Safety and Efficacy of DES in Women: An Individual Patient-Level Pooled Analysis of 26 Randomized Trials Including 11,557 Women

1
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

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Drug-Eluting StentsStefanini G, Holmes D. N
Engl J Med 2013 368254-65
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
3
Mortality and Repeat Revascularization with Early
Generation DES versus Bare Metal Stents
Stettler C et al. Lancet 2007370937-48
Mortality
Repeat Revasc
HR (95 CI)
HR (95 CI)
SES vs BMS
1.00 (0.82-1.25)
SES vs BMS
0.30 (0.24-0.37)
PES vs BMS
1.03 (0.84-1.22)
PES vs BMS
0.42 (0.33-0.53)
SES vs PES
0.96 (0.83-1.24)
SES vs PES
0.70 (0.56-0.84)
1
02
2
5
05
1
02
2
5
05
NNT35 (CI 23-65)
NNT
NNT8 (CI 7-10)
NNT7 (CI 6-8)
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New DES Have Further Improved Outcomes
DES Safety Risk of Stent Thrombosis
Everolimus-Eluting Stents Baber U et al. J Am
Coll Card 2011 581569-1577
Biodegradable Polymer DES Stefanini G et al.
Lancet 2011 3781940-8
BP-DES
DP-SES
RR (95 CI)
EES
Control
RR (95 CI)
ISAR-TEST 3
1/202
2/202
050 (005, 547)
ISAR-TEST 4
9/1299
9/652
050 (020, 126)
LEADERS
20/857
32/850
062 (036, 108)
Overall (I-squared 00, p092)
058 (037, 093)
1
01
02
2
5
05
Favours biodegradable polymer DES
Favours durable polymer SES
RR
However, female participants in DES trials were
less than 30 !
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Issued on December 19th, 2011
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Gender Data ForumOn DevicesSeptember 24,
2012 Heart House, Washington, DC
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WIN Gender Data Forum

• 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

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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

9
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

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Trial Year N N of Women of Women
RAVEL 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

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Analytic Methods

• 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

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

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Investigated Devices

• 1. Bare Metal Stents (BMS)
• 2. Early-generation DES
• Cypher SES (Cordis, JohnsonJohnson)
• 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)

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Baseline Characteristics
  Overall (N11557) BMS (N1108) Early DES (N4171) Newer DES (N6278) 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  0.627
Hypertension 75.6  77.4 75.8 75.1 0.229
Hypercholesterolemia  67.4 67.7 67.6 67.2  0.595
Smoking  26.6 23.6 26.6 27.1 0.044 
Family history  38.7  44.6 39.1 37.7 lt0.001
Prior MI  18.9  24.2 18.6 18.1  lt0.001
Prior PCI  20.6 16.1  20.9 20.9 0.022
Prior CABG  5.0 4.7  4.9 5.0 0.946 
Multivessel disease  28.8  22.7 25.3 31.8 lt0.001
Indication to PCI         lt0.001 
Stable CAD  56.1 52.5  59.1 54.8  
ACS  43.8 47.3  40.9  45.2  
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Angiographic and Procedural Characteristics
  Overall (N11557) BMS (N1108) Early DES (N4171) Newer DES (N6278) P-value
N lesions/patient 1.3 0.6  1.16 0.5 1.2 0.5 1.3 0.6 lt0.001
N stents/patient 1.5 0.9  1.3 0.77 1.4 0.7 1.5 0.9 lt0.001
Stent diameter 2.9 0.4   3.0 0.4 2.98 0.3 2.9 0.3 lt0.001
Stent length 29.1 18.7  25.6 15.7 27.6 16.8 30.6 20.1 lt0.001
B2/C lesions 63.4  66.9  63.0 63.2 0.078
Bifurcation lesions  18.7 12.8  19.9 19.5 lt0.001
at least 1 per patient
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Adverse Events in Women Compared to Overall Trial
Populations at 3 Years
Women
Overall Population
Incidence,
Event
Event rates in overall populations are based on
summary data and represent crude estimates
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Death or MI Through 3 Years
Cumulative Event Rates at 1, 2 and 3 Years
Incidence,
YEAR
17
Definite/Probable ST Through 3 Years
Cumulative Event Rates at 1, 2 and 3 Years
Incidence,
YEAR
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TLR Through 3 Years
Cumulative Event Rates at 1, 2 and 3 Years
Incidence,
YEAR
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Death or MI by Stent Type
BMS
Early-generation DES
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Newer-generation DES
12.8
10.9
10
9.2
Cumulative incidence ()
Overall P0.001
5
Early vs. Newer DES P0.01
0
0
1
2
3
Years after PCI
Number at risk
998
822
544
Bare metal stents
1108
3788
3191
2019
Early-generation DES
4171
5210
3379
2008
Newer-generation DES
6278
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Definite/Probable ST by Stent Type
BMS
Early-generation DES
8
Newer-generation DES
Overall P0.01
6
Early vs. Newer DES P0.002
4
Cumulative incidence ()
2.1
2
1.3
1.1
0
0
1
2
3
Years after PCI
Number at risk
1056
859
574
Bare metal stents
1108
3919
3297
2099
Early-generation DES
4171
5382
3476
2074
Newer-generation DES
6278
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TLR Through 3 Years by Stent Type
Overall Plt0.001
BMS
Early-generation DES
Newer-generation DES
20
18.6
15
Early vs. Newer DES P0.005
Cumulative incidence ()
10
7.8
6.3
5
0
0
1
2
3
Years after PCI
Number at risk
898
710
457
Bare metal stents
1108
3764
3113
1955
Early-generation DES
4171
5217
3307
1951
Newer-generation DES
6278
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Adjusted Risk for Outcomes Associated with Early-
and Newer-Generation DES vs. BMS
  BMS Early DES HR (95 CI) P Newer DES HR (95 CI) P P (Early vs. Newer DES)
Death or MI 10 (ref) 094 (069-127) 067 070 (051-097) 003 0002
Definite or probable ST 10 (ref) 095 (041-217) 091 055 (024-126) 016 002
TLR 10 (ref) 046 (033-065) lt0001 044 (031-064) lt0001 068
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.
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Death or MI in Major Subgroups
Early DES vs. BMS
Newer DES vs. BMS
24
TLR in Major Subgroups
Newer DES vs. BMS
Early DES vs. BMS
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Limitations

• 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
• 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
• 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.

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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

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