothesis 2 Enrollment by CountryHypothesis 2 Enrollment by Country

1000 patients

96 clinical sites

23 countries

1231 days

1000 patients

96 clinical sites

23 countries

1231 days

Hypothesis 2Hypothesis 2 Surgical ventricular reconstruction (SVR) combined with Surgical ventricular reconstruction (SVR) combined with

CABG and evidence-based medical therapy (MED) CABG and evidence-based medical therapy (MED) decreases death or cardiac hospitalization compared to decreases death or cardiac hospitalization compared to CABG and MED without SVR.CABG and MED without SVR.

90% power for 20% reduction assuming 90% power for 20% reduction assuming ≥45% 3-year event ≥45% 3-year event rate allowing for 20% treatment crossovers.rate allowing for 20% treatment crossovers.

7% of CABG and 9% of CABG + SVR patients did not 7% of CABG and 9% of CABG + SVR patients did not receive assigned operation.receive assigned operation.

Follow-up 99% complete over median of 48 months.Follow-up 99% complete over median of 48 months.

All outcomes reported by operation assigned by All outcomes reported by operation assigned by randomization.randomization.

Conduct of operation reported by procedure receivedConduct of operation reported by procedure received ..

Baseline Clinical CharacteristicsBaseline Clinical Characteristics

Characteristic CABGN = 499

CABG + SVRN = 501

Age, median 25Age, median 25thth, 75, 75thth, years, years 62 (54, 66)62 (54, 66) 62 (56, 69)62 (56, 69)

FemaleFemale 78 (16%)78 (16%) 69 (14%)69 (14%)

WhiteWhite 90%90% 92%92%

DiabetesDiabetes 35%35% 34%34%

Creatinine, >0.5 mg/dLCreatinine, >0.5 mg/dL 8%8% 9%9%

Prior stroke 6% 6%

Mitral Regurgitation by Treatment in 1,000 Mitral Regurgitation by Treatment in 1,000 Hypothesis 2 PatientsHypothesis 2 Patients

Mitral Regurgitation Severity

CABGN = 499

CABG + SVRN = 501

None or trace 173 (35%) 190 (38%)

Mild (≤2+) 233 (47%) 216 (44%)

Moderate (3+) 72 (15%) 70 (14%)

Severe (4+) 16 (3%) 20 (4%)

Not assessed 5 (4%) 5 (3%)

18%18%18%18%

Site Reported Left Ventricular Function for Site Reported Left Ventricular Function for 1,000 Hypothesis 2 Patients by Treatment1,000 Hypothesis 2 Patients by Treatment

LV Function CABGN = 499

CABG + SVRN = 501

Site Qualifying Study

Echocardiogram (%) 66% 63%

Contrast ventriculogram 13% 18%

CMR 11% 9%

Gated SPECT 10% 10%

LVEF, median (25th, 75th) .28 (.23, .31) .28 (.24, .31)

ESVI, median (25th, 75th), mL/m2 82 (65, 102) 82 (66, 105)

% anterior wall with akinesia/dyskinesia, median (25th, 75th) 56 (40, 60) 50 (40, 60)

Coronary Anatomy by Treatment for Coronary Anatomy by Treatment for 1,000 Hypothesis 2 Patients1,000 Hypothesis 2 Patients

Major Coronary Major Coronary Arteries with Arteries with

StenosisStenosis

% Stenosis% Stenosis CABGCABGN = 499N = 499

CABG + SVRCABG + SVRN = 501N = 501

OneOne ≥≥50%50% 7%7% 10%10%

LM stenosisLM stenosis 50-74%50-74% 14%14% 12%12%

OneOne ≥≥ 75%75% 17%17% 20%20%

TwoTwo ≥≥ 75%75% 41%41% 42%42%

ThreeThree ≥≥ 75%75% 41%41% 36%36%

Proximal LADProximal LAD ≥≥ 75%75% 78%78% 74%74%

LM stenosisLM stenosis ≥≥ 75%75% 6%6% 7%7%

Duke coronary Duke coronary disease index*disease index*

MedianMedian(25(25thth, 75, 75thth)) 65 (43, 91)65 (43, 91) 65 (39, 91)65 (39, 91)

