Safety and Efficacy of DES in Women: An Individual Patient-Level Pooled Analysis of 26 Randomized Trials

Including 11,557 Women

Roxana Mehran, MD, FESC, FACC, FAHA, FSCAI

on behalf of the WIN Gender Data Forum Investigators

Drug-Eluting Stents

Stefanini G, Holmes D. N Engl J Med 2013; 368:254-65

“PCI is the most frequently performed therapeutic

intervention in medicine”

“DES are implanted in more than 500,000 patients every

year in the United States”

Mortality and Repeat Revascularization with Early Generation DES versus Bare Metal Stents

Mortality Repeat Revasc

10·2 2 50·5

SES vs BMS

PES vs BMS

SES vs PES

1.00 (0.82-1.25)

1.03 (0.84-1.22)

0.96 (0.83-1.24)

10·2 2 50·5

SES vs BMS

PES vs BMS

SES vs PES

0.30 (0.24-0.37)

0.42 (0.33-0.53)

0.70 (0.56-0.84)

HR (95% CI)

SES vs BMS PES vs BMS SES vs PES0

10

20

30

40

50

NNT=7(CI 6-8)

NN

T

NNT=8(CI 7-10)

NNT=35(CI 23-65)

HR (95% CI)

Stettler C et al. Lancet 2007;370:937-48

Overall (I-squared = 0·0%, p=0·92)

LEADERS

ISAR-TEST 4

ISAR-TEST 3

20/857

9/1299

1/202

32/850

9/652

2/202

0·58 (0·37, 0·93)

0·62 (0·36, 1·08)

0·50 (0·20, 1·26)

0·50 (0·05, 5·47)

10·1 0·2 2 50·5

Favours biodegradable polymer DES

Favours durable polymer SES

BP-DES DP-SES RR (95% CI)

DES Safety – Risk of Stent Thrombosis

Everolimus-Eluting StentsBaber U et al. J Am Coll Card 2011; 58;1569-1577

Biodegradable Polymer DESStefanini G et al. Lancet 2011; 378:1940-8

New DES Have Further Improved Outcomes

EES Control RR (95% CI)

RR

However, female participants in DES trials were less than 30% !

Issued on December 19th, 2011

Gender Data Forum

On Devices

September 24, 2012 | Heart House, Washington, DC

• The Women in Innovation (WIN) Initiative convened a Gender Data Forum to discuss outcomes of DES in women

• The Gender Data Forum was held in Washington, DC on September 24, 2012

• The Gender Data Forum led to the request to investigate the efficacy and safety profile of DES in women by performing a patient-level pooled analysis of female participants from available randomized DES trials

WIN – Gender Data Forum

GENDER DATA FORUM

•Physician Steering Committee: CHAIR - Roxana Mehran, MD, FSCAI, FACC, FESC – Mt Sinai

School of Medicine, New York, NY Alaide Chieffo, MD, FSCAI, FESC – San Raffaele Hospital, Milan,

Italy Dipti Itchhaporia, MD, FACC - Presbyterian, Newport Beach,

CA Laxmi Mehta, MD, FACC – Ohio State University, Columbus,

OH

Data Collection

• Principal investigators and industry sponsors of randomized DES trials participating to the Gender Data Forum were contacted

• A preformatted extraction sheet was distributed in order to obtain patient-level data of female participants

• Patient-level data of 26 randomized clinical trials on DES were pooled

Trial Year N N of Women % of WomenRAVEL 2002 238 58 24%SIRIUS 2003 1058 305 29%E-SIRIUS 2003 352 103 29%C-SIRIUS 2004 100 31 31%TAXUS I 2003 61 7 11%TAXUS II SR 2003 267 67 25%TAXUS IV 2004 1314 367 28%TAXUS V 2005 1156 353 31%SIRTAX 2005 1012 231 23%ENDEAVOR II 2006 1197 283 24%ENDEAVOR III 2006 436 133 31%ENDEAVOR IV 2009 1548 500 32%PROTECT 2012 8709 2061 24%RESOLUTE AC 2010 2292 529 23%TWENTE 2012 1391 382 27%SPIRIT II 2006 300 80 27%SPIRIT III 2008 1002 314 31%SPIRIT IV 2010 3687 1189 32%COMPARE 2010 1800 526 29%COMPARE-2 2013 2707 693 26%BASKET-PROVE 2010 2314 565 24%EXCELLENT 2011 1443 512 35%RESET 2012 3197 742 23%PRODIGY 2012 2013 473 23%LEADERS 2008 1707 430 25%ISAR-TEST 4 2009 2603 623 24%

