Monday, March 13, 2006

Plavix & Aspirin -- Fusion or Fission?

There was some interesting data presented yesterday at the American College of Cardiology's annual meeting regarding the use of the combination of aspirin and Plavix. For years, good old fashioned aspirin has been touted as the best medication for the average person to take to reduce their risk of heart attack and stroke. More recently, the advent of statins has greatly influenced the treatment and outcomes of these diseases --- but these are meant only for those patients with established hyperlipidemia. Aspirin was initially thought to be good for everybody; it affects platelet function by blocking the production by platelets of thromboxane A-2, the chemical that causes platelets to clump, theoretically decreasing the likelihood of development of a thrombotic event in all who take it. More recently, however, there has been good research that shows aspirin is best reserved for those patients at highest risk for cardiovascular disease --- those with a prior history of MI or stroke, those with hyperlipidemia, etc. Interestingly, the benefits of aspirin use are clearly different depending upon one's gender, with men getting a bit more bang for the buck.

There is a "dark side" to aspirin -- the risk of the development of bleeding ulcers, which may require endoscopic treatment or occasionally surgery. That risk is known with all of the NSAIDS, whether they are COX-1 or COX-2 inhibitors. While my own experience is only anecdotal, most of the patients I have been called to operate upon with bleeding (or more commonly, perforated) ulcers due to aspirin use have been aspirin abusers, not simply taking a baby aspirin for the prevention of MI or stroke.

With the antiplatelet effect of aspirin seen as a good thing, and its GI side effects seen as a bad thing, researchers looked for other ways to inhibit platelet function. The thienopyridines were developed to block ADP receptors on platelets, thereby inhibiting platelet clumping. The most widely prescribed thienopyridine is Plavix --- which may be a well-known drug to non-medical folks due to the aggressive ad campaign waged by its manufacturer. A combination of aspirin and Plavix has been shown to significantly reduces the risk in patients being treated for an acute MI of a second MI or death. Initially approved for use in 1997, Plavix is currently approved for the following uses (from the Sanofi web site):

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease --For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral artery disease, PLAVIX has been shown to reduce the rate of a combined end point of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
Acute Coronary Syndrome -- For patients with acute coronary syndrome (unstable angina/nonĂ‚–Q-wave MI), including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, PLAVIX has been shown to decrease the rate of a combined end point of cardiovascular death, MI, or stroke as well as the rate of a combined end point of cardiovascular death, MI, stroke, or refractory ischemia.
What is hidden in that mass of medical gumbo is that Plavix is a good drug when used for the above-mentioned situations, and there is some pretty good science available to endorse its utilization in those circumstances.

And therein lies the problem. Plavix has become the "go to" drug for many physicians who are looking for something that will decrease the stroke or MI risk in the patient who comes with those concerns, but who does not fit into the above categories of indicated usage. In particular, I have seen a huge increase in patients given Plavix for a history of TIA, despite the clear statement in the prescribing information:
PLAVIX is not indicated for TIA
This is important, because Plavix is a long-lasting drug that does not have a readily available antidote --- once you take it, your platelets are pretty much out of commission for about 7-10 days, the time it takes for your body to get rid of the old platelets and make new ones. That's why I, as a surgeon, really, really (REALLY) don't like this drug --- an emergency big operation on a patient taking Plavix can be either a death-defying highwire act above Niagara Falls, or a death-producing disaster.

To come full circle, the study from the Cleveland Clinic was designed to determine whether expanding the use of the aspirin/Plavix combination was a good thing. Kudos to the investigators, who reported the exact opposite, despite being funded by Sanofi:
The drug combination not only didn't help most people in a newly released study, but it unexpectedly almost doubled the risk of death, heart attack or stroke for those with no clogged arteries but with worrisome conditions like high blood pressure and high cholesterol. "They actually were harmed," said Dr. Eric Topol. "This was a trial to determine the boundaries of benefit, and it did. You don't use this drug for patients without coronary artery disease." Nothing in the study changes recommendations that people who recently have had heart attacks or a procedure to unclog an artery take those medicines. This study dealt with expanding use of the drug to other people....doctors thought the drug combination might prevent "heart attacks waiting to happen" in people with very clogged arteries or lots of risk factors like heavy smoking, diabetes and high cholesterol....Adding Plavix made little difference for the group as a whole except for slightly reducing hospitalizations. But for the 20 percent with no signs of heart disease, the drug combination proved dangerous. Heart-related deaths almost doubled, from 2.2 percent of those taking only aspirin to 3.9 percent of those who added Plavix.

The only people even modestly helped by adding Plavix were those with established heart disease. Their risk of heart attack, stroke or death was about 7 percent versus 8 percent for those taking aspirin alone.

The study results will be published in the April 20 edition of the New England Journal of Medicine, and apparently there will be a strong editorial accompaniment to the article. My hope is that it will mirror my bottom line for Plavix:
  1. It's a good drug, but may be only marginally better than aspirin.
  2. Use it for, and only for, the right indications.
  3. Please understand that it has some pretty big problems for patients who may require surgery, so go back and read number [2] a few more times.