Safety of Drug Eluting Stents Do 2nd generation DES have a lower risk of stent thrombosis?

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Safety of Drug Eluting StentsDo 2nd generation
DES have a lower risk of stent thrombosis?

• Keith G Oldroyd
• West of Scotland Regional Heart Lung Centre
• Golden Jubilee National Hospital

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Conflicts of InterestAdvisory boards for
Biosensors Cordis BSCI
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Safety of Drug Eluting Stents

• Cypher/Taxus vs BMS
• Cypher/Taxus vs Endeavor
• Cypher/Taxus vs Xience/Promus
• Cypher vs Biomatrix
• Cypher vs Yukon

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Safety and Efficacy of Sirolimus Eluting
Stents(NEJM 2007 356 998-1008)
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Safety and Efficacy of Paclitaxel Eluting
Stents(NEJM 2007 356 998-1008)
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Scottish Coronary Revascularisation
RegisterAll-cause mortality for off-label use
of DES
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HORIZONS - Stent Thrombosis (ARC Definite or
Probable)
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MASS Registry PS matched risks and risk
differences at 3 years in diabetic patients
Garg P et al. Circulation 2008
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Meta-analysis DES vs BMS

• In 22 RCTs involving 9,470 patients randomized to
  DES or BMS and followed for 1 year, DES resulted
  in
• A non-significant 3 reduction in mortality - HR
  0.97 (0.81,1.15)
• A non-significant 6 reduction in MI - HR 0.94
  (0.79,1.13)
• A significant 55 reduction in TVR HR 0.45
  (0.37,0.54)
• In 30 Registries with 174,302 patients treated
  with either DES or BMS and followed for 1 year,
  DES resulted in
• A significant 20 reduction in mortality - HR
  0.80 (0.72,0.88)
• A significant 11 reduction in MI HR 0.89
  (0.80-0.98)
• A significant 47 reduction in TVR HR 0.53
  (0.47-0.61)

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• This is not a class effect for drug-eluting
  stents. The sirolimus-eluting CYPHER stent has a
  wide therapeutic window and does not have a
  problem with either early or late
  thromboses Jeff Moses. TCT 04

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Pooled Odds Ratio
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Endeavor IIStent thrombosis
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• Does even distribution of neointima explain the
  unsurpassed stent thrombosis rates with
  Endeavor? Professor Martin Rothman 2005

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ENDEAVOR IV 2 year outcomes
TCT 08
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SORTOUT-III Definite Stent Thrombosis
Hazard Ratio (95 CI) 4.62 (1.33 16.1) p0.02
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SORTOUT-III Myocardial Infarction
Hazard Ratio (95 CI) 3.47 (1.14 10.5) p0.03
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SORTOUT-III Clinically Significant Restenosis
Hazard Ratio (95 CI) 6.59 (2.57 16.9) plt0.0001
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Western Denmark Heart RegistryEndeavor vs Cypher
Thuesen L. TCT 2008
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SPIRIT III - 2 Year ResultsARC Definite /
Probable Stent Thrombosis
P0.77
PNR
PNR
P0.34
SPIRIT III Presentation, Gregg W. Stone, MD, PCR
2008.
Refer to glossary
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SPIRIT III - 2 Year ResultsProtocol Stent
Thrombosis
ACS with thrombus or unexplained death or AMI in
the target lesion distribution within 30 days.
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Xience/Promus vs Cypher?
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LEADERSCardiac Death Myocardial Infarction
Biolimus Stent Sirolimus Stent
6.7
6.6
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LEADERSDefinite Stent Thrombosis
2.0
2.0
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ISAR-TEST 3
Yukon
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Conclusion

• There is as yet no convincing evidence of any
  important safety differences between any of
  the currently available DES.
• It may never be possible to convincingly
  demonstrate such differences even if they exist.
• Any differences that do exist in the risk of
  stent thrombosis between DES are very small and
  less important than several other potential
  causative factors including
• the patient
• the lesion
• the operator
• response to and premature discontinuation of DAPT

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(No Transcript)
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ISAR-TEST 3
Yukon
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Future Studies on DES Safety - DAPT

• Designed to enroll more than 15 000 patients
  being treated with one of the four DES currently
  approved in the US and more than 5000 patients
  treated with a BMS.
• All patients will receive DAPT - clopidogrel or
  prasugrel for 12 months.
• At 12 months, after the exclusion of any patients
  with MACCE or major bleeding patients will be
  randomised to either placebo or ongoing DAPT out
  to 30 months.
• Follow-up will end at 33 months, to include a
  possible "rebound period.
• The co-primary end points will be stent
  thrombosis and MACCE, and the major safety end
  point will be major bleeding.

