Gerald S. Werner, MD, FESC, FACC Klinikum Darmstadt, Germany
Safety and Efficacy of DES in Women: An Individual Patient-Level Pooled Analysis of 26 Randomized...
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Transcript of Safety and Efficacy of DES in Women: An Individual Patient-Level Pooled Analysis of 26 Randomized...
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