COGENT Published: Lead Investigator Says He'll Use a PPI in Patients on Dual Antiplatelet Therapy

October 07, 2010

October 7, 2010 (Boston Massachusetts) — The COGENT trial, showing no clinical interaction in terms of cardiovascular events between omeprazole and clopidogrel, has now been published online October 6, 2010 in the New England Journal of Medicine [1].

The results, which were first released in preliminary form at the last year's TCT meeting, also showed a significant reduction in GI events in clopidogrel-treated patients taking omeprazole compared with those on placebo.

Lead investigator Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA) commented to heartwire : "The TCT presentation was very preliminary; the data were only two days old. It was just the top-line results that we released for public-health reasons. We have now had two academic statisticians run the analysis separately. The cardiovascular safety message is a similar one to that reported at TCT--there is no signal of harm or any evidence of a cardiovascular interaction. I would say therefore that at least at the population level there is no harmful interaction between [proton-pump-inhibitors] PPIs and clopidogrel to worry about."

He added: "But the main purpose of the study was to show whether prophylactic PPI treatment reduced GI bleeding in patients taking dual antiplatelet therapy. I think this has been lost to much of the cardiology community because of the focus on the clopidogrel-PPI interaction. This is the first randomized clinical trial that has shown that prophylactic PPIs do reduce GI bleeding. It has been shown before that PPIs reduce recurrent GI bleeding in patients who have already had a GI bleed, but this is the first time it has been shown in patients not at particularly high risk of GI bleeding. This is the primary message of COGENT."

The COGENT trial patients with an indication for dual antiplatelet therapy all received aspirin and were randomized to clopidogrel in combination with 20-mg omeprazole or clopidogrel and placebo. The trial had planned to enroll 5000 patients but was stopped prematurely after 3873 had been randomized, and 3761 were included in the analysis. The median duration of follow-up was 106 days, with a maximum of 341 days.

Results showed a significant reduction in GI events in the omeprazole group, but no differences in cardiovascular events between the two groups.

COGENT: Major Results

Outcome Omeprazole (%) Placebo (%) HR (95% CI) p
Composite of GI events* 1.1 3.4 0.34 (0.18–0.63) <0.001
Overt GI bleeding 0.2 1.2 0.13 (0.03–0.56) 0.001
Composite of cardiac events 4.9 5.7 0.99 (0.68–1.44) 0.96
MI 1.2 1.5 0.92 (0.44–1.90) 0.81
Revascularization 4.0 4.6 0.91(0.59–1.38) 0.64

*Primary end point: GI bleeding, symptomatic GI ulcer, gastric pain with >5 gastroduodenal erosions, obstruction, or perforation

The number of patients who would need to be treated for six months to prevent one GI event was 55 and to prevent one overt GI bleed was 98.

Discussing the apparent lack of an effect of omeprazole on cardiovascular events, when observational and mechanistic studies have suggested an interaction, Bhatt said: "I believe that randomized data such as these trump observational data. Obviously, there are caveats in our results, one of which is that the trial was stopped early, but it is still a large randomized clinical trial, and no harm was seen for the duration of the study period of several months. The hazard ratio for cardiovascular events is 0.99. That is pretty neutral. I think it is very unlikely that we would have seen a hazard even if the trial had continued."

He added: "I think this trial gives strong evidence that one should consider prophylactic PPIs now for patients on dual antiplatelet therapy. But I'm not telling doctors what they should do. In my own practice, I will now use a PPI in my patients on dual antiplatelet therapy with the aim of reducing GI bleeds based on these results. These results have not come out of a vacuum. They are well supported by smaller biological and mechanistic studies. I wouldn’t mind a confirmatory trial, but I think we can say prophylactic PPI use is a good thing from these results."

He said it was difficult to know what the optimum duration of treatment with a PPI would be. "In this study we gave the treatment for about six months, so I would say that was fine, and I would perhaps continue for as long as dual antiplatelet therapy is used."

Although Bhatt and his colleagues have not done any cost-effectiveness calculations, he believes such use of PPI treatment would be cost-effective, especially if just given for a few months and if a generic PPI were used. "Side effects such as diarrhea and osteoporosis may become more of an issue if used longer term, but these were not a problem when used for just six months," he noted. Diarrhea occurred in 3% of the omeprazole patients vs 1.8% of the placebo patients in COGENT (p=0.01).

He concluded, "If a doctor elects to apply the COGENT results for six months, I think they would be unlikely to see adverse events, but there is still room for further study of longer-term use."

New Mechanistic Study Suggests Dose Effect for PPI Clopidogrel Interaction

In another new mechanistic study of the clopidogrel-omeprazole interaction published recently, a dose of omeprazole 40 mg did reduce the antiplatelet effects of clopidogrel, but not as much as was seen with a dose of 80 mg in previous studies [2].

The new study, published online in Circulation: Cardiovascular Interventions on September 21, 2010, involved 20 healthy volunteers who were randomized to receive omeprazole (40 mg daily) concomitantly or staggered by eight to 12 hours for one week on a background of clopidogrel therapy in a crossover fashion, with a two- to four-week washout period between treatments. After another two- to four-week washout period, all subjects were treated for one week with clopidogrel alone. Results showed that platelet-reactivity index values were significantly lower with the clopidogrel-alone regimen than with either of the clopidogrel/omeprazole regimens. There were no differences between the concomitant or staggered regimens.

The data also suggest that the interaction between omeprazole and clopidogrel may be confined to the maintenance phase of treatment, and there were no differences in platelet reactivity observed in the acute phase following the 600-mg loading dose of clopidogrel. The researchers suggest that the high loading dose of clopidogrel may overcome this interaction.

Senior author of the paper, Dr Dominic Angiolillo (University of Florida, Jacksonville), pointed out to heartwire that these latest results raise the possibility of a dose-related effect regarding the omeprazole-clopidogrel interaction. He noted that previous mechanistic studies performed by their group showed a larger effect of omeprazole used at an 80-mg dose on inhibiting the antiplatelet effect of clopidogrel. "In this study we used a 40-mg dose, which falls a little bit more within the dose range used in clinical practice, and while we still showed a significant effect, it was less than we saw with 80 mg in the earlier studies."

He added that while there is definitely a clear-cut pharmacodynamic interaction between omeprazole and clopidogrel, how this appears clinically needs more understanding. He also raised the idea that the pharmacodynamic negative interaction between these two agents may be offset by the clinical benefits of omeprazole reducing GI bleeding. "We know that increased bleeding causes increased cardiovascular events and mortality, and GI bleeding is part of that. So if omeprazole reduces GI bleeding, as shown in COGENT, this may well offset any harm seen from the reduced effect of clopidogrel on platelets."

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