NOVEMBER 12, 2008

REMIND ME WHY I SHOULD BE ON PLAVIX?

A study of 16,690-persons whose results were released today by Medco Health Solutions found that patients taking Plavix (clopidogrel) with a proton pump inhibitor (PPI) like Nexium or Prilosec have a 50% increase in risk of major cardiovascular event and 74% increase in heart attacks compared to people taking Plavix alone. Since Plavix is given to prevent heart attacks as an expensive alternative to aspirin, it seems these people are losing their benefit.

Where does that leave us? Well since about half of plavix users are on Nexium or another PPI to prevent stomach bleeding, we have to ask what is the benefit of Plavix for these people? So what has the data been for Plavix in the prevention of cardiovascular events been up to now.

In the CAPRIE study Plavix treated patients showed an 5.32% annual rate of a composite measure of stroke, heart attack, or vascular death, compared with 5.83% on aspirin treated patients, a difference that was barely statistically significant (CAPRIE 1996). In the CHARISMA trial of patients with heart disease or risk factors for heart disease there was no significant difference between those who were given clopidogrel plus aspirin or aspirin alone in the combined incidence of heart attack, stroke, or death from cardiovascular causes (Bhatt, Fox et al. 2006). In the CLOpidogrel and Metoprolol Infarction Trial (COMMIT) 45852 patients with a heart attack within the past 24 hours were given clopidogrel or placebo in addition to aspirin. Clopidogrel patients had a 9% reduction in a combined measure of death, heart attack or stroke, a difference that was statistically significant (COMMIT 2006). An analysis of all of the published studies showed a 10% reduction in heart attacks and strokes in patients with a history of cardiovascular disease when clopidogrel was added to aspirin (ATC 2002). These differences, however, translate into a less than 1% reduction in absolute risk. In the Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH)(Diener, Bogousslavsky et al. 2004) study 7599 patients with recent stroke or TIA with one other risk factor for heart disease were randomly assigned to receive clopidogrel or clopidogrel plus aspirin. There was no difference in rates of combined stroke, heart attack, or hospitalization between clopidogrel (17%) and clopidogrel plus aspirin (16%); a 1.3% increase in bleeding was not statistically significant. In a study of 320 patients who had developed a bleeding ulcer while taking aspirin to prevent heart disease, after the patients’ ulcers healed they were randomized for a year to re-treatment with aspirin or clopidogrel. All of them also received esomeprazole. The patients who took clopidogrel had more gastrointestinal bleeding (8.6%) than aspirin patients (0.7%), a difference that is striking (Chan, Ching et al. 2005).

It looks like with these new study results it looks like whatever meagre advantage Plavix has over aspirin are more than offset in people on Nexium as well. It is hard to see what role Plavix has now in heart attack prevention relative to the cheaper aspirin.

ATC (2002). "Antithrombotic Trialists' Collaboration: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients." British Medical Journal 324: 71-86.

Bhatt, D., K. A. a. Fox, et al. (2006). "Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events." New England Journal of Medicine 354: 1706-1717.

CAPRIE (1996). "A randomised, blinded trial of Clopidogrel versus Aspirin in Patients At Risk of Ischaemic Events (CAPRIE)." The Lancet 348(9038): 1329-1339.

Chan, F. K. L., J. Y. L. Ching, et al. (2005). "Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding." New England Journal of Medicine 352(3): 238-244.

COMMIT (2006). "Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial." The Lancet 366: 1607-1621.

Diener, H.-C., J. Bogousslavsky, et al. (2004). "Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial." The Lancet 364: 331-337.

COMMENTS

Dan Abshear commented on November 12, 2008

Notable is that Plavix is the number 2 best selling drug, and Nexium is the number 3 best selling drug. Both have held this position for years. Perhaps they have been promoted to be prescribed together in this manner as well, one may speculate.

As to the etiology with increased CV events when both are used together, that has not been explained, I understand.

Yet as Nexium molecularly is identical to Prilosec, which is now OTC, Plavix can and has been considered simply an expensive aspirin with no significant benefits when comparing these two drugs. It appears there needs to be a warning letter to doctors regarding this danger, along with clarification on efficacy issues as well.

Doug Bremner commented on November 12, 2008

I think the speculation is that Nexium affects an enzyme involved in Plavix metabolism. I think many physicians do prescribe Nexium to avoid bleeding problems with Plavix or aspirin. Yes this does seem to be another boondoggle with many people taking a drug combo that could have made their problems worse.

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