PMID- 21304094
OWN - NLM
STAT- MEDLINE
DCOM- 20110728
LR  - 20111027
IS  - 1941-7705 (Electronic)
IS  - 1941-7713 (Linking)
VI  - 4
IP  - 2
DP  - 2011 Mar
TI  - The impact of postrandomization crossover of therapy in acute coronary syndromes 
      care.
PG  - 211-9
LID - 10.1161/CIRCOUTCOMES.109.853598 [doi]
AB  - BACKGROUND: In the Superior Yield of the New Strategy of Enoxaparin, 
      Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study, patients 
      assigned enoxaparin or unfractionated heparin (UFH) were treated with alternative 
      anticoagulant therapy after randomization at physician discretion, a practice 
      made possible because the trial was open label. Using SYNERGY as an example, we 
      demonstrate the difficulty of evaluating the effect of postrandomization events 
      in clinical trials and discuss possible methodology. METHODS AND RESULTS: 
      Patients with and without postrandomization crossovers were characterized and 
      event rates analyzed. Statistical modeling was performed using inverse 
      probability weighting and landmark analyses to evaluate the potential impact of 
      postrandomization crossovers on event rates and treatment effect. Of 9978 SYNERGY 
      patients, 9613 (96.3%) received at least 1 dose of randomized therapy and are 
      included in these analyses. Of these, 740 (7.7%; 554 enoxaparin; 186 UFH) had 
      postrandomization crossover. Crossover patients had higher unadjusted rates of 
      30-day death/myocardial infarction (MI) (18.9% versus 14.0%), thrombolysis in MI 
      (TIMI) bleeding (16.9% versus 7.6%), Global Use of Strategies to Open Occluded 
      Coronary Arteries bleeding (4.5% versus 2.3%), and transfusions (32.3% versus 
      15.2%). Adjustment for timing of crossover relative to the events attenuated the 
      difference noted in death/MI but accentuated the association with TIMI bleeding. 
      After adjustment using the inverse probability weighting technique, only a modest 
      difference in the absolute treatment effect was observed between enoxaparin and 
      UFH on death/MI (0.6% [unadjusted] versus 0.8% [adjusted]) and TIMI major 
      bleeding (1.5% [unadjusted] versus 1.0% [adjusted]). The landmark analysis 
      indicated a significant association between crossover from enoxaparin to UFH and 
      TIMI bleeding but not in the other direction, and no crossover association was 
      found in death/MI. CONCLUSIONS: Postrandomization events in clinical trials are 
      accompanied by substantial confounders that require careful consideration. In 
      SYNERGY, postrandomization crossovers occurred in nearly 10% of patients, abetted 
      by the open-label trial design. These patients had increased incidence of 
      bleeding and death/MI, but after adjustment using several modeling techniques, 
      only a modest impact of postrandomization crossovers on treatment effect was 
      observed. The usual methods of analyzing end points cannot adequately address 
      biases in changing treatment in these patients. The potential biases of 
      membership in a postrandomization subgroup, as well as the methods used to 
      account for the biases, should be considered when weighing the strength of 
      results. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique 
      identifier: NCT00043784.
FAU - Mahaffey, Kenneth W
AU  - Mahaffey KW
AD  - Division of Cardiology and Duke Clinical Research Institute, Duke University 
      Medical Center, Durham, NC 27715, USA. mahaf002@mc.duke.edu
FAU - Pieper, Karen S
AU  - Pieper KS
FAU - Lokhnygina, Yuliya
AU  - Lokhnygina Y
FAU - Califf, Robert M
AU  - Califf RM
FAU - Antman, Elliott M
AU  - Antman EM
FAU - Kleiman, Neal S
AU  - Kleiman NS
FAU - Goodman, Shaun G
AU  - Goodman SG
FAU - White, Harvey D
AU  - White HD
FAU - Rao, Sunil V
AU  - Rao SV
FAU - Hochman, Judith S
AU  - Hochman JS
FAU - Cohen, Marc
AU  - Cohen M
FAU - Col, Jacques J
AU  - Col JJ
FAU - Roe, Matthew T
AU  - Roe MT
FAU - Ferguson, James J
AU  - Ferguson JJ
CN  - SYNERGY Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT00043784
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20110208
PL  - United States
TA  - Circ Cardiovasc Qual Outcomes
JT  - Circulation. Cardiovascular quality and outcomes
JID - 101489148
RN  - 0 (Anticoagulants)
RN  - 0 (Enoxaparin)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Acute Coronary Syndrome/*drug therapy
MH  - Aged
MH  - Anticoagulants/*therapeutic use
MH  - Cross-Over Studies
MH  - Enoxaparin/*therapeutic use
MH  - Female
MH  - Hemorrhage/epidemiology
MH  - Heparin/*therapeutic use
MH  - Humans
MH  - Incidence
MH  - Male
MH  - Middle Aged
MH  - Myocardial Infarction/epidemiology
MH  - Treatment Outcome
EDAT- 2011/02/10 06:00
MHDA- 2011/07/29 06:00
CRDT- 2011/02/10 06:00
PHST- 2011/02/10 06:00 [entrez]
PHST- 2011/02/10 06:00 [pubmed]
PHST- 2011/07/29 06:00 [medline]
AID - CIRCOUTCOMES.109.853598 [pii]
AID - 10.1161/CIRCOUTCOMES.109.853598 [doi]
PST - ppublish
SO  - Circ Cardiovasc Qual Outcomes. 2011 Mar;4(2):211-9. doi: 
      10.1161/CIRCOUTCOMES.109.853598. Epub 2011 Feb 8.