View Full Version : Plavix & PPI May Contribute to Heart Attack

03-04-2009, 06:42
When you've reached a certain age and you have to rely on these types of meds, findings like these cause some concern.

These findings were made public yesterday. (3/3/09) As stated the findings are not conclusive, but still adds room for concern.

Study: Drug Combination Could Harm Heart Health
Dr. Maria Simbra PITTSBURGH (KDKA) ―

Lots of people take clopidogrel, brand name Plavix, after a heart attack, chest pain, or cardiac stents.

It's kind of like a super aspirin and works against clotting cells called platelets. It keeps the blood thinner, so it can flow more easily through heart vessels.

"There's quite a bit of benefit from taking both aspirin and Plavix for a period of time, up to one year," says Dr. Tony Farah, a cardiologist at Allegheny General Hospital.

With these drugs, there's a small risk of bleeding outweighed by the protection they give to the heart.

Many people also take medications to protect the stomach, against ulcers, for instance. They're called proton pump inhibitors -- medicines like Prilosec, Prevacid, Aciphex, Protonix, and Nexium.

A recent study in the "Journal of the American Medical Association" shows that taking these the stomach drugs in combination with Plavix could increase the risk of another heart attack by 25 percent, a trend doctors have been noticing across other studies.

The stomach drugs might interfere with how it's processed in the body.

"The stomach drugs are metabolized through the liver, and so there may be an interaction there that lowers the effectiveness of Plavix," explains Dr. Farah.

This is based on observing 8,000 heart attack patients who were put on Plavix at the Denver Veterans Administration Hospital. It's making doctors think carefully about prescribing proton pump inhibitors to this group.

"The physicians, obviously, based on this new data, should take a look and make sure that those patients absolutely need this type of medication, and if not, maybe that should be stopped," Dr. Farah urges.

If you take both kinds of drugs, call your doctor before making any changes. Additional study is needed, specifically comparing Plavix plus the stomach drugs against Plavix alone and watching for any difference in outcomes before drawing any firm conclusions about the combination's role in heart attack.

03-04-2009, 17:31
Thank you for this article, I currently take Plavix and an aspirin daily but my 1 year is coming up and my cardiologist feels I won't need to be on it much longer since I'm doing so well. :lifter BUT, it's good to know...just in case.

03-09-2009, 16:42
Important to note that the study noted an increase by 25% of death or rehospitalization due to ACS in the Plavis plus PPI group as compared to the Plavix alone group. Just including a point of reference. You are still safer taking both medications than taking neither.

This particular possible interaction is of great interest to me as I spend about 50% of my day taking people off PPIs who do not need to be on them. (The other 50% is putting people on PPIs who do need to be on them.)

For a little background, Plavix (clopidogrel) is an anti-platelet medication that binds to the platelets in the bloodstream and prevents them from aggregating and forming clots. Aspirin is also an anti-platelet medication and is commonly used in combination with Plavix as they work in different ways. These medications are commonly used following hospitalization after acute coronary syndromes (ACS), where clots in the coronary arteries lead to less blood flow and less oxygen to the heart. Plavix usually being used for 1 year while the aspirin is continued indefinately.

PPIs (Prilosec, Prevacid, Aciphex, Protonix, Nexium), are usually started along with anti-platelet therapy to suppress acid production in the stomach in order to prevent ulcers and help promote coagulation in the stomach. Otherwise, with an acidic stomach and taking anti-platelet medication, if a GI bleed starts, it may never stop. The ACC/AHA recommendations in 2007 state that in patients with a history of GI bleed "when ASA (aspirin) and clopidogrel (Plavix) are administered alone or in combination, drugs to minimize the risk of recurrent gastrointestinal bleeding (e.g., proton-pump inhibitors) should be prescribed concomitantly."

In practice PPI use is very commonplace. Of the 5 listed above, Prevacid (8), Protonix (17), and Nexium (2) are all in the top 20 brand name medications by sales in 2007, while Aciphex, a relative newcomer is at #46. Omeprazole (Prilosec) is available as a generic and over the counter without a prescription.

Our understanding of this interaction is very limited at this time. Clopidogrel is inactive, it has to be activated by the liver in order to work and connect to the platelets. PPI's (some more than others) can inhibit some of the enzymes in the liver (CYP2C19). In addition, it is well recognized that patients in which this enzyme does not work as well do not respond as well to Plavix. The seemingly obvious conclusion is that the PPI's prevent this enzyme from activating Plavix and therefore it doesn't work as well.