Summary of Included Trials

• 26 Randomized Trials

• Years 2002 to 2013

• Overall 43,904 Patients

• 11,557 (26%) Women

Analytic Methods

Endpoints• Primary safety EP: composite of death and MI• Secondary safety EP: ARC definite/probable ST• Primary efficacy EP: TLR

Analysis• All patient level data aggregated and harmonized into

a single dataset• Event-free survival calculated using the Kaplan-Meier

Method and compared across stent strata with the log-rank test

• Observations censored at time of death, last follow-up or trial end, whichever occurred first

• Multivariable-adjusted associations evaluated using Cox Proportional Hazards regression with trial included as a random effect

Investigated Devices

1. Bare Metal Stents (BMS)

2. Early-generation DES• Cypher SES (Cordis, Johnson&Johnson)• Taxus PES (Taxus, Boston Scientific)

3. Newer-generation DES• Xience/Promus EES (Abbott, Boston Scientific) • Endeavor ZES (Medtronic) • Resolute ZES (Medtronic) • Biomatrix/Nobori BES (Biosensors, Terumo) • Yukon PC SES (Translumina)

Baseline Characteristics Overall

(N=11557)BMS

(N=1108)Early DES(N=4171)

Newer DES(N=6278) P-value

Age 67.1 ± 10.6 66.6 ± 10.5 67.2 ± 10.7 67.1 ± 10.5 0.229

BMI 28.1 ± 5.8 28.8 ± 6.2 28.1 ± 5.9 27.9 ± 5.6 0.003

Diabetes 31.2% 27.8% 32.0% 31.1% 0.055 ID-diabetes 10.4% 9.8% 10.6% 10.3% 0.627Hypertension 75.6% 77.4% 75.8% 75.1% 0.229Hypercholesterolemia 67.4% 67.7% 67.6% 67.2% 0.595Smoking 26.6% 23.6% 26.6% 27.1% 0.044 Family history 38.7% 44.6% 39.1% 37.7% <0.001Prior MI 18.9% 24.2% 18.6% 18.1% <0.001Prior PCI 20.6% 16.1% 20.9% 20.9% 0.022Prior CABG 5.0% 4.7% 4.9% 5.0% 0.946 Multivessel disease 28.8% 22.7% 25.3% 31.8% <0.001Indication to PCI <0.001 Stable CAD 56.1% 52.5% 59.1% 54.8% ACS 43.8% 47.3% 40.9% 45.2%

Angiographic and Procedural Characteristics

Overall(N=11557)

BMS(N=1108)

Early DES(N=4171)

Newer DES(N=6278) P-value

N lesions/patient 1.3 ± 0.6 1.16 ± 0.5 1.2 ± 0.5 1.3 ± 0.6 <0.001

N stents/patient 1.5 ± 0.9 1.3 ± 0.77 1.4 ± 0.7 1.5 ± 0.9 <0.001

Stent diameter 2.9 ± 0.4 3.0 ± 0.4 2.98 ± 0.3 2.9 ± 0.3 <0.001

Stent length 29.1 ± 18.7 25.6 ± 15.7 27.6 ± 16.8 30.6 ± 20.1 <0.001

B2/C lesions* 63.4% 66.9% 63.0% 63.2% 0.078

Bifurcation lesions* 18.7% 12.8% 19.9% 19.5% <0.001

*at least 1 per patient

Adverse Events in Women Compared to Overall Trial Populations at 3 Years*

Death MI Def/Prob ST TLR0%

5%

10%

15%

5.7% 5.5%

1.6%

8.0%

5.9%

4.5%

1.6%

8.3%

Event

Inci

denc

e, %

* Event rates in overall populations are based on summary data and represent crude estimates

