The Voice in the Ear -- Burt's Stent Blog
<< To Blog Home >> Follow Burt on TWITTER
DVD Special Offer
"The Stent Blog is a must-read resource"

Subscribe to
email alerts


November 17, 2009 -- 11:30pm EST

PPIs and Plavix -- Confusion Reigns Supreme
Plavix (clopidogrel)Patients taking Plavix (a.k.a. clopidogrel) -- and that would be all stent patients -- sometimes experience a side effect of gastric upset, heartburn or even bleeding. So they are given a Proton Pump Inhibitor (PPI) with a brand name of Prilosec, Nexium, Prevacid or Protonix to alleviate these symptoms.

In the past a number of observational studies (namely from Medco and the Veterans Administration) have shown that patients who take PPIs and Plavix experience an increased risk of adverse events, such as heart attacks. However, other studies have shown no clinical effect. In fact it was only a short while ago that a panel of cardiologists, commented during this year's TCT meeting on the COGENT trial (COGENT examined the clinical results of taking Plavix with PPIs). The panel exclaimed quite pointedly that the COGENT study, a randomized clinical trial (not a retrospective observational study) was THE study that revealed the truth -- and that truth was that there was NO increase in adverse clinical events when PPIs were taken with Plavix. They even did a Colbert-like "wag of the finger" to the medical news outlets that published inflammatory headlines about the non-existent danger.

So it was a bit of a shock to these and other cardiologists assembled at the American Heart Association Annual Scientific Sessions in Orlando to read today's warning from the FDA:

The concomitant use of omeprazole [Prilosec] and clopidogrel should be avoided because of the effect on clopidogrel's active metabolite levels and anti-clotting activity. Patients at risk for heart attacks or strokes, who are given clopidogrel to prevent blood clots, may not get the full protective anti-clotting effect if they also take prescription omeprazole or the OTC form (Prilosec OTC)....

This warning also mentioned other drugs to be avoided when taking clopidogrel, such as esomeprazole (Nexium), cimetidine (Tagamet) and so on.

In addition, yet another observational study about PPIs and Plavix was presented yesterday at the AHA meeting. This retrospective study, which looked at patient records from Mt. Sinai in New York, showed an increase in adverse events. These two provided a double whammy to the results of the COGENT trial.

Christopher Cannon MDSo earlier today I asked Dr. Christopher Cannon about this new study (two months ago he stated in no uncertain terms that the COGENT study proved that there was no increased risk for patients when taking Plavix and PPIs). Dr. Cannon is the senior investigator of the Thrombolysis in Myocardial Infarction (TIMI) Study Group, and has led some of the most well-known practice-changing guidelines in the treatment of heart disease He replied:

These new studies are observational ones -- with exactly the same flaws as the prior Medco and VA database studies -- [and] they get the same wrong answer...

The difference between a randomized clinical trial (RCT) and a retrospective observational study is an important one here in understanding the different results. An RCT is a carefully-designed scientific test of a hypothesis -- patients are randomized to two different treatments in a way that negates differences in ages, states of health, and other "confounding" data. An observational study looks at patient data that already exists. Attempts can be made to normalize the patient groups for comparison's sake, but the results are not necessarily accurate when measuring two treatments, for example. This is why the FDA normally requires that an RCT be done before a new treatment is approved. Observational studies, however, can point to possible problems, or can generate hypotheses for future randomized scientific trials. They can show associations, but not necessarily prove cause and effect.

This is, in effect, what happened with PPIs and Plavix, and why the COGENT trial was done: to answer the questions raised by the early observational studies.

Dr. Chet Rihal, director of the catheterization lab at Mayo Clinic put it another way (as quoted in HealthDay):

All this shows is that people taking PPIs have a worse outcome than those not taking PPIs. This does not prove there's causation. That would be like saying that carrying matches is associated with lung cancer. It is associated, but it doesn't mean it causes lung cancer.

Indeed, one explanation for these different results is that patients who are having gastric distress and require Prilosec may be sicker or older patients, thus skewing the results of any observational study against the group taking PPIs -- they may have worse outcomes because they started off sicker or older -- and the worse outcomes are not "caused" by the PPIs.

As for the FDA warning, which involves a label change to the drug clopidogrel, Dr. Cannon noted to me that it was more carefully worded, and did not claim that PPIs caused more adverse events, only that PPIs have been shown to reduce the antiplatelet effect, something that was shown in a small study last year, titled OCLA (Omeprazole CLopidogrel Aspirin) -- a study conducted by Dr. Deepak L. Bhatt, Cannon's colleague at Brigham and Women's in Boston. Dr. Cannon continues:

But, as we know from COGENT, there is not a difference in clinical events when combining omeprazole [Prilosec] and clopidogrel. Thus, as we have seen before, often small changes in the level of platelet inhibition don't translate into a clinical effect. The label is careful to stick to the platelet data. It is reasonable to know of the platelet data, but the FDA needs to see the COGENT data -- and, of course, we all need to give much more weight to the randomized trials, not the confounded observational studies.

So should you stop taking your Prilosec or Nexium with your clopidogrel? Most doctors say no -- in fact suddenly stopping either medication could cause serious problems. However, you should call or see your cardiologist and ask him or her about these studies.

Meanwhile the FDA has placed this issue on the agenda for the November meeting of its Drug Safety Oversight Board and HealthDay reports that new AHA/ACC recommendations on the use of PPIs with Plavix will be announced tomorrow (Wednesday) during the American Heart meeting.

« comment »        « back to top »

  Donate to this Site
Click here for more information about these