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DES and BMS for Acute Myocardial Infarction
N4,016 patients with DES for MI
N3,200 patients with BMS for MI
Propensity score matched pairs
2629 MI
2629 MI
2,453 (61.1) DES for NSTEMI
1,382 (43.2) BMS for NSTEMI
matched pairs
1,221 NSTEMI
1,221 NSTEMI
1,563 (38.9) DES for STEMI
1,818 (56.8) BMS for STEMI
matched pairs
1,302 STEMI
1,302 STEMI
Mauri L et al. N Engl J Med 2008 3591330-1342.
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DES and BMS for Acute Myocardial Infarction
Risk Differences in Matched MI Patient Groups at
2 years
Risk Difference (95 CI), DES v. BMS
Recurrent MI
Death
-2.7 -4.5, 0 P0.002
-1.5 -3.1, 0.2 P0.08
-2.4 -5.0, 0.3 P0.07
-1.9 -4.6, 0.9 P0.18
-3.1 -5.4, -0.8 P0.009
-1.6 -3.7, 0.5 P0.127
Mauri L et al. N Engl J Med 2008 3591330-1342.
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SPIRIT III 2 year outcomes
Among patients who stopped DAPT _at_ 6 months there
were fewer stent thrombosis "episodes" in Xience
V-treated patients compared to Taxus-treated
patients but .
E-PCR 2008
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SORTOUT-III Cardiac Mortality
Hazard Ratio (95 CI) 2.17 (0.75 6.24) p0.14
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Meta-analysis DES vs. BMSMortality RCT and
Registry Analysis
Mortality All Registries 161,232 patients, 28
registries
Mortality All RCTs 8,867 patients, 21 trials
Estimate (95 CI)
Weight ()
Estimate (95 CI)
Weight ()
0.97 (0.81,1.15) 0.97 (0.81,1.15), p0.72
Random Effects Fixed Effects (I20.0)
Random Effects (I270.1) Fixed Effects
0.80 (0.72,0.88), plt0.001 0.83 (0.79,0.86)
Favors DES
Favors BMS
Favors DES
Favors BMS
lt1.0 ? Favors DES significant
All-cause mortality data was available in 21 of
22 RCTs and 28 of 30 Registries.
Presented by Gregg W. Stone MD and Ajay Kirtane
MD, ACC 2008. Point estimates are represented by
red circles Confidence intervals by red lines
and Weight by yellow boxes (based on primary
model) No significant effect of number of
patients (total or DES patients) or diabetic
patients by meta-regression Random effects used
except if I2lt25.
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Meta-analysis DES vs. BMSMI RCT and Registry
Analysis
MI All RCTs 8,850 patients, 20 trials
MI All Registries 129,955 patients, 24
registries
Estimate (95 CI)
Weight ()
Estimate (95 CI)
Weight ()
Random Effects Fixed Effects (I23.0)
0.94 (0.78,1.13) 0.94 (0.79,1.13), p0.54
0.89 (0.80,0.98), p0.023 0.96 (0.91,1.01)
Random Effects (I257.9) Fixed Effects
Favors DES
Favors BMS
Favors DES
Favors BMS
lt1.0 ? Favors DES significant
MI data was available in 20 of 22 RCTs and 24
of 30 Registries
Presented by Gregg W. Stone MD and Ajay Kirtane
MD, ACC 2008. Point estimates are represented by
red circles Confidence intervals by red lines
and Weight by yellow boxes (based on primary
model) No significant effect of number of
patients (total or DES patients) or diabetic
patients by meta-regression Random effects used
except if I2lt25.
Refer to glossary
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Drug-Eluting and Bare Metal Stenting for Acute
Myocardial InfarctionPatient Characteristics
after Match
SD Percent Standardized Difference Values
lt10 reflect well-matched characteristics
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Drug-Eluting and Bare Metal Stenting for Acute
Myocardial InfarctionPatient Characteristics
after Match
SD Percent Standardized Difference Values
lt10 reflect well-matched characteristics
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Drug-Eluting and Bare Metal Stenting for Acute
Myocardial InfarctionProcedure Indications after
Match
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Drug-Eluting and Bare Metal Stenting for Acute
Myocardial InfarctionProcedural Characteristics
after Match
SD Percent Standardized Difference Values
lt10 reflect well-matched characteristics
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Drug-Eluting Bare Metal Stenting in
Massachusetts Risk Differences in Matched MI
Patient Groups at 2 years
Risk Difference (95 CI), DES v. BMS
Revascularization
TVR
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Angiographic results, accounting for 32 of
treated lesions, in CREATE
Han Y. American College of Cardiology 2008
Scientific Sessions/ i2 Summit-SCAI Annual
Meeting March 31, 2008 Chicago, IL.
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Clinical outcomes in CREATE
Primary end point MACEmajor adverse cardiac
events TLRtarget-lesion revascularization
Han Y. American College of Cardiology 2008
Scientific Sessions/ i2 Summit-SCAI Annual
Meeting March 31, 2008 Chicago, IL.
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Angiographic outcomes at six months and two years
in SPIRIT-2 Xience-V vs Taxus
Serruys PW, et al. March 31, 2008 Chicago, IL.
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Intravascular ultrasound measurements at six
months and two years in SPIRIT-2 Xience-V vs
Taxus
Serruys PW, et al. March 31, 2008 Chicago, IL.
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Clinical outcomes at six months and two years in
SPIRIT-2 Xience-V vs Taxus
Serruys PW, et al. March 31, 2008 Chicago, IL.
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S.T.E.N.T. Registry
SES PES (n2282)
(n1476) n n
p Death 61 2.7 31 2.1
0.26 MI 50 2.2 27 1.8
0.44 TVR 95 4.2 50 3.4 0.23
CABG Target Vessel 12 0.5 11 0.7
0.40 Re-PCI Target Vessel 84 3.7 41
2.8 0.13 MACE 180 7.9 100
6.8 0.20 Stent Thrombosis
15 0.7 7 0.5 0.52 lt 24 hours
1 2 24 hours to 30 days 11 1 gt
30 days 3 4
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Future Studies on DES SafetyDAPT

