Medco study: PPIs reduce clopidogrel efficacy post-stenting 2

The efficacy of clopidogrel after stent implantation is reduced by the concomitant use of proton pump inhibitors (PPIs), according to a study presented today at the Society for Cardiovascular Angiography and Interventions (SCAI) Scientific Sessions in Las Vegas. Researchers at Medco used data from 16,690 patients taking clopidogrel after stenting and found that the risk of major adverse cardiovascular events was raised from 17.9% to 25.1% in patients also taking PPIs.

The elevation in risk remained statistically significant for the individual PPIs omeprazole, esomeprazole, pantoprazole, and lansoprazole. The results are consistent with a recent VA study of 8,000 ACS patients published in JAMA.

“Given the large number of patients who undergo coronary stent procedures each year, and the recommended and wide use of clopidogrel following this procedure, our findings have implications for many thousands of patients across the United States,” said Eric J. Stanek, PharmD, senior director of research, personalized medicine research and development, Medco Health Solutions, Franklin Lakes, NJ, and the study’s principal investigator, in a SCAI press release. “Clopidogrel should continue to be taken as prescribed, and the need for PPI therapy should be carefully evaluated to ensure that it is prescribed only when clearly indicated.”

SCAI also issued a statement about the study and made several recommendations:

“SCAI believes more research is needed on this topic. However, given the thousands of patients who receive stents each year, coupled with the significant risks demonstrated in this study, SCAI recommends the use of alternative medications for GI symptoms in patients with stents when appropriate.  Other effective treatments for heartburn and ulcers include histaminergic (H2) blockers (Zantac, Tagamet) or antacids.  In some patients the use of PPIs may still be warranted  based on the patient’s medical problems and should be taken at the direction of the patient’s cardiologist, gastroenterologist or primary physician.

“Importantly, patients should never stop taking any prescribed medication without first discussing with their doctor.  Guidelines authored by SCAI and other cardiovascular organizations recommend dual-antiplatelet therapy for no less than one year following stent implantation. Clinical trials have shown this drug regimen effectively prevents blood clots that can lead to rare but potentially life-threatening cardiac events.”

Here is the full SCAI statement:

SCAI Statement on “A National Study of the Effect of Individual Proton Pump Inhibitors on Cardiovascular Outcomes in Patients Treated with Clopidogrel Following Coronary Stenting:  The Clopidogrel Medco Outcomes Study”

Results of the Clopidogrel Medco Outcomes Study presented today during SCAI’s Annual Scientific Sessions found the anti-clotting benefits of clopidogrel (Plavix) may be reduced when taken concurrently with commonly used heartburn medications called proton pump inhibitors (PPIs).  In the study, patients taking clopidogrel and a PPI experienced a:

50% increase in the combined risk of hospitalization for heart attack, stroke, unstable angina, or repeat revascularization, including:
70% increase in the risk of heart attack or unstable angina
48% increase in the risk of stroke or stroke-like symptoms
35% increase in the need for a repeat coronary procedure

Dual antiplatelet therapy, which commonly consists of clopidogrel and aspirin, is routinely prescribed to patients following insertion of stents to prevent life-threatening blood clots. PPIs are also frequently prescribed to these patients for brief periods (approximately 30 days) following stent insertion to treat unpleasant but non-life-threatening side effects of clopidogrel such as nausea.  In some patients PPIs may also be taken routinely for gastrointestinal conditions like peptic ulcer disease.

The Clopidogrel Medco Outcomes Study is the largest to date to examine the outcomes of patients who are taking clopidogrel and a PPI.  However, two smaller, earlier studies came to opposite conclusions concerning adverse effects when patients were taking both medications. The first study, a database analysis, found an increase in cardiac events in patients taking clopidogrel along with a PPI, while the CREDO study found no adverse effect when clopidogrel was taken along with a PPI.

The current study examined outcomes of patients taking common PPI medications including pantoprazole (Protonix), esomeprazole (Nexium), omeprazole (Prilosec), and lansoprazole (Prevacid).  It did not review outcomes in patients taking any of the newer PPIs, such as rabeprazole (Aciphex) or dexlansoprazole (Kapidex).  Patients in the study took PPIs for an average of nine months.

SCAI believes more research is needed on this topic. However, given the thousands of patients who receive stents each year, coupled with the significant risks demonstrated in this study, SCAI recommends the use of alternative medications for GI symptoms in patients with stents when appropriate.  Other effective treatments for heartburn and ulcers include histaminergic (H2) blockers (Zantac, Tagamet) or antacids.  In some patients the use of PPIs may still be warranted  based on the patient’s medical problems and should be taken at the direction of the patient’s cardiologist, gastroenterologist or primary physician.

