Stopping Clopidogrel 1 Year After MI Raises Risk in PCI Patients

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Contrary to some recent reports indicating a full 12 months of dual antiplatelet therapy following percutaneous coronary intervention (PCI) is unnecessary, a large Danish registry study shows that halting clopidogrel after 1 year raises the risk of death and reinfarction in myocardial infarction (MI) patients. Interestingly, the same does not apply to patients treated with medication alone, researchers report in a paper appearing online July 12, 2012, ahead of print in the European Heart Journal,

Researchers led by Mette Charlot, MD, of Copenhagen University Hospital (Gentofte, Denmark), looked at 29,268 MI patients aged 30 years or older in the Danish National Patient Registry treated with and without PCI between 2004 and 2009. All received a clopidogrel prescription within 30 days.

Roughly one-third were treated only medically (33.6%; n = 9,819) while the rest received PCI (66.4%; n = 19,449). Medically treated patients had 12,181 interruptions/discontinuations of clopidogrel therapy during follow-up, of which 3,524 (29%) lasted under 10 days. PCI patients had a total of 29,676 interruptions/discontinuations during follow-up, of which 10,102 (34.0%) lasted less than 10 days. 

Death/MI Risk Higher, But Just in PCI Patients

After 12 months of clopidogrel, PCI patients had a higher risk of death and reinfarction in the first 90 days of discontinuation compared with the next 90 days (incidence rate ratio [IRR] 1.59; 95% CI 1.11-2.30; P = 0.013). The same was not true for patients treated only medically (IRR 1.07; 95% CI 0.65-1.76; P = 0.79). Of note, risk for the combined endpoint was higher in PCI patients with STEMI as their index event (IRR 2.65; 95% CI 1.25-5.64; P = 0.011) compared with NSTEMI patients treated with PCI (IRR 1.24; 95% CI 0.78-1.99; P = 0.37).

The combined endpoint appeared to be driven in PCI patients by the risk of reinfarction, which was higher in the first 90 days of clopidogrel discontinuation compared with the next 90 days after a year of treatment (IRR 1.87; 95% CI 1.11-3.15; P = 0.019). As with the combined endpoint, this was not true in medically treated patients (IRR 0.77; 95% CI 0.36-1.67; P = 0.51). The risk of death, meanwhile, was not elevated in the first 90 days of discontinuation compared with the next 90 days in PCI patients (IRR 1.18; 95% CI 0.73-1.91; P = 0.51) or medically treated patients (IRR 1.56; 95% CI 0.85-2.87; P = 0.153).

The likelihood of severe or fatal bleeding did not differ significantly for patients who continued or discontinued clopidogrel treatment, whether they received only medical therapy or had undergone PCI.

The main results remained consistent across subgroups defined by sex, age, presence of diabetes or heart failure, and year of inclusion.

Authors Point to DES as Culprit

“Since we found an increased risk related to the discontinuation of clopidogrel treatment in PCI-treated patients and not in patients treated only medically, we suspect that the difference in the risk… can be explained by the PCI-related implantation of intracoronary stents,” the authors observe.

Specifically, they note, DES are associated with an increased risk of stent thrombosis with recurrent MI. Based on a different Danish study, Dr. Charlot and colleagues state that at least 75% of stents used in the current paper were DES. The results have important clinical implications for the length of dual antiplatelet therapy after MI, and until large randomized trials investigate this further, “the question remains whether patients treated with [DES] should continue clopidogrel therapy for an extended period of time,” they caution.

Just as important, though, is the lack of a safety signal with regard to bleeding. “This is relevant because it illustrates that PCI-treated patients who continue treatment beyond 1 year do not have significantly higher risk of bleeding than patients who discontinue treatment,” the authors point out.

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), noted that the study methodology was difficult to follow and made drawing any firm conclusions difficult. Nevertheless, the paper does demonstrate that “there’s passivation of the arteries after an event, so as time passes, the rate of events is less and less,” he said. “If you look at the rate [of death and reinfarction], it declines,” in both medically treated and PCI patients whether or not they discontinued clopidogrel.

Current Guidelines Appropriate

Dr. Brener noted that the only real way to draw conclusions would be to look at chart data and determine the actual relationship between clopidogrel therapy and events, something an administrative database such as the one used in the current study unfortunately does not allow.

Regardless, current guidelines recommending 12 months of clopidogrel therapy after an MI are appropriate, he affirmed, and in some cases longer therapy may be called for. “You should treat for 12 months, we have randomized clinical data to support that,” Dr. Brener said. “And I think patients who are tolerating the medication well—meaning they don’t have bleeding and can afford [clopidogrel]—should potentially be continued for a longer duration of therapy, because we know from the CHARISMA trial [which looked at dual therapy vs. aspirin alone in patients at risk of atherothrombotic events] that there was a reduction of events in the subset of patients with coronary disease up to 2.5 years of therapy. It makes sense to me that we should continue with that.”

But studies such as the recent CREDO-Kyoto PCI/CABG Registry and PRODIGY, which showed no benefit from dual antiplatelet therapy even beyond 6 months, also have a point, Dr. Brener observed.

“It’s a very realistic thought with respect to stent thrombosis. I’m very convinced that with the new stents, probably 3 months is enough and frankly maybe less than that, who knows?” he said. “But here we’re not just trying to prevent stent thrombosis, we’re trying to prevent any MI that’s related to plaque destabilization. It has nothing to do with the stent. We still should treat patients for 12 months after their ACS event because that’s the minimum duration of time it takes to passivate the coronary tree to prevent new plaque ruptures.”

Study Details

Mean duration of clopidogrel therapy before complete discontinuation was 311 days for medically treated patients and 375 days for PCI-treated patients. In medically treated patients, the rate of the combined endpoint (death or reinfarction) was 20.0%, and the rate of reinfarction was 9.4%. The same endpoints were 6.4% and 4.0%, respectively, in PCI-treated patients.

Patients treated medically were older, more often women, and had more comorbidities than PCI patients. Most patients in the medical treatment (78.3%) and PCI (88.3%) groups also received aspirin.

 


Source:
Charlot M, Nielsen LH, Lindhardsen J, et al. Clopidogrel discontinuation after myocardial infarction and risk of thrombosis: A nationwide cohort study. Eur Heart J. 2012;Epub ahead of print.

 

Disclosures:

  • The study was supported by the Danish Heart Foundation.
  • Drs. Charlot and Brener report no relevant conflicts of interest.

 

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