68 yo Female

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Late Events and Durationof Therapy

• Laura Mauri, MD, MSc
• Brigham and Womens Hospital
• Harvard Clinical Research Institute

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Bare-Metal Stent Thrombosis
30-day Rates
18
16
16
14
12
Warfarin
10
Stent Thrombosis ()
High-pressure balloons and ticlopidine
8
6
3.5
4
1.4
0.8
0.6
2
0
ISAR4
PS1
STRESS2
Colombo3
STARS5
1. Schatz RA et al. Circulation. 199183148-61.
2. Fischman DL et al. N Engl J Med.
1994331496-501. 3. Colombo A et al.
Circulation.1995911676-88. 4. Schömig A et al.
New Engl J Med. 19963341084-9. 5. Leon MB et
al. N Engl J Med. 19983391665-71.
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Antiplatelet Therapy Post-BMS
HCRI Stent Database (n6186)
1.0
Ticloplidine
0.8
No Ticlopidine
0.6
with ST
0.4
0.2
0
0
4
8
12
16
20
24
28
Days from procedure
BMS bare-metal stent ST stent
thrombosis. Cutlip DE et al. Circulation.
20011031967-71.
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Late Stent ThrombosisWas a problem anticipated?

• Mechanism of delayed healing in DES might
  increase risk or extend duration of risk for
  stent thrombosis
• Longer antiplatelet therapy was given empirically
  post DES (3-6 month) vs post BMS (1 month)
• DES RCT monitored stent thrombosis rates at later
  time points (1 year, and yearly to 5 years) vs
  BMS trials (30 d)

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DES Thrombosis
10 Randomized Studies, 1-year Follow-up
BMS vs. DES
5
2,602
2,428
BMS
DES
4
3
P1.00
P1.00
of Patients
2
1
0.58
0.54
0.23
0.25
0
Stent Thrombosis
Late Thrombosis
Moreno R et al. J Am Coll Cardiol. 200545954-9.
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BASKET and BASKET-LATE Trials
These P values reported at ACC 2006 but not in
subsequent publication.
Kaiser C et al. Lancet. 2005366921-9.
Pfisterer M et al. J Am Coll Cardiol.
2006482584-91.
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ESC
August 2006

• Camenzind et al. present combined published
  results from DES trials and found a higher rate
  of the composite death nonfatal MI for 1st
  generation DES versus BMS. Analysis at each year
  of follow-up did not yield significant
  differences. (Available at http//www.escardio.org
  /knowledge/congresses/CongressReports/hotlinesandc
  tus/707009_Camenzind.htm)
• Nordmann et al. present a meta-analysis of 17
  published DES trials where noncardiac mortality
  at 2 years was greater for sirolimus-eluting
  stents than for bare metal. Other time points
  and endpoints (cardiac mortality) did not show
  significant differences. (Eur Heart J .
  2006272784814.)

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Stent Thrombosis Pooled analysis of 8 RCT Trials
ARC Definition Definite and Probable
1.7 1.5
1.8 1.4
LR P0.52
LR P0.70
Mauri, L. N Engl J Med 20073561020-9.
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Stent Thrombosis Cumulative Incidence
ARC Definition Definite and Probable
LR P0.70
LR P0.52
Proportional hazards assumption not rejected
Mauri L et al. N Engl J Med. 20073561020-9.
Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and
C-SIRIUS
Pooled Data from TAXUS 1 2 4 and 5
ARC Academic Research Consortium.
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Antiplatelet Therapy
Stent Thrombosis
Mauri L et al. N Engl J Med. 20073561020-9.
Pooled Data from RAVEL, SIRIUS, C-SIRIUS, E-SIRIUS
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Overall Clinical Outcomes4 year cumulative
incidence
Overall, stent thrombosis accounts for lt10 of
total mortality at 4y
Mauri, L. N Engl J Med 20073561020-9.
Stone, G. N Engl J Med 2007356998-1008.
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Randomized Trial Data
Dual antiplatelet therapy beyond 3-6 months did
not prevent all late events (BMS or DES)