* 0 = coronary angiogram shows no coronary disease, 100 = * 0 = coronary angiogram shows no coronary disease, 100 = ≥95% LM stenosis≥95% LM stenosis* 0 = coronary angiogram shows no coronary disease, 100 = * 0 = coronary angiogram shows no coronary disease, 100 = ≥95% LM stenosis≥95% LM stenosis

Medication at BaselineMedication at Baseline

Medication CABGN = 499

CABG + SVRN = 501

Beta blockerBeta blocker 85%85% 87%87%

ACE inhibitor or angiotensin ACE inhibitor or angiotensin receptor blockerreceptor blocker

87%87% 89%89%

ACE inhibitorACE inhibitor 80%80% 82%82%

DigoxinDigoxin 17%17% 14%14%

DiureticDiuretic 69%69% 66%66%

AspirinAspirin 77%77% 77%77%

Aspirin or warfarinAspirin or warfarin 81%81% 83%83%

StatinStatin 79%79% 75%75%

Operative Conduct by Operation Received Operative Conduct by Operation Received in 979 Hypothesis 2 Patientsin 979 Hypothesis 2 Patients

VariableVariable CABGCABGN = 490N = 490

CABG + SVRCABG + SVRN = 489N = 489

PP

Status at Operation

Elective operation 84% 83% 0.54

Urgent 13% 13%

Emergency 3% 4%

Bypass Grafts 0.34

1 or more arterial grafts 93% 89%

2 or less total grafts 27% 30%

3 or more total grafts 73% 70%

Mitral surgery 17% 19% 0.50

SVR patch 59%

Efficiency of Operative Care Efficiency of Operative Care in 979 Hypothesis 2 Patientsin 979 Hypothesis 2 Patients

Duration of OperationDuration of Operation CABGCABGN = 490N = 490

CABG + SVRCABG + SVRN = 489N = 489

PP

Total time in operating room (median, 25th, 75th), hours

4.9 (4.1, 6.0) 5.5 (4.7, 6.6) <0.001

Cardiopulmonary bypass time(median, 25th, 75th), minutes

99 (73, 125) 124 (99, 158) <0.001

Aortic occlusion (median, 25th, 75th), minutes

62 (45, 84) 80 (62, 106) <0.001

Requirements for Postoperative Care

Endotracheal intubation (median, 25th, 75th), hours

15.1 (10.9, 22.1) 16.6 (12.0, 25.2) 0.002

Acute care (median, 25th, 75th), hours

49.8 (28.8, 95.5) 69.5 (42, 137) <0.001

Hospitalization >30 days 22 (5%) 31 (6%) 0.20

Baseline 4 Months0

20

40

60

80

CABG(N = 212)

Baseline 4 MonthsCABG+SVR

(N = 161)

Baseline and Four Month End-Systolic Volume Baseline and Four Month End-Systolic Volume Index (ESVI) in 373 Hypothesis 2 Patients With Index (ESVI) in 373 Hypothesis 2 Patients With Quantitative Echocardiogram at Both IntervalsQuantitative Echocardiogram at Both Intervals

ESVI 82 ml/m2 77 ml/m2 83 ml/m2 67 ml/m2

P<0.001P<0.001P<0.001P<0.001

Baseline(N = 499)

LatestFollow-up(N = 435)

0

100

200

300

400

500

CABGCCS Angina Class

Baseline(N = 501)

LatestFollow-up(N = 428)

CABG+SVRCCS Angina Class

Canadian Cardiovascular Society Angina Class in Canadian Cardiovascular Society Angina Class in Hypothesis 2 Patients at Baseline and Latest Follow-upHypothesis 2 Patients at Baseline and Latest Follow-up

