Clopidogrel Pretreatment Reduces Cardiac Events, Not Mortality, After PCI

Patients who receive a clopidogrel loading dose prior to percutaneous coronary intervention (PCI) derive protection against major cardiac events as a whole. However, pretreatment is not associated with lower mortality risk, according to a meta-analysis published in the December 19, 2012, issue of the Journal of the American Medical Association.

Gilles Montalescot, MD, PhD, of Pitié-Salpȇtrière Hospital (Paris, France), and colleagues analyzed data on 37,814 patients from 6 randomized controlled trials (n = 8,608), 2 observational analyses of randomized controlled trials (n = 10,945), and 7 observational studies (n = 18,261) published between August 2001 and September 2012.

Little Overall Effect with Pretreatment

Analysis focusing on the randomized trials showed no association between clopidogrel pretreatment and all-cause mortality or major bleeding, the primary efficacy and safety endpoints, though pretreatment was related to a reduction of major cardiac events (table 1).

Table 1. Clinical Outcomes in Randomized Trials


Clopidogrel Pretreatment

No Pretreatment

OR (95% CI)

P Value

All-Cause Mortality



0.80 (0.57-1.11)


Major Bleeding



1.18 (0.93-1.50)


Major Cardiac Events



0.77 (0.66-0.89)

< 0.001




0.75 (0.62-0.92)


Minor bleeding data, only available from 5 randomized controlled trials, showed increased risk for patients who received clopidogrel loading compared with those who did not (3.66% vs. 2.74%; OR 1.47; 95% CI 1.02-2.14; P = 0.04). However, this was not confirmed by the observational analyses of randomized trials or by the observational studies.

Stent thrombosis, reported in only 1 randomized trial, was not associated with clopidogrel pretreatment (P = 0.30) and neither was stroke (P = 0.11) nor urgent revascularization (P = 0.71), both reported in 5 trials. Cardiovascular death, reported in 4 trials, also appeared to be unaffected by pretreatment (P = 0.41).

In patients with STEMI, clopidogrel pretreatment cut the risk of death (1.28% vs. 2.54%; OR 0.50; 95% CI 0.26-0.96; P = 0.04) and major cardiac events (3.56% vs. 6.36%; OR 0.54, 95% CI 0.36-0.81; P = 0.003) roughly in half. Patients with NSTE ACS also saw lower rates of major cardiac events after pretreatment (13.91% vs. 17.19%; OR 0.78; 95% CI 0.66-0.91; P = 0.002) though lower-risk patients undergoing elective PCI did not.

STEMI Patients Obtain Greatest Benefit

“Although no significant heterogeneity existed for clinical presentation, the higher-risk STEMI population appeared to gain the most benefit from pretreatment,” Dr. Montalescot and colleagues write. “In contrast, patients undergoing elective PCI had no apparent benefit from clopidogrel pretreatment, questioning the need of such a systematic strategy at least in low-risk patients.”

The authors explain that the lack of mortality reduction after pretreatment of stable patients could stem from several factors. “First, the benefit of this treatment may be related to baseline platelet reactivity, which is lower in more stable patients,” they say. “Second, clopidogrel, both for loading and maintenance doses, is associated with moderate level of inhibition and a wide variability in response that may explain the absence of effect on mortality.”

Guidelines have recommended thienopyridine pretreatment for PCI patients for years, but “this study shows the limits of the available evidence, with no significant benefit on hard outcomes,” the authors conclude. “The value of pretreatment, including with new antiplatelet agents, needs to be assessed in large prospective studies.”

Pretreatment Not Necessary for All 

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), commented that the major “inherent” issue with the meta-analysis is that it combines different populations. “Mixing them together is not a good practice,” he said.

“If you look at the data from the randomized trials of elective patients, the picture is pretty clear that there is no effect on mortality and there probably isn’t a major effect on coronary events,” he said. “Maybe there is a little bit less periprocedural myocardial infarction, although if you really look at the large trials that are purely elective patients, you don’t even see that.”

The major driver behind clopidogrel pretreatment’s effect on MI, Dr. Brener reported, is the ACS population. “I think the message is that in ACS, treatment should be very, very early. In the rest of the patients, the risk is quite low, so it doesn’t quite matter or maybe it matters less than we thought,” he said.

Going forward, “the only question we haven’t completely answered is whether it matters if you have a very small periprocedural myocardial infarction,” Dr. Brener concluded. “But I think that the preponderance of the evidence would suggest that [these] are probably not critical.”


Bellemain-Appaix A, O’Connor SA, Silvain J, et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: A systematic review and meta-analysis. JAMA. 2012;308:2507-2516.



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  • Dr. Montalescot reports receiving research grants, consulting fees, and speaking honoraria from multiple pharmaceutical companies.
  • Dr. Brener reports no relevant conflicts of interest.

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