• Events occurred at variable times after
  discontinuation of therapy

Stent thrombosis at 4y accounts for lt10 total
mortality

• Extended antiplatelet therapy may influence stent
  thrombosis AND non-stent thrombosis events
  related to underlying CAD

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Bern Rotterdam Data N8146 DES
Daemen, J. Lancet 2007 Feb 24369(9562)667-78.
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Swedish Coronary Angiography and Angioplasty
Registry (SCAAR)
Propensity Score Adjusted Cumulative Mortality
DES
BMS
N at Risk BMS DES
Lagerqvist, B. N Engl J Med 20073561009-19.
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Observational Study Data

• Diverse patient population
• Higher rates of stent thrombosis, myocardial
  infarction and mortality than in randomized
  trials
• DES may have a different impact in higher risk
  patients

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Late Events Duration of antiplatelet therapy
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DES Thrombosis
In addition to conventional BMS thrombosis risk
factors, DES may be affected by

• Late drug and polymer interactions - delayed
  endothelialization
• Increasing mechanical complexity (bifurcations,
  longer stent lengths, total occlusions)
• These result in a greater need for compliance
  with antiplatelet therapy, over a longer duration

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Premature Cessation of Thienopyridine Therapy
(lt30d)

• PREMIER registry MI and DES, 19 centers, 500
  subjects
• Early discontinuation associated with mortality
  (7.5 vs 0.7, plt0.0001)

• Factors related to premature cessation
• Older age
• Not having completed high school
• Not being married
• Not receiving discharge instructions for
  medication use
• Not being referred for cardiac rehabilitation
• Greater likelihood of having preexistent
  cardiovascular disease or anemia
• Not seeking health care because of cost

Spertus JA. Circulation 2006482584-91.
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Stent ThrombosisEarly Discontinuation of
Anti-platelet Therapy ( before 6m)
Overall stent thrombosis 1.3 (P0.09, N2229)
Incidence ()
Unstable angina
Thrombus
Diabetes
Unprotected left main
Bifurcation
Renal failure
Prior brachy Rx
Premature antiplateletdiscontd
Iakovou et al. JAMA. 20052932126.
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Effect of Clopidogrel on 24-Month Events in
Patients Who Were Event-Free at 6 Months
24-Month Events

• With Without Clopidogrel Clopidogrel Differenc
  e (95 CI) P Value
• Drug-Eluting Stent (DES)
• Patients (n) 637 579
• Death 2.0 5.3 -3.3 (-6.3 to -0.3) 0.03
• Death or MI 3.1 7.2 -4.1 (-7.6 to
  -0.6) 0.02
• Bare-Metal Stent (BMS)
• Patients (n) 417 1,976
• Death 3.7 4.5 -0.7 (-2.9 to 1.4) 0.50
• Death or MI 5.5 6.0 -0.5 (-3.2 to
  2.2) 0.70

Exclusions DES group (Death 62, nonfatal MI 18,
revasc 76, meds not reported 129 (total
285/1502) BMS group (Death 123, nonfatal MI
94, revasc 289, meds not reported 266 (total
772/3165)
Eisenstein EL et al. JAMA. 2007297159-68.
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ACC/AHA PCI Scientific Advisory 2007

• Recommend 12 months of dual antiplatelet therapy
  in patients without excess risk of bleeding
• Avoid of drug-eluting stents when surgery cannot
  be deferred 12 months after PCI
• Educate patients and provide mechanisms for
  antiplatelet therapy compliance
• Bridging therapies are not recommended

Grines, C. JACC. 2007 Feb 13 49(6)734-9
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Late events and Duration of therapyConclusions

• Extending antiplatelet therapy to 1 year may
  prevent some late events, but not all
• Events may occur on dual therapy compliant
  patients
• Events occur beyond one year
• Beyond 1 year, benefit and risks are unknown
• Future needs
• Larger and longer term follow up randomized
  trials
• More consistent and safe platelet inhibition
• Meanwhile, recommend a common-sense approach to
  improve patient education and compliance
  regarding antiplatelet therapy

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