Patients who have undergone percutaneous coronary intervention (PCI) in a saphenous vein graft (SVG) face a more than doubled risk of death or myocardial infarction (MI) in the first 90 days after clopidogrel discontinuation, regardless of the duration of antiplatelet therapy. The findings, published online November 7, 2012, ahead of print in the Journal of the American College of Cardiology, challenge clinicians to develop strategies to cope with this early high-risk period, the authors say.

Investigators led by Somjot S. Brar, MD, MPH, of Kaiser Permanente (Los Angeles, CA), looked at 603 patients who underwent PCI of a diseased SVG at their institution between January 2000 and December 2009. At operator discretion, approximately half of the cohort received DES (27% PES, 22% SES, and 2% EES) and half BMS.

All patients received 75 mg clopidogrel daily plus 325 mg aspirin for the first 90 days and 81 mg daily thereafter indefinitely