Another trial studying the interarction of Clopidogrel and PPIs has been done. Two trials were earlier discussed on this blog in Septmeber.
Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) to assess the efficacy and safety of concomitant administration of clopidogrel and PPIs in patients with coronary artery disease who are receiving clopidogrel plus aspirin has been publihedd in the recent issue of New Eng J of Med.
COGENT was an international, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, phase 3 study of the efficacy and safety of CGT-2168, a fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg), as compared with clopidogrel alone. All patients were to receive enteric-coated aspirin at a dose of 75 to 325 mg daily. Blinded study kits and open-label enteric-coated aspirin were supplied by Parexel to the investigators.
The initial planned sample size was 3200 patients, with an accrual period of 1 year and a maximum follow-up period of 2 years. The target sample size was increased to 4200 and then to 5000 to ensure an adequate number of gastrointestinal events. The study was designed to end once 143 gastrointestinal events had occurred; however, the study ended prematurely, when the sponsor suddenly and unexpectedly lost its financial backing; the sponsor is now defunct.
The event rate, based on Kaplan–Meier analysis, for the primary gastrointestinal end point was reduced from 2.9% with placebo to 1.1% with omeprazole at 180 days after randomization (P<0.001 by the log-rank test)
The rate of the composite end point of overall (overt and occult) clinical gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (P=0.001), as was the rate of the composite end point of overt gastroduodenal bleeding or overt upper gastrointestinal bleeding of unknown origin: from 1.2% in the placebo group (occurring in 15 of 1885 patients) to 0.2% (occurring in 2 of 1876 patients) (P=0.001).
There was also a significant reduction in the number of patients with investigator-defined gastrointestinal events with omeprazole (39 patients) as compared with placebo (68 patients) (P=0.005).
The rate of symptoms of gastroesophageal reflux disease at 180 days was 0.2% in the omeprazole group and 1.2% in the placebo group (P=0.01). There was one case of gastrointestinal obstruction in each of the two groups, with no perforations in either group.
There were 109 adjudicated cardiovascular events (54 in the placebo group and 55 in the omeprazole group), with no significant difference in the rate of the primary cardiovascular end point between the two groups (P=0.98 by the log-rank test)
The event rate at 180 days after randomization was 5.7% in the placebo group and 4.9% in the omeprazole group .
The rate of adjudicated nongastrointestinal bleeding events did not differ significantly between the omeprazole group (0.5%) and the placebo group (0.1%).
There was a significant reduction in the risk of gastrointestinal clinical events, including overt upper gastrointestinal bleeding, in patients receiving dual antiplatelet therapy who were randomly assigned to also receive a PPI.
Furthermore, this prospective, double-blind, randomized trial did not show any significant increases in the risk of cardiovascular events with concomitant use of clopidogrel and omeprazole, a finding that was consistent even in high-risk subgroups and for individual end points.
Conflicting results in this regard are available.
There are limitations to this analysis. First, since the trial was terminated prematurely, its power is limited, owing to a smaller number of events than had been anticipated. Second, because the confidence interval around the hazard ratio for cardiovascular events is wide, the absence of interaction between clopidogrel and omeprazole cannot be viewed as a definitive finding. Given that 94% of the population was white, the expected prevalence of homozygosity for the loss-of-function cytochrome P-450 gene CYP2C19 was 2 to 3%, and in homozygous patients, PPIs may further reduce the level of the active metabolite of clopidogrel to a degree that does indeed blunt the effectiveness of clopidogrel.
The absence of an effect on nongastrointestinal bleeding also supports the absence of an interaction between clopidogrel and omeprazole, since if PPIs diminish the antiplatelet effect of clopidogrel, they should also decrease the rate of nongastrointestinal bleeding.
An additional limitation of the study is that the single-pill formulation we used differs from generic omeprazole with respect to its release kinetics.
The authors concluded that this study provides reassurance that there is no clinically significant cardiovascular interaction between PPIs and clopidogrel PPIs in patients with coronary artery disease who were receiving dual antiplatelet therapy.
Further research will be necessary to determine the optimal approach to reducing the risk of gastrointestinal adverse events among patients receiving potent antithrombotic therapy, but prophylactic proton-pump inhibition appears to be promising.
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