• No stent-stent or drug-drug comparisons
• Only the FDA and the DSMB will have access to all
  the device- and drug-level data
• This is fully appropriate given the lack of any
  statistical power in a study this size to make
  comparisons between devices or drugs.
• Dr William Maisel (Beth Israel Deaconess Medical
  Center) commented "I find it ironic that after
  months and years of hearing about how stents are
  different and that one company's stent, for
  biologic or platform or endothelialisation
  reasons, has different rates of stent thrombosis,
  we're suddenly lumping them all together."

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Massachusetts Registry -2 year risk-adjusted
outcomes
Mauri L et al. N Engl J Med 2008 3591330-1342.
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SPIRIT III Clinical Trial 2-Year ResultsARC
Definite / Probable Stent Thrombosis
P NR
P 0.77
Incidence Rate ()
TAXUSTM Express2TM Stent n333
XIENCE V (PROMUS) Stent n669
P Value from Log Rank test
Adapted from SPIRIT III Presentation, Gregg W.
Stone, MD, PCR 2008.
Refer to glossary
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SPIRIT III Clinical Trial 2-Year
ResultsProtocol Stent Thrombosis
P NR
P 0.35
Incidence Rate ()
TAXUSTM Express2TM Stent n333
XIENCE V (PROMUS) Stent n669
ACS with thrombus or unexplained death or AMI in
the target lesion distribution within 30 days.
P Value from Log Rank test
Adapted from SPIRIT III Presentation, Gregg W.
Stone, MD, PCR 2008.
Refer to glossary
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ENDEAVOR II, III, and IV Studies9-month Safety
Results
p0.342
p1.00
p0.772
p0.287
pNA
p1.00
QWMI ()
Death ()
95 CI 0.1, 1.6
p0.224
pNA
p0.124
pNR
pNR
ARC (Def Prob) ST ()
Protocol ST ()
92.3 of EndeavorTM Stent patients were on DAPT
through 6 months
ENDEAVOR II
ENDEAVOR III
ENDEAVOR IV
EndeavorTM Stent n 592
EndeavorTM Stent n 323
EndeavorTM Stent n 740
DriverTM Stent n 591
CypherTM Stent n 113
TAXUSTM Stent n 734
ENDEAVOR II Fajadet et al, Circulation, August
22, 2006. ENDEAVOR III Kandzari et al., JACC,
December 19, 2006. ENDEAVOR IV www.fda.gov.
All ARC (defprob) stent thrombosis rates
www.fda.gov.
Refer to glossary
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SORT-OUT III (Danish)RCT Endeavor vs Cypher
Lassen JF. TCT 2008
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ENDEAVOR IV 2 year outcomes
TCT 08
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REALITY12 MONTH OUTCOMES
Morice et al. JAMA 2006, 295 895-904.
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SORTOUT II 9 MONTH OUTCOMES
PNS
PNS
PNS
PNS
PNS
PNS
Incidence Rate ()
TAXUS N 1033
Cypher N 1065
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Meta-analysis of Stent ThrombosisSES vs PES
Moreno et al. Br J Clin Pharmacol. 2007 July
64(1) 110112. Risk of stent thrombosis after
sirolimus or paclitaxel eluting coronary stent
implantation
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Pooled odds ratio
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Pooled odds ratio
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LEADERS Clinical outcomes at nine months
Windecker S et al. Lancet 2008
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• Does even distribution of (MORE) neointima
  explain the unsurpassed stent thrombosis rates
  with Endeavor? Professor Martin Rothman
  2005