Plavix, Heartburn Drugs May Be Risky Combination

Patients with coronary artery stents should discuss the use of these meds with their doctor

Proton-pump inhibitors ( PPIs) are medications used for heartburn. These medications include esomeprazole (Nexium, AstraZeneca), omeprazole, pantoprazole (Protonix, Wyeth), lansoprazole, or rabeprazole (Aciphex, Eisai/Ortho-McNeil-Janssen Pharmaceuticals). Plavix anti-platelet therapy is given to patients to prevent clots especially those who have a history of or tendency for strokes or after getting a stent for coronary artery disease.

So the combination of both Plavix and a PPI up to now has been relatively common.

Recent studies, however, show that one-year risk of cardiovascular events is increased more than 50% in patients taking a proton-pump inhibitor (PPI) on top of clopidogrel, as compared with patients not taking a PPI.

In addition, the risk seems to be a class effect for all the PPI medications, according to this latest retrospective cohort study of more than 16,700 patients who received clopidogrel post-stenting for coronary artery disease. Professional society guidelines recommend the use of PPIs to treat and prevent gastrointestinal ulcers and bleeding in patients on antiplatelet therapy. However, increasing use of PPIs in this setting has raised questions as to whether PPIs may attenuate clopidogrel's antiplatelet response by interfering with CYP2C19-mediated clopidogrel metabolism. This means that the same enzyme in the liver metabolizes both Plavix and PPIs. Therefore, the addition of a PPI can spur a less active form of Plavix to be produced, reducing its beneficial effects.

This new data the results of the Clopidogrel Medco Outcomes study was presented May 6, 2009 as a late-breaking clinical trial during the first day of the Society for Cardiovascular Angiography and Interventions (SCAI) 2009 Scientific Sessions. The study compared major adverse cardiovascular events (MACE).

Higher MACE [major adverse cardiovascular events] occur with PPIs

One study showed that this combination is associated with a 70 percent increased risk of heart attack, a 48 percent increased risk of stroke and a 35 percent increased risk for the need for repeat coronary procedures. The overall incidence of major adverse cardiovascular events was 51 percent higher in those taking Plavix and a PPI than in those taking Plavix alone.

In this latest study, one-year risk of MACE was significantly higher in PPI-treated subjects, at 25.1%, as compared with patients who did not take a PPI, at 17.9%. They also looked at the CV risk associated with individual PPIs, restricting their analysis to PPIs with sufficient patient numbers to detect a difference in risk similar to that seen in the overall population, with adequate statistical power. Don’t be fooled by those who claim rabeprazole is safer than all the other PPIs. Due to low numbers, rabeprazole, taken by just 298 patients, could not be addressed in this analysis, however, each of the PPIs, individually, was associated with a higher risk of major cardiovascular events vs no PPI use, ranging from a 24.3% increased risk with lansoprazole to a 29.2% risk with pantoprazole.

Caveat:
While this particular study is the largest to date to address the question of a PPI-clopidogrel interaction, two other, smaller studies have found disparate results.
Of note, hospitalization rates for upper-GI bleeding were low across all groups of PPI use, in the range of 1.1%. Also of interest, investigators looked at PPI use among patients who were not treated with clopidogrel and found no increased risk of CV events in this group, as compared with patients taking neither a PPI nor clopidogrel.

BOTTOM LINE:
These results provide further support for the hypothesis that PPIs attenuate the effects of clopidogrel. Considering all available evidence, PPI use should be limited to situations clearly indicated in patients on clopidogrel after coronary stenting.

Considering all the available evidence, PPI use should be limited in patients taking clopidogrel, based on the physician's judgment.

Physicians need to do a better job of discriminating between patients who are just at risk of GI symptoms or who may have had previous GI disease and patients who actually have current GI problems. It is the latter group in whom concomitant PIs are likely to be useful. Physicians are urged to take the time to discuss the risks and benefits with patients and to emphasize that patients should not because stop clopidogrel therapy if so prescribed by your doctor.

Concomitant H2-receptor-antagonist therapy showed no effects of these other ant heartburn agents on CV events. In an analysis of 9862 patients taking clopidogrel, but not a PPI, 472 received an H2 blocker, while 9390 did not. The incidence of cardiovascular events was 20.3% for patients taking H2 blockers and 17.8% in patient not taking these agents, a statistically nonsignificant difference.

Given the thousands of patients who receive stents each year, coupled with the significant risks demonstrated in this study, it might be better to use alternative medications for GI symptoms in patients with stents when appropriate. These alternative heartburn medications include histamine (H2) blockers (Zantac [ranitidine, Boehringer Ingelheim], Tagamet [cimetidine, GlaxoSmithKline]) or antacids. In those patients when the use of PPIs may still be warranted, based on the patient's medical problems, it should be taken at the direction of the patient's cardiologist, gastroenterologist, or primary physician and closely monitored.

REFERENCES:
• Platelet-function test finds fault with omeprazole/clopidogrel combo, but not with other PPIs
[Acute Coronary Syndromes > Acute coronary syndromes; Apr 10, 2009]
• More data support adverse clopidogrel and proton-pump inhibitor interaction
[Acute Coronary Syndromes > Acute coronary syndromes; Mar 03, 2009]
• Increased risk of reinfarction with clopidogrel and proton-pump inhibitors
[Acute Coronary Syndromes > Acute coronary syndromes; Jan 29, 2009]
• FDA continuing to study effectiveness of clopidogrel
[Acute Coronary Syndromes > Acute coronary syndromes; Jan 26, 2009]
• Omeprazole reduces antiplatelet effect of clopidogrel?
[Clinical cardiology > Clinical cardiology; Jan 14, 2008]