Patients

No Angina121

Class I-II130

Class III-IV248

No Angina339

Class I-II88 Class III-IV

8

No Angina128

Class I-II129

Class III-IV244

No Angina339

Class I-II83 Class III-IV

6

Angina symptoms improved by an average of 1.7 classes Angina symptoms improved by an average of 1.7 classes in both cohorts (P=0.84).in both cohorts (P=0.84).Angina symptoms improved by an average of 1.7 classes Angina symptoms improved by an average of 1.7 classes in both cohorts (P=0.84).in both cohorts (P=0.84).

Baseline(N = 499)

LatestFollow-up(N = 436)

0

100

200

300

400

500

CABGNYHA HF Class

Baseline(N = 501)

LatestFollow-up(N = 435)

CABG+SVRNYHA HF Class

New York Heart Association Heart Failure Class in New York Heart Association Heart Failure Class in Hypothesis 2 Patients at Baseline and Latest Follow-upHypothesis 2 Patients at Baseline and Latest Follow-up

Patients

Class I 36

Class II222

Class III-IV241

Class I165

Class II190

Class III-IV80

Class I 50

Class II207

Class III-IV244

Class I179

Class II190

Class III-IV80

Baseline(N = 499)

LatestFollow-up(N = 435)

Baseline(N = 501)

LatestFollow-up(N = 429)

CABGNYHA HF Class

CABG+SVRNYHA HF Class

Baseline and Four Month 6-Minute Walk in 693 Baseline and Four Month 6-Minute Walk in 693 Hypothesis 2 Patients with Baseline AssessmentHypothesis 2 Patients with Baseline Assessment

Patients

30-Day Mortality30-Day Mortality

OutcomeOutcome CABGCABGN = 499N = 499

CABG + SVRCABG + SVRN = 501N = 501

PP

Death Within 30 Days After Randomization

All patients by intention to treat

22/499 (4.4%) 30/501 (6.0%) 0.26

Death During or Within 30 Days of Operation

Operated patients by intention to treat

25/490 (5.1%) 26/489 (5.3%) 0.88

Operated patients by operation received

23/498 (4.6%) 28/481 (5.8%) 0.40

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5

Eve

nt R

ate

Years from Randomization

CABG

499501

319319

270275

220216

9911

2323

CABGCABG+SVR

No. at Risk

Death or Cardiac Hospitalization Death or Cardiac Hospitalization Kaplan-Meier Estimates of Primary Endpoint Kaplan-Meier Estimates of Primary Endpoint

292 events

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5

Eve

nt R

ate

Years from Randomization

CABG

CABG+SVR

HR 0.99 (95% CI: 0.84, 1.17), P=0.90

499501

319319

270275

220216

9911

2323

CABGCABG+SVR

No. at Risk

Death or Cardiac HospitalizationDeath or Cardiac Hospitalization Kaplan-Meier Estimates of Primary Endpoint Kaplan-Meier Estimates of Primary Endpoint

292 events

289 events

Mortality (All-Cause)Mortality (All-Cause) Kaplan-Meier Estimates Kaplan-Meier Estimates

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5

Mor

talit

y R

ate

Years from Randomization

CABG

499501

434429

417404

363352

201193

5953

CABGCABG+SVR

No. at Risk

141 deaths

Mortality (All-Cause)Mortality (All-Cause) Kaplan-Meier Estimates Kaplan-Meier Estimates

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5

Mor

talit

y R

ate

Years from Randomization

CABG+SVR

HR 1.00 (95% CI: 0.79, 1.26), P=0.98

499501

434429

417404

363352

201193

5953

CABGCABG+SVR

No. at Risk

141 deaths 138 deaths

CABG

Summary of Outcomes in STICH H2Summary of Outcomes in STICH H2

OutcomesOutcomes CABGCABGN = 499N = 499

CABG + SVRCABG + SVRN = 501N = 501

Hazard RatioHazard Ratio95% CI95% CI

PP

Death or cardiac Death or cardiac hospitalizationhospitalization 292 (59%)292 (59%) 289 (58%)289 (58%) 0.99 (0.84, 1.17)0.99 (0.84, 1.17) 0.900.90

