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Stopping Plavix Doubles Risk of Heart Attack or Death for 90 Days, With or Without Stents
New Study in JAMA Suggests a "Rebound Effect" for Clopidogrel;
May Have Major Implications for Acute Coronary Syndrome and Stent Patients;
Study Author Gives Advice for Patients

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"Incidence of Death and Acute Myocardial Infarction Associated With Stopping Clopidogrel After Acute Coronary Syndrome"
-- Journal of the American Medical Association
(2008;299[5]:532-539

February 5, 2008 -- A study appearing in tomorrow's Journal of the American Medical Association (JAMA) reports a two-fold increase in death and heart attack in the 90 days after heart patients completed their prescribed course of medical therapy with clopidogrel (Plavix). The increased risk occurred whether or not patients had received stents and was similar for all durations of clopidogrel therapy studied: from less than six months to more than a year. The study itself was generated by anecdotal reports from heart patients, similar to those posted in Angioplasty.Org's Patient Forums.

Titled "Incidence of Death and Acute Myocardial Infarction Associated With Stopping Clopidogrel After Acute Coronary Syndrome", the study raises the possibility of a "rebound effect" with clopidogrel which has major implications for the millions of patients currently taking the drug. Plavix, the brand name of clopidogrel, is the world's second largest-selling drug, with annual sales of $5.9 billion. The study also may impact the concerns over late stent thrombosis that have significantly reduced the use of drug-eluting stents over the past year.

P. Michael Ho, MD, PhD and John S. Rumsfeld, MD, PhD of the Denver VA Medical Center in Colorado and colleagues studied a group of 3,137 patients with ACS discharged from 127 Veterans Affairs hospitals with an average follow-up of six months after cessation of clopidogrel. Approximately half of the patients were treated with medical therapy only and half with angioplasty/stents. 17% of those on the medical therapy group died or had a heart attack in this period, but almost two-thirds of those events occurred in the first 90 days. A similar pattern was seen in the angioplasty/stent cohort. Heart attacks are caused by sudden blood clots in the coronary artery which cut off the blood supply to the heart.

While the authors stress this is an observational study, the results suggest that immediately following the stopping of clopidogrel, there may be a short period of increased platelet activation which would in turn promote blood clot formation. The article calls for urgent research into possible mechanisms, which also might lead to strategies for safe weaning or tapering off of the drug, avoiding this risky effect.

What Should Patients Do Now?
Concerned that the reports of their study may confuse patients, or cause patients not to comply with their prescriptions, for fear that there is something negative about taking clopidogrel, co-author Dr. John Rumsfeld told Angioplasty.Org that it is quite the opposite:
John Rumsfeld, MD, PhD
John Rumsfeld, MD, PhD

"What needs to be reinforced, number one, is to take the full course of clopidogrel that the guidelines recommend, which is following a heart attack twelve months, whether or not you got a stent. We know that clopidogrel is beneficial in this setting.

"The result of this study is that when you get to 12 months, we don't know what the right answer is. Is it still the best thing to stop at 12 months because longer courses may not confer benefits and do come with some risk of bleeding? Then there's obviously the cost of the drug. Is it going to turn out to be important to continue the medication for a longer course or indefinitely to try to avoid this clustering or grouping of events? Our study can't answer that, so the recommendation has to be to take the full 12 months, and after 12 months it will have to be an individual decision of a patient with their clinician.

I would anticipate at that point the clinician would evaluate that individual patient's overall risk profile: their severity of their heart disease, what type of stent they received, how many heart attacks they've had, etc., and how well they've done on the clopidogrel. It may be that a patient who’s had no side effects of the clopidogrel, that the individual clinician and patient may decide together as a team that they'd like to continue the medication indefinitely to avoid this potential rebound effect until its proven whether that is what it is or not."

Plavix and Stents
Clopidogrel is a major blood-thinning drug used in heart disease, one which is normally prescribed after stent implantation because its antiplatelet properties help keep the blood from forming clots around the stent structures. Plavix is prescribed for three months or less after bare metal stent implantation, but it is prescribed for 6-12 months or longer for drug-eluting stents.

In the fall of 2006, several studies raised concerns that blood-clots, called stent thromboses, were occurring in drug-eluting stent (DES) patients well after the 6-12 month period. Drug-eluting, or drug-coated, stents contain a medication that prevents excess tissue from growing in the stented area, an advantageous property which has lowered the rate of stent restenosis (or reblocking) by half. While these blood clots were small in number, they were of great concern because a clot can acutely block the artery and cause a potentially fatal heart attack. Theories were presented that medications in the drug-eluting stents may inhibit tissue growth too aggressively and thus delay the healing of the stented area, leaving it vulnerable to clotting. Late stent thrombosis was the subject of a two-day FDA panel in December 2006 and continuing concerns have significantly impacted the use of drug-eluting stents worldwide. In the U.S. the percentage of stent patients receiving the drug-eluting variety has dropped from 90% to 60% in the past year alone.

The JAMA study specifically looked at patients who did not have a stent implanted, in order to remove the confounding presence of the stent. Dr. Rumsfeld told Angioplasty.Org, "In those patients, these adverse events cannot be attributed to a stent, because they didn't receive one. It further bolsters the hypothesis of a potential rebound associated with clopidogrel."

Whether or not a portion of the "drug-eluting stent problem" of late stent thrombosis may be attributable to this potential rebound effect of clopidogrel, and not the stent, will no doubt be the subject of many studies.

The Importance of Patients' Observations
An interesting background for the Denver VA study was that it began because of a single patient's story. Dr. Rumsfeld explains:

"A relative of one of the co-authors made the observation that, after completing a full course of clopidogrel and then stopping it, he had a recurrent problem shortly thereafter. That coupled with other anecdotes from patients, and many of those are evident on Angioplasty.Org, the same anecdotes of patients taking the fully prescribed course of clopidogrel and then right after stopping it, having a second heart attack, these patient-driven anecdotes actually led to us evaluating this question in our study and, sure enough, revealed evidence that, after completing a course of clopidogrel, there appears to be a short-term period of high risk of another heart attack."

Dr. Rumsfeld continued that this type of observational information, especially from patients, may open up a new and previously untapped source of data:

" I think one of the lessons of this study may be that the medical community needs to pay more attention to patients' input on how therapies work in the real world, and that a clustering of anecdotes, where patients are all reporting the same thing, saying 'I found that as well', or a family member of mine did, probably the medical community needs a better mechanism of hearing, of getting this information from patients. In this particular case it actually provided the hypothesis for the study -- that's probably a model that has rarely happened in the history of medical research but one that should be used more, proving the value of patient partnership in our evaluation of care."

We at Angioplasty.Org could not agree more, having presented this very concept in testimony to the FDA over a year ago. Over a thousand patient stories can be found on the Heart Patients Discussion Forum at Angioplasty.Org.