Women Overall Population

Death or MI Through 3 YearsCumulative Event Rates at 1, 2 and 3 Years

1 2 30%

5%

10%

15%

20%

6.3%

8.4%

10.3%

YEAR

Inci

denc

e, %

Definite/Probable ST Through 3 YearsCumulative Event Rates at 1, 2 and 3 Years

1 2 30%

2%

4%

6%

0.9%1.3%

1.6%

YEAR

Inci

denc

e, %

TLR Through 3 YearsCumulative Event Rates at 1, 2 and 3 Years

1 2 30%

5%

10%

15%

20%

5.5%6.8%

8.0%

YEAR

Inci

denc

e, %

Death or MI by Stent Type

5

15

5210 3379 2008Newer-generation DES

3788 3191 2019Early-generation DES

998 822 544Bare metal stents

Number at risk

0 1 2 3Years after PCI

BMSEarly-generation DESNewer-generation DES

10

0

Cu

mu

lativ

e in

cid

en

ce (

%)

6278

4171

1108

12.8%

10.9%

9.2%

Overall P=0.001

Early vs. Newer DES P=0.01

Definite/Probable ST by Stent Type

5382 3476 2074

3919 3297 2099

1056 859 574

0 1 2 3

Newer-generation DES

Early-generation DES

Bare metal stents

Number at risk Years after PCI

6278

4171

1108

0

2

4

6

8

Cu

mu

lativ

e in

cid

en

ce (

%)

1.3%

2.1%

1.1%

Overall P=0.01

Early vs. Newer DES P=0.002

BMSEarly-generation DESNewer-generation DES

TLR Through 3 Years by Stent Type

5217 3307 1951

3764 3113 1955

898 710 457

0 1 2 3

Cu

mu

lativ

e in

cid

en

ce (

%)

5

20

Years after PCI

10

0

15

Newer-generation DES

Early-generation DES

Bare metal stents

Number at risk

6278

4171

1108

18.6%

7.8%

6.3%

Overall P<0.001

Early vs. Newer DES P=0.005

BMSEarly-generation DESNewer-generation DES

BMS Early DESHR* (95% CI) P Newer DES

HR* (95% CI) PP

(Early vs. Newer DES)

Death or MI 1·0 (ref) 0·94(0·69-1·27) 0·67 0·70

(0·51-0·97) 0·03 0·002

Definite or probable ST 1·0 (ref) 0·95

(0·41-2·17) 0·91 0·55 (0·24-1·26) 0·16 0·02

TLR 1·0 (ref) 0·46(0·33-0·65) <0·001 0·44

(0·31-0·64) <0·001 0·68

Adjusted Risk for Outcomes Associated with Early- and Newer-Generation DES vs. BMS

* HR calculated for 3-year outcomes using random effects Cox Proportional Hazards models with trial included as random effect. Models are adjusted for stent group, age, body mass index, diabetes, prior MI, family history CAD, prior PCI, multivessel CAD, acute coronary syndrome, smoking, number of stents, and B2/C lesions.

Death or MI in Major Subgroups

Early DES vs. BMS Newer DES vs. BMS

TLR in Major SubgroupsNewer DES vs. BMSEarly DES vs. BMS

Limitations1. Trials were conducted over 10 years, during which clinical practice

has been subject to changes • However, we accounted for time-related treatment effect modifications

by including trial as a random effect in all analyses

2. Inclusion criteria in the 26 pooled trials had some degree of heterogeneity. Early trials focused on simple patients with stable CAD, whereas later trials had broader inclusion criteria opening to more complex patients with MVD and ACS • Nevertheless, in order to limit this heterogeneity, trials focusing on

specific patient and lesion subsets (e.g., AMI, LM, CTO, etc.) were not included in the present analysis

3. The 26 pooled trials were not primarily intended to investigate outcomes in women • However, the overall large number of patients included in our analysis

provides sufficient precision to evaluate DES safety and efficacy in women. In addition, our findings are consistent with available trials investigating DES in populations comprising both women and men.

Conclusions• Women comprise only one-fourth of patients

recruited in randomized DES trials.

• The use of DES in women is safe and effective compared with BMS during long-term follow-up

• Newer-generation DES are associated with an

improved safety profile compared with early-generation DES in women

• Patient-based pooled analysis of prior trials allow for analysis of safety and efficacy in under-represented populations: ie: Women