DeathDeath 141 (28%)141 (28%) 138 (28%)138 (28%) 1.00 (0.79, 1.26)1.00 (0.79, 1.26) 0.980.98

Hospitalization Hospitalization (cardiac)(cardiac) 211 (42%)211 (42%) 204 (41%)204 (41%) 0.97 (0.80, 1.18)0.97 (0.80, 1.18) 0.730.73

Hospitalization Hospitalization (all cause)(all cause) 272 (55%)272 (55%) 268 (53%)268 (53%) 0.98 (0.83, 1.16)0.98 (0.83, 1.16) 0.820.82

Acute MIAcute MI 22 (4%)22 (4%) 20 (4%)20 (4%) 1.01 (0.54, 1.87)1.01 (0.54, 1.87) 0.960.96

StrokeStroke 31 (6%)31 (6%) 23 (5%)23 (5%) 0.77 (0.45, 1.32)0.77 (0.45, 1.32) 0.350.35

0.5 1.0 2.0

CABG+SVG Better

CABGBetter

Hazard Plots of Selected Baseline CharacteristicsHazard Plots of Selected Baseline Characteristics

Subgroup N HR (95% CI) P ValueAll Subjects 1000 0.99 (0.84, 1.17)Age 0.48 ≥ 65 391 1.06 (0.83, 1.35) < 65 609 0.94 (0.76, 1.17)Gender 0.60 Male 853 1.01 (0.84, 1.20) Female 147 0.90 (0.58, 1.39)Race 0.44 Minority 124 0.83 (0.51, 1.36) Non-minority 876 1.01 (0.85, 1.20)Current NYHA HF class 0.97 I or II 515 0.99 (0.78, 1.25) III or IV 485 0.99 (0.79, 1.24)

CABG+SVRBetter

CABGBetter

0.5 1.0 2.0

CABG+SVG Better

CABGBetter

Hazard Plots of Selected Baseline Characteristics contHazard Plots of Selected Baseline Characteristics cont

Subgroup N HR (95% CI) P ValueCCS angina class 0.39 ≤ Class II 508 0.92 (0.73, 1.16) Class III or IV 492 1.06 (0.85, 1.34)Baseline diabetes 0.20 Yes 344 1.14 (0.87, 1.50) No 656 0.92 (0.75, 1.12)LVEF (site reported) 0.33 ≤ 28 534 1.07 (0.86, 1.31) > 28 466 0.90 (0.70, 1.17)# of diseased vessels ≥ 50% 0.21 1 or 2 362 0.87 (0.65, 1.13) 3 638 1.07 (0.87, 1.31)Left main ≥ 50% or proximal LAD ≥ 75% 0.53 No 179 0.89 (0.61, 1.30) Yes 821 1.02 (0.85, 1.22)

CABG+SVRBetter

CABGBetter

0.5 1.0 2.0

CABG+SVG Better

CABGBetter

Hazard Plots of Selected Baseline Characteristics contHazard Plots of Selected Baseline Characteristics cont

Subgroup N HR (95% CI) P ValueMitral regurgitation 0.44 None or trace 363 0.89 (0.68, 1.17) Mild (≤ 2+) 449 1.12 (0.88, 1.43) Mod. or severe 178 0.94 (0.65, 1.36)Stratum 0.44 B 141 1.15 (0.76, 1.76) C 859 0.96 (0.81, 1.15)Region 0.41 Poland 288 1.02 (0.76, 1.37) USA 200 1.10 (0.79, 1.54) Canada 154 0.77 (0.50, 1.18) West Europe 164 0.80 (0.53, 1.22) Other 194 1.24 (0.81, 1.91)

CABG+SVRBetter

CABGBetter

Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559

ConclusionsConclusions

The STICH trial definitively shows adding SVR to CABG The STICH trial definitively shows adding SVR to CABG provides no clinical benefit beyond that of CABG alone in provides no clinical benefit beyond that of CABG alone in the study population.the study population.

