VA Registry Finds Long-term Benefit from Clopidogrel Beyond 12 Months

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Patients taking clopidogrel beyond 12 months after stenting have a lower risk of death and myocardial infarction (MI) over the subsequent 3 years compared with those who stop the drug earlier. According to registry findings from Veterans Affairs (VA) hospitals published online June 5, 2012, ahead of print in Circulation: Cardiovascular Interventions, clopidogrel’s protective effect is especially potent in patients implanted with drug-eluting stents (DES).

Current American College of Cardiology/American Heart Association guidelines recommend that dual antiplatelet therapy should last a minimum of 12 months after DES and at least 1 month but preferably for a year after BMS placement.

David P. Faxon, MD, of Brigham and Women’s Hospital (Boston, MA), and colleagues identified all 42,254 patients in the VA National Patient Care database who received stents from 2002 to 2006. A total of 29,175 patients met study inclusion criteria, of whom 51% received DES and 49% BMS. Two-thirds presented with ACS. In addition, more than 20% had heart failure, more than 40% had diabetes, and more than 20% had chronic lung disease.

At the 12-month landmark, clopidogrel was still being taken by 43% of DES patients and 25% of BMS patients. Mean duration of clopidogrel use in this subgroup was 18.3 months for DES and 21.8 months for BMS, while in the subgroup taking clopidogrel for less than 12 months, the durations were 6.1 months and 4.3 months, respectively.

DES Patients Derive the Most Benefit

Between 1 and 4 years after stenting, patients receiving clopidogrel beyond 12 months had a lower likelihood of death as well as the combined endpoint of death or MI, with DES patients experiencing the greatest gains. Stroke, repeat revascularization, and major bleeding requiring hospitalization were equally distributed regardless of prolonged clopidogrel use for patients receiving either stent type (table 1).

Table 1. Risk from 1 to 4 Years Based on Clopidogrel Use > 12 Months

a P < 0.01.
^b P = 0.02.

The results remained consistent after multivariate adjustment, but in a propensity-adjusted model, BMS patients no longer derived significant protection with regard to death or death/MI. In a sensitivity analysis that only included patients who had not experienced major outcomes prior to the 12-month landmark, the likelihood of death was reduced by prolonged clopidogrel for DES (HR 0.75; 95% CI 0.63-0.90) but not BMS (HR 0.90; 95% CI 0.79-1.02).

Subgroup analyses, meanwhile, found that patients with ACS or insulin-treated diabetes had significantly lower mortality risk when taking clopidogrel longer than 12 months but again only when implanted with DES rather than BMS. On the other hand, patients without diabetes saw no survival benefit from prolonged clopidogrel even if they received DES.

‘A Moving Target’

Dr. Faxon told TCTMD in a telephone interview that one advantage of the trial was that the large cohort enabled researchers to capture a “meaningful difference” from extended clopidogrel. Importantly, “the value continues out during follow-up,” he said. “The curves continue to separate [up to 4 years].” However, he pointed out, the VA population tends to be sicker and have better medication compliance than patients normally seen at private hospitals, both factors that could enhance the observed benefit.

In a telephone interview, Deepak L. Bhatt, MD, MPH, also of Brigham and Women's Hospital, told TCTMD that beyond the study’s size and strong methodology, its “results. . . are believable and consistent with other data sets.”

The stent-dependent effect of clopidogrel is particularly interesting, Dr. Bhatt said. “Part of the answer of how long to continue might be a moving target as stents are getting better and safer. But I think one thing that’s more or less constant is the clinical scenario in which a stent is implanted or dual antiplatelet therapy is considered,” he noted, adding that ACS is the indication where extended dual antiplatelet therapy “most likely has a bang for its buck.”

Though it is unknown how much of a difference clopidogrel would make for those receiving next-generation stents, Dr. Faxon noted, “you could speculate that the newer stents have less need for long-term [therapy].” He reported that the researchers are continuing their registry study in a cohort of patients treated between 2006 and 2011.

But the finding that even BMS patients derive some benefit demonstrates “that there is value in patients with this degree of atherosclerosis irrespective of stent type, and it also speaks to the issue that bare-metal stents are not devoid of complications,” Dr. Faxon commented. “Neoatherosclerosis does form in bare-metal stents as shown by a number of studies, and it can rupture and cause stent thrombosis and sudden death and myocardial infarctions.”

As to why the trial did not show increased bleeding with prolonged clopidogrel, Dr. Faxon proposed that it might be the “pretty high bar” set by considering only major bleeding that led to hospitalization. Both physicians pointed out that when clinically important bleeding events occur with clopidogrel, they tend to happen in the early phase of treatment and cause patients to simply stop taking the drug.

The timing of the paper is particularly apt, Dr. Bhatt noted, because clopidogrel just went generic in the United States. “Once the cost comes down substantially, which it’s starting to do and will continue to do, that even further shifts things toward a longer duration, at least in ACS patients,” he said.

Several ongoing trials are addressing the question of how long to maintain dual antiplatelet therapy: ISAR-SAFE, PRODIGY, CYPRESS, DAPT, and OPTIMIZE.

 

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Source:
Faxon D, Lawler E, Young M, et al. Prolonged clopidogrel use after bare-metal and drug-eluting stent placement: The Veterans Administration Drug-Eluting Stent Study. Circ Cardiovasc Interv. 2012;Epub ahead of print.

 

 

Related Stories:

• CREDO-Kyoto Published: Extended DAPT Appears to Raise Bleeding Without Curbing Ischemic Events
• Landmark Analyses Show Downside of Prolonged Antiplatelet Therapy
• Stopping Antiplatelet Therapy Often Unrelated to Major Bleeding, Surgery

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