Here is where it gets fuzzy. We don't know exactly what enzymes are responsible for activating Plavix. The prevailing theory is that it is an enzyme in the liver called CYP3A4. So why do patients with genetic abnormalities in the aforementioned CYP2C19 enzyme not respond well to Plavix. It is thought that this is due to the fact that patients with this genetic makeup also have abnormalities in their platelets that do not allow the Plavix to bind to them. So the question remains, then what is the mechanism of the interaction. And the answer is that we do not know. And we don't even know if there is an interaction at all.

This study published in JAMA was the first large study published on the topic. Yet it was still a retrospective epidemiological study. Patient baseline characteristics were not similar either. Patients in the group treated with both drugs had greater history of heart attack, heart failure, and lower incidence of surgical intervention, among many things. So this study, while very interesting, will probably not greatly change current prescribing practice to a great extent. Future studies may do that.

From the FDA back in January:
Until further information is available FDA recommends the following:

* Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke.
* Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel.
* Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including Prilosec OTC.

Whether or not this study will change these recommendation I do not know. If it does, I expect a shift in these patient towards using Protonix for the PPI (which does not inhibit the enzyme CYP2C19 and has not been shown to interact with Plavix, or towards H2 blockers like Zantac or Pepcid.

One thing that I hope it does, however, is reinforce the notion that PPI's are not benign drugs. And I also hope that patients reading stories like this will look at their medication list and start to ask "do I need to be on these medications?" "Do any of these medications interact?" "Are there any side effects I need to be aware of?"

03-09-2009, 19:03
shr7 that is an excellent analysis of a complex problem that we don't have all the data we need.
A couple of points.
Plavix (clopidogrel) is not a benign drug. Especially when used with aspirin there is an increased risk of GI bleed. In the elderly (which a number of these people are) only the PPIs have been shown to reduce this risk. I am concerned that the cardiologist (or their nurse practioner) will take a number of patients off their PPIs and there will be an increase in the number of GI bleeds.
Generally Plavix (clopidogrel) is not indicated for greater than one year unless the patient is unable to take aspirin. I have seen a number of patients the cardiologist have left them on it indefinately.
IF Protonix turns out to not have the same negative effect as omeprazole, will it be covered? Most of the insurance I deal with now only cover omperazole since it is OTC and in a generic form.

I agree with you. The question with ANY drug is, "Do I (or does the patient) need to be on this medication?"

03-20-2009, 14:41
This is extremely important to me since I've been updated to Plavix from baby aspirin because of my current heart condition. I'm also taking Prilosec which now has me concerned. Thanks for the feedback,need to discuss with my primary next visit to the VA.................. :confused:

GB TFS :munchin

04-03-2009, 03:04

04-03-2009, 05:37

I couldnt find an in depth test result from cardiologists Tony Farah.

But to someone like me that does have G.E.R.D. and have been diagnosed with an ulcer, and having had two Cardio "incidents'. This study does pose a lot of concern.

04-07-2009, 16:16
The link to the PubMed citation is below:


I would post the .pdf of the study as an attachment, but it requires a paid subscription to JAMA. I've got access through my school, but I don't think it would be kosher to post it online. However, if mods ok, I am more than willing.


04-07-2009, 16:49
Excellent info. I take Prilosec (lake it's candy) but not Plavix. Ill keep this in mind for future reference.




You know what. I just realized it's not Prilosec I'm taking it's Nexium. Prilosec stopped working for me so they put me on Nexium.

Darn Halvsheimers disease is running rampant.

Now I feel like an idiot. Nexium works great but if I skip a dose or two I pay the price. I

I have a heidal (spelling ???) hernia which of course contributes to the acid reflux. I'd had it for years.

03-31-2010, 10:21
Bringing back an older thread here. Some updated data on the PPI and Plavix front.

PPIs May Help Reduce Hospitalizations for Gastroduodenal Bleeding in Patients Treated With Clopidogrel


In an accompanying editorial, it is stated that this study provides a "counterpoint" to previous studies investigating co-prescription of Plavix and PPIs. Not sure if I agree. If memory serves right, in previous studies Protonix was considered one of the drugs least likely to interact while Prilosec was one of the most likely. In this study, Protonix accounted for 62% of the PPIs used and Prilosec only 9%.