Both operative strategies provided similar short- and long-Both operative strategies provided similar short- and long-term relief of angina and HF and improvement in 6-minute term relief of angina and HF and improvement in 6-minute walk test performance.walk test performance.

SVR added to CABG decreased LV size significantly more SVR added to CABG decreased LV size significantly more than CABG alone and confirms the anatomic change than CABG alone and confirms the anatomic change reported in prior SVR studies.reported in prior SVR studies.

Further analyses of STICH Hypothesis 2 data may identify Further analyses of STICH Hypothesis 2 data may identify patient characteristics associated with benefit or harm from patient characteristics associated with benefit or harm from adding SVR to CABG.adding SVR to CABG.

MOTIVI DI DUBBIO

PUR AUMENTANDO LA COMPLESSITA’ DELLA PRUCEDURA CHIRURGICA LA MORTALITA’ NON CAMBIA

NONOSTANTE LA DIMINUZIONE DEL VOLUME DEL 20% NON VI E’ NESSUN BENEFICIO SULLA SOPRAVVIVENZA

SONO STATI CAMBIATI I CRITERI DI ARRUOLAMENTO DURANTE LO STUDIO, NELLA VERSIONE 2003 SCOMPARE IL SINTOMO SCOMPENSO

IL VOLUME NON E’ PIU’ UN CRITERIO DI ARRUOLAMENTO E PERMANE SOLAMENTE LA FE < 35%

LO STUDIO PERDE LA SUA CARATTERISTICA PRINCIPALE DI STUDIO SU MALATI SCOMPENSATI PER DIVENIRE UNO STUDIO SU PAZIENTI ISCHEMICI

LIMITI DI UNO STUDIO RANDOMIZZATO SU UNA PRATICA CHIRURGICA BEN CONOSCIUTA CON RISULTATI NOTI

NON ETICA LA RANDOMIZZAZIONE IN PAZIENTI IN CUI IL BENEFICIO ERA EVIDENTE

OFFRIRE IL MEGLIO DELLA TERAPIA MEDICA E CHIRURGICA CONOSCIUTA E DISPONIBILE IN BASE AL CONCETTO DI EQUIPOSE DI CIASUN CENTRO.

RANDOMIZZAZIONE COINVOLGE MENO DEL 20% DEI PAZIENTI ELIGIBILI.

80% DEI PAZIENTI ELIGIBILI è STATO SOTTOPOSTO A SVR PER EVIDENZA DELLA SUPERIORITà DELLA PROCEDURA

L’INTERVENTO DI SVR è INDICATO COME PUBBLICATO OVUNQUE IN PRESENZA DI SINTOMI DI SCOMPENSO DETERMINATO DA UN INGRANDIMENTO DELLA CAVITà SINISTRA DOPO INFARTO TRANSMURALE,IN PRESENZA QUINDI DI TESSUTO CICATRIZIALE, NON QUANDO VI SIA TESSUTO VITALE.

LA TECNICA CHIRURGICA INFLUENZA PESANTEMENTE IL RISULTATO

SE LA RIDUZIONE VOLUMETRICA è TROPPO SPINTA VI è IL RISCHIO DI AVERE UNA DISFUNZIONE DIASTOLICA IMPORTANTE.

SE LA RIDUZIONE è LIMITATA NON VI è ALCUN BENEFICIO.

VIENE RIPORTATA UNA RIDUZIONE VOLUMETRICA DEL 5% NEI PAZIENTI SOTTOPOSTI A CABG E DEL 20% IN QUELLI OPERATI SVR, SI PUò ARGUIRE CHE L’INTERVENTO DI SVR DIMINUISCE IL VOLUME DEL 15%

E’ SUFFICIENTE UNA RIDUZIONE DEL 20% DEL VOLUME ?

