CardioExchange Archive

From time to time, a sales representative visits my office promoting clopidogrel (Plavix) as a drug that patients who present with unstable angina/non–ST-segment-elevation MI (UA/NSTEMI) should start immediately as an up-front load. That strategy hasn’t been uniformly accepted in my clinician community because of concern about using an irreversible antiplatelet agent to treat patients who might need coronary artery bypass graft (CABG) surgery. Yet, this notion of clopidogrel pretreatment before cardiac catheterization is widely viewed as a given.

Like most busy practitioners, I can be a fast-food consumer of the clinical trial literature. I often rely on experts for summary recommendations, and I can be susceptible to marketing and other influences. So to delve into the clopidogrel issue, I had to stop and take time to review ACC/AHA guidelines and data from clinical trials. When I did that, I discovered that the evidence for treating patients with unknown coronary anatomy with an up-front load of clopidogrel is weak and indirect.

What I Found

No question, clopidogrel is a useful, effective drug. It has enabled the use of stents, particularly drug-eluting stents, and a loading dose of clopidogrel speeds the onset of action. So, up-front loading makes perfect sense for patients scheduled for PCI. But for the larger group of patients with UA/NSTEMI, there’s a substantial downside. In the large CURE trial, 16.5% of patients required CABG. A 5-day “Plavix washout” for so many patients creates severe logistical problems. If you extrapolate to the 1.24 million UA/NSTEMI patients admitted to U.S. hospitals each year, “Plavix washout” would result in more than a million patient-days in hospitals — an enormous expense and inconvenience just to compensate for up-front loading.

What’s the evidence that this costly strategy works? The CURE trial, which is widely referenced, really didn’t test up-front loading. It assessed the effect of adding clopidogrel as a loading and maintenance dose to aspirin over a follow-up period of up to 12 months. Patients were loaded as soon after randomization as possible, but the trial’s protocol did not specify the timing of cardiac catheterization. Patients who underwent PCI experienced a median delay to PCI of 10 days, hardly reflecting current care in the U.S. And clopidogrel treatment came with a cost of excess bleeding, particularly at vascular access sites.

In the CURRENT-OASIS 7 trial, a strategy of double-dose clopidogrel as an up-front load and for 6 days, followed by standard dosing, was compared with standard loading and dosing in acute coronary syndrome patients (ACS) who were referred for an invasive strategy. The primary endpoint did not differ significantly between the two treatment groups. The study did not specifically isolate the issue of up-front loading, but up-front loading and 6-day treatment with a stronger dosing regimen did not show a benefit.

Then there’s the CREDO trial, in which patients undergoing PCI either received a 300-mg clopidogrel preload then 75 mg daily for 12 months or no load at all then 75-mg daily for 28 days. Preloading and long-term clopidogrel showed a significant advantage in reducing a combined endpoint of death, MI, or stroke over a year — but not in a combined endpoint of death, MI, or urgent target-vessel revascularization over 28 days — suggesting that the benefit was due to long-term treatment, not the up-front load. PCI-CURE, a subgroup analysis of CURE that is also widely referenced, showed a favorable effect of clopidogrel in patients undergoing PCI but did not specifically address the timing of drug initiation.

How I Reason

No trial has specifically compared up-front clopidogrel loading with loading that is delayed until after a patient’s coronary anatomy is known. Furthermore, the argument for up-front loading ignores the availability and proven benefits of short-acting, reversible glycoprotein IIb/IIIa-receptor antagonists. Also, faster-acting thienopyridines (prasugrel and, soon, ticagrelor) that can be loaded at the time of cardiac catheterization are available. The most logical strategy would be to determine the coronary anatomy quickly so that the best revascularization treatment can be planned and appropriate adjunctive therapy can be started in a timely fashion. If catheterization is delayed, a glycoprotein IIb/IIIa-receptor antagonist could be used to bridge the gap in high-risk patients. This common-sense approach prevails in my clinician community.

So how did the practice of up-front clopidogrel loading gain such momentum without stronger evidence from clinical trials? For the sales force, there’s an obvious commercial motivation; for others, perhaps some overinterpretation of industry-funded trials. But for us clinicians, the issue may be overtreatment bias: ACS patients remain at risk for unfavorable outcomes, and doctors are motivated to mitigate that risk. If clopidogrel and similar agents weren’t double-edged swords, erring on the side of overtreatment might be justified, but we must remember that our first principle is to do no harm.

What I Conclude

My assessment is that clopidogrel loading before cardiac catheterization of UA/NSTEMI patients has not been directly studied, has no proven benefit, and carries the obvious disadvantage of irreversibly affecting platelet function in patients who may require CABG. Until proven otherwise by direct clinical evidence, this widely promoted assumption should be rejected and common sense should prevail. That’s how I see the issue. What about you?