Importantly, patients should never stop taking any prescribed medication without first discussing with their doctor.  Guidelines authored by SCAI and other cardiovascular organizations recommend dual-antiplatelet therapy for no less than one year following stent implantation. Clinical trials have shown this drug regimen effectively prevents blood clots that can lead to rare but potentially life-threatening cardiac events.

Here is the SCAI press release:

Study Shows Benefits of Anti-Clotting Medications Reduced by
Common Heartburn Drugs

Proton Pump Inhibitors Interfere With Anti-Clotting Protection of Clopidogrel

LAS VEGAS, NV (May 6, 2009) — The anti-clotting action of the medication clopidogrel (Plavix) can be compromised by common drugs for the treatment of heartburn and ulcers resulting in a roughly 50% increase in the combined risk of hospitalization for heart attack, stroke and other serious cardiovascular illnesses, according to a new study presented today at the Society for Cardiovascular Angiography and Interventions (SCAI) 32nd Annual Scientific Sessions. The study specifically focused on the effects of proton pump inhibitors (PPI) omeprazole (Prilosec), esomeprazole (Nexium), pantoprazole (Protonix), and lansoprazole (Prevacid), which together accounted for about 96% of PPI use in the study.

Patients who receive a drug-eluting stent benefit from taking anti-clotting medications, including thienopyradines (such as clopidogrel or ticlopidine) and aspirin, for at least one year following the procedure. Doctors often also prescribe PPIs to patients taking clopidogrel because of pre-existing stomach disease or to reduce the risk of common side effects such as nausea and gastroesophageal reflux (heartburn). Before clopidogrel can exert its anti-clotting effects, it must be converted from its inactive, pro-drug form to an active drug by enzymes in the liver. PPIs—the sixth most commonly prescribed drug class in the U.S.—can interfere with those liver enzymes, according to the study.

“Given the large number of patients who undergo coronary stent procedures each year, and the recommended and wide use of clopidogrel following this procedure, our findings have implications for many thousands of patients across the United States,” said Eric J. Stanek, PharmD, senior director of research, personalized medicine research and development, Medco Health Solutions, Franklin Lakes, NJ, and the study’s principal investigator. “Clopidogrel should continue to be taken as prescribed, and the need for PPI therapy should be carefully evaluated to ensure that it is prescribed only when clearly indicated.”

For the study, researchers analyzed integrated data on pharmacy and medical claims from more than 10 million patients, including 16,690 patients taking clopidogrel for a full year following coronary stenting. Of these, 41% also took a PPI, on average, for more than nine months of the year. Over that 12-month period when patients took clopidogrel, investigators evaluated the risk of hospitalization for major adverse cardiovascular events (MACE), which they defined as a combination of heart attack, unstable angina, stroke or temporary stroke-like symptoms, repeat coronary procedures, or cardiovascular death.

The overall MACE risk was 51% higher among patients taking any PPI. The findings were equally concerning when the effects of individual PPIs were analyzed. Omeprazole correlated with a 39% increased risk of MACE, esomeprazole to a 57% increased risk, pantoprazole to a 61% increased risk and lansoprazole to a 39% increased risk. All of the associations were highly statistically significant. Overall, the incidence of hospitalization for upper gastrointestinal bleeding was only 1.1% among patients taking a PPI and 0.07% among those not taking a PPI.

Additional research is needed to determine whether newer, less widely used PPIs such as rabeprazole (Aciphex) and dexlansoprazole (Kapidex) are also associated with increased cardiovascular risk in patients taking clopidogrel. Researchers are also interested in examining how genetic variations in the liver enzymes that activate clopidogrel might alter the impact of PPIs on clopidogrel effectiveness, the potential influence of the timing of PPI administration, the effect of alternate dosing of clopidogrel, and the comparative effectiveness of other anti-clotting medications.

This study was supported independently by Medco Health Solutions, Inc, and conducted in collaboration with investigators from the Indiana University School of Medicine.

About SCAI
Headquartered in Washington, D.C., the Society for Cardiovascular Angiography and Interventions is a 4,000-member professional organization representing invasive and interventional cardiologists in more than 60 nations. SCAI’s mission is to promote excellence in invasive and interventional cardiovascular medicine through physician education and representation, and advancement of quality standards to enhance patient care. SCAI’s annual meeting has become the leading venue for education, discussion, and debate about the latest developments in this dynamic medical specialty. SCAI’s patient and physician education program, Seconds Count, offers comprehensive information about cardiovascular disease. For more information about SCAI and Seconds Count, visit http://www.scai.org or http://www.seconds-count.org.

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2 comments

  1. Pingback: TCT: COGENT provides reassurance on use of PPIs with clopidogrel « CardioBrief

  2. Pingback: PPIs and Clopidogrel: new study finds evidence that pantoprazole may also be a problem « CardioBrief

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