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 Drug- Eluting Stents Stefanini G, Holmes D. N Engl J Med 2013; 368: “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 10·2250·5 SES vs BMS PES vs BMS SES vs PES 1.00 ( ) 1.03 ( ) 0.96 ( ) 1 0·2250·5 SES vs BMS PES vs BMS SES vs PES 0.30 ( ) 0.42 ( ) 0.70 ( ) HR (95% CI) NNT=7 (CI 6-8) NNT 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) 10·10·2250·5 Favours biodegradable polymer DES Favours durable polymer SES BP-DESDP-SESRR (95% CI) DES Safety – Risk of Stent Thrombosis Everolimus-Eluting Stents Baber U et al. J Am Coll Card 2011; 58; Everolimus-Eluting Stents Baber U et al. J Am Coll Card 2011; 58; Biodegradable Polymer DES Stefanini G et al. Lancet 2011; 378: Biodegradable Polymer DES Stefanini G et al. Lancet 2011; 378: New DES Have Further Improved Outcomes EESControlRR (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

TrialYearNN of Women% of Women RAVEL % SIRIUS % E-SIRIUS % C-SIRIUS % TAXUS I % TAXUS II SR % TAXUS IV % TAXUS V % SIRTAX % ENDEAVOR II % ENDEAVOR III % ENDEAVOR IV % PROTECT % RESOLUTE AC % TWENTE % SPIRIT II % SPIRIT III % SPIRIT IV % COMPARE % COMPARE % BASKET-PROVE % EXCELLENT % RESET % PRODIGY % LEADERS % ISAR-TEST % 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 Age67.1 ± ± ± ± BMI28.1 ± ± ± ± Diabetes31.2% 27.8%32.0%31.1% ID-diabetes10.4% 9.8%10.6%10.3% Hypertension75.6% 77.4%75.8%75.1%0.229 Hypercholesterolemia 67.4%67.7%67.6% 67.2% Smoking 26.6%23.6%26.6%27.1%0.044 Family history 38.7% 44.6%39.1%37.7%<0.001 Prior MI 18.9% 24.2%18.6%18.1% <0.001 Prior PCI 20.6%16.1% 20.9% Prior CABG 5.0%4.7% 4.9%5.0%0.946 Multivessel disease 28.8% 22.7%25.3%31.8%<0.001 Indication 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/patient1.3 ± ± ± ± 0.6<0.001 N stents/patient1.5 ± ± ± ± 0.9<0.001 Stent diameter2.9 ± ± ± ± 0.3<0.001 Stent length29.1 ± ± ± ± 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* Event Incidence, % * Event rates in overall populations are based on summary data and represent crude estimates WomenOverall Population

Death or MI Through 3 Years Cumulative Event Rates at 1, 2 and 3 Years YEAR Incidence, %

Definite/Probable ST Through 3 Years Cumulative Event Rates at 1, 2 and 3 Years YEAR Incidence, %

TLR Through 3 Years Cumulative Event Rates at 1, 2 and 3 Years YEARIncidence, %

Death or MI by Stent Type Newer-generation DES Early-generation DES Bare metal stents Number at risk 0123 Years after PCI BMS Early-generation DES Newer-generation DES 10 0 Cumulative incidence (%) % 10.9% 9.2% Overall P=0.001 Early vs. Newer DES P=0.01

Definite/Probable ST by Stent Type Newer-generation DES Early-generation DES Bare metal stents Number at risk Years after PCI Cumulative incidence (%) 1.3% 2.1% 1.1% Overall P=0.01 Early vs. Newer DES P=0.002 BMS Early-generation DES Newer-generation DES

TLR Through 3 Years by Stent Type Cumulative incidence (%) 5 20 Years after PCI Newer-generation DES Early-generation DES Bare metal stents Number at risk % 7.8% 6.3% Overall P<0.001 Early vs. Newer DES P=0.005 BMS Early-generation DES Newer-generation DES

BMS Early DES HR* (95% CI) P Newer DES HR* (95% CI) P P (Early vs. Newer DES) Death or MI1·0 (ref) 0·94 (0·69-1·27) 0·67 0·70 (0·51-0·97) 0·030·002 Definite or probable ST 1·0 (ref) 0·95 (0·41-2·17) 0·91 0·55 (0·24-1·26) 0·160·02 TLR1·0 (ref) 0·46 (0·33-0·65) <0·001 0·44 (0·31-0·64) <0·0010·68 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 Subgroups Newer DES vs. BMS Early DES vs. BMS

Limitations 1.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