Transcript Observational Analyses in PCI: Extending clinical trial results to real

Safety and effectiveness of bivalirudin
in routine care of patients undergoing
percutaneous coronary intervention
JA Rassen, MA Mittleman, RJ Glynn, A Brookhart, S Schneeweiss
Dept of Pharmacoepidemiology and Pharmacoeconomics, Brigham & Women’s Hospital; Depts of
Epidemiology and Biostatistics, Harvard School of Public Health; Beth Israel Deaconess
Eur Heart J, Nov 25, 2009
Objectives
● Bivalirudin has been studied as an alternative to heparin
plus GP IIb/IIIa inhibitor during PCI; trials have
indicated that bivalirudin is non-inferior to heparin with
respect to death and repeat revascularization and may
decrease the risk of major bleeds.
● To evaluate the effectiveness and safety of bivalirudin
as used in routine care (transfusion, repeat PCI and
death)
Authors supported by Agency for Healthcare Research and Quality, National Institute
of Aging, and National Institute of Mental Health
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
2
Methodology:
● A total of 127,185 PCI procedures were identified from
the database between June 2003 through December
2006
● Patient groups were defined as having received either
bivalirudin plus provisional GPIIb/IIIa or the
comparator, heparin plus GPIIb/IIIa
● Primary outcome: blood transfusion (whole blood,
RBC, FFP, platelets, cryoprecipitate)
● Secondary outcomes: in hospital mortality and repeat
PCI within the same hospital admission
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
Patient Population
Patients with their first inpatient admission between
June 2003 and December 2006 in which they underwent PCI
(N= 326 556)
• Recorded charge for bivalirudin (+/- GPI) with no heparin
OR
•Heparin (at least 1000 U) + GPI
Exclusions
• Outpatient procedures
• Rural hospitals, or those with < 2 PCI/day average
• No record of antithrombotic treatment, other
antithrombotic regimen or GPI only
• History of hemostatic disorders
Overall Analysis Population
N=127,185
Treated with bivalirudin
N=32, 541 (26%)
Treated with heparin+ GPI
N=94,644 (74%)
Data on file. Premier Perspective™ Database.
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
Methodology: statistical analysis
Adjusted for:
● Patients’ socio-demographic factors: age, sex, race, income,
and married or living with partner vs. living alone, year of
admission, urgent admission basis.
● Patient co-morbidities: diabetes, hypertension, liver disease,
COPD/asthma, cancer, smoking, old MI, old stroke,
endocarditis, ischaemic heart disease, peripheral artery
disease, and chronic kidney disease.
● Hospital factors: teaching vs. non-teaching status, location
(midwest, northeast, south, or west of the USA, and
urban/rural), hospital size (number of beds), and high volume
hospitals (an average of 10 or more PCIs performed per day).
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
Methodology: statistical analysis
● Primary analysis: estimated unadjusted and adjusted
hazard ratios (Cox proportional hazards models);
● Secondary analysis: examined cumulative incidence on
the risk difference (least squares) and odds ratio
(logistic regression) scales.
● Sensitivity analyses for urgency of PCI/elective PCI, and
for heparin alone group
● Instrumental variable analysis conducted using hospital
preference for treatment of PCI patients with bivalirudin
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
Results
● Percentage of hospitals reaching threshold of administering bivalirudin to
<5% and >80%of patients receiving PCI, and hospitals administering
bivalirudin to >1% of those patients
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
Results
● By quarter of calendar time, % of PCI patients exposed to bivalirudin in
hospitals in the Premier Perspective Database.
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
Results: Transfusion*
Hazards Ratio
± 95% CI
OR (95% CI)
Unadjusted
0.93 (0.85–1.00)
Unadjusted IV
subpopulation
0.77 (0.69–0.86)
Fully adjusted
0.67 (0.61–0.73)
Instrumental
variable analysis
0.72 (0.12–4.47)
0
1
Bivalirudin
Better
2
Heparin + GP IIb/IIIa
Inhibitor Better
* At least one unit of any blood product
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
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Results: Repeat PCI
Hazard Ratio
± 95% CI
OR (95% CI)
Unadjusted
0.83 (0.78–0.89)
Unadjusted IV
subpopulation
0.82 (0.76–0.89)
Fully adjusted
0.96 (0.90–1.03)
Instrumental
variable analysis
0.83 (0.49–1.40)
0
1
Bivalirudin
Better
2
Heparin + GP IIb/IIIa
Inhibitor Better
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
11
Results: Death
● In-hospital mortality rate: bivalirudin 0.8%, 2.1% heparin + GPI
Hazard Ratio
± 95% CI
OR (95% CI)
Unadjusted
0.57 (0.49–0.65)
Unadjusted IV
subpopulation
0.56 (0.46–0.66)
Fully adjusted
0.51 (0.44–0.60)
Instrumental
variable analysis
0.51 (0.34–0.78)
0
1
Bivalirudin
Better
2
Heparin + GP IIb/IIIa
Inhibitor Better
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
12
Results
● Hazard ratio point estimates and standard errors for models of
mortality in the Premier and clinical trial databases
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437
Conclusions
● Bivalirudin is protective compared to heparin plus GPI with
regard to the risk of blood transfusions and death
● Mortality benefit may even exceed trial estimates
● Because of conventional analyses’ potential for bias as a result
of residual confounding, IVA-based methods, with their known
limitations, may help in studying the safety and effectiveness of
medications outside the constrained setting of clinical trials.
Rassen JA et al Eur Heart J 2009 On line ahead of print Nov 25 doi:10.1093/eurheartj/ehp437