I do like that the study investigates other causes of morbidity that just the cardiovascular endpoints. It helps to define the benefit in the risk-benefit analysis for using these medications. So, as before, I suppose we will just have to wait and see.


03-31-2010, 11:03
PPIs May Help Reduce Hospitalizations for Gastroduodenal Bleeding in Patients Treated With Clopidogrel
Laurie Barclay, MD

Explore a hypothetical case in insomnia March 20, 2010 Concurrent use of proton pump inhibitors (PPIs) in patients with serious coronary heart disease treated with clopidogrel is associated with fewer hospitalizations for gastroduodenal bleeding, according to the results of a retrospective cohort study reported in the March 16 issue of the Annals of Internal Medicine.

"We need to make sure that the medicines we give patients help and don't harm," said the Agency for Healthcare Research and Quality (AHRQ) director Carolyn M. Clancy, MD, in a news release. "This evidence on benefits and risks helps inform the combined use of these two drugs."

"Although...PPIs are commonly prescribed with clopidogrel to reduce the risk for serious gastroduodenal bleeding, concern is growing that this practice decreases the efficacy of clopidogrel," write Wayne A. Ray, PhD, from Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System in Nashville, Tennessee, and colleagues.

Using automated data from the Tennessee Medicaid program, the investigators identified 20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) who received clopidogrel between 1999 and 2005 after hospitalization for coronary heart disease, which was defined as myocardial infarction, coronary artery revascularization, or unstable angina pectoris.

Automated records of dispensed prescriptions allowed determination of baseline and follow-up drug use. The main study endpoints were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease, defined as fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death.

Concurrent PPI use included pantoprazole in 62% and omeprazole in 9% of patients. Compared with nonusers of PPIs, concurrent PPI users had a 50% lower adjusted incidence of hospitalization for gastroduodenal bleeding (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.39 - 0.65). PPI use was associated with an absolute reduction of 28.5 (95% CI, 11.7 - 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years, for those patients at highest risk of bleeding.

For the entire cohort, the HR associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (95% CI, 0.82 - 1.19). For the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization, HR was 1.01 (95% CI, 0.76 - 1.34).

Limitations of this study include possible unmeasured confounding, misclassification of exposure and endpoints, and difficulties comparing PPI users from one hospital vs nonusers from a different hospital.

"In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding," the study authors write. "The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk."

Editorial: Study a Counterpoint to Previous Studies

In an accompanying editorial, Michael E. Griswold, PhD, from University of Mississippi Medical Center in Jackson and colleagues discuss applications of propensity score adjustment with multilevel data to this study and others.

"Consistency in the overall results for Ray and colleagues' analyses is comforting and offers a counterpoint to previous studies. Given multiple other studies with conflicting or uncertain results, we believe that the safety of coprescription of PPIs and clopidogrel remains an unanswered question," the editorialists write.

The AHRQ and the National Heart, Lung, and Blood Institute at the National Institutes of Health supported this study.

Ann Intern Med. 2010;152:337-345, 393-395. Abstract

03-31-2010, 11:17
Along with this particular issue discussed above ...

I recently heard some leading Cardio docs discussing the genetic predisposition for an inneffective Plavix response. When this gene was found to be homozygous, it renders Plavix almost completely useless. Even in the heterozygous case, the function of plavix was severely reduced in its ability to affect the platelet aggregation.

The reason for this relationship is based on the fact that the genetic marker indicates that the patient does not have the enzyme function needed in the liver to metabolize the Plavix into its "active" form. Plavix is not an actual drug. It is a prodrug. It has to be "converted" in the body by a certain liver enzyme to become the substrate that will actually prevent platelets from forming the inital clots (aggregates).

Of course, the literature notes this as a problem but really doesn't recommend what the best course of action is. Just another side note to consider if the med Plavix is not effecting your clotting pathways as predicted.

FWIW, if it was recommended that I take Plavix w/wo Asa or PPI's.. I would take it. I would just have testing done periodically to make sure the effect was within the range that the MD wanted.

02-01-2013, 16:29
I work in this field directly now. We prescribe Prilosec (omeperzole) along with plavix routinely. Let me clarify, if the Pt. was on plavix pre-procedure, they can stay on it with plavix. Uptodate advises for new PPI start with concurrent plavix, that pantroprazole (CYP2C19 inhibitor) is preferred.