GLI STUDI OSSERVAZIONALI PUBBLICATI RIPORTANO UNA DIMINUZIONE DEL VOLUME TRA IL 30% ED IL 50%

L’INTERVENTO DI SVR NON è UN INTERVENTO COSMETICO

Average % ESV reduction following CABG plus SVR

-60

-50

-40

-30

-20

-10

0Ath

anas

uleas

(200

4)

Cirillo

(220

4)

Men

icant

i(2007

)

Aguiar

Ribe

rio (2

006)

Yamag

uchi (

2006

)

O`Neil

l (20

06)

Conte (

2004

)

STICH (2

009

%

LA VARIABILITà GEOGRAFICA DEI RISULTATI SEMBRA CONFERMARE I DUBBI SULLA OMOGENEITà DEL TRATTAMENTO CHIRURGICO.

MENO DEL 50% DEI PAZIENTI ERANO IN CLASSE III E IV

13% DEI PAZIENTI NON AVEVANO STORIA DI INFARTO MIOCARDICO ACUTO

25% DEI PAZIENTI NON PRESENTAVA LESIONE CRITICA DELA IVA

LO STICH TRIAL RAPPRESENTA UN VASO DI PANDORA SE I DATI PUBBLICATI CON UNA CERTA FRETTA SARANNO ANALIZZATI APPROFONDITAMENTE PROBABILMENTE DARANNO ALCUNE RISPOSTE CHE SI CERCAVANO, SE ALTRIMENTI CI SI FERMERà SOLAMENTE AGLI OUTCOME PRIMARI ALLORA SARà UN TRIAL NEUTRO CHE NON CONTRIBUISCE ALLA COMPRENSIONE DEL FENOMENO SCOMPENSO.

0

50

100

150

200

250

Baseline Follow-Up

Class 1

Class 2

Class 3-4

N=213 N=170

120

84

9

18

75

75

NYHA Functional Class changes following CABG+SVRSan Donato Experience

STICH NEJM 2009Baseline EF</=35%

0

20

40

60

80

100

Baseline 4 months

83 ml/m2

67ml/m2

ESVI Changes following CABG + SVR

STICH Patients (n=161) San Donato Patients (n=110)

0

20

40

60

80

100

Baseline 8 months

93ml/m2

60 ml/m2

(NEJM March 2009) (Unpublished data)

-19% - 35%

Baseline EF </=35%

0

20

40

60

80

100

120

140

Baseline 8 months

EDVI

126 ml/m2

93 ml/m2

- 26%

0

5

10

15

20

25

30

35

40

EF

Baseline 8 months

28%36%

0.0001

0.001+22%

Baseline EF </=35%

ESVI Changes following CABG + SVR (San Donato Experience)

0

20

40

60

80

100

Baseline Follow-Up

% pts

0

20

40

60

80

100

Baseline Follow-Up

III-IV

II

I

III-IV

II

I

I

I

II

IIIII-IV

III-IV

% pts

NYHA functional class changes (% distribution)

STICH

San Donato

Baseline EF</=35%

0

10

20

30

40

50

60

70

80

90

100

Baseline Follow-Up

Class 1

Class 2

Class 3-4

49%

41%

10%

14%

44%

42%

0

10

20

30

40

50

60

70

80

90

100

Baseline Follow-Up

Class 1

Class 2

Class 3-4

56%

39%

5%

10%

45%

45%

STICH

Milano

Pre and Post-operative NYHA functional class distribution

Baseline EF</=35%

-40

-30

-20

-10

0

10

20

30

EDVI ESVI SVI EF

Hemodynamic Changes following CABG plus SVR in STICH-like patients (Baseline vs FUP)

Average FUP= 1 year

-26%-35%

+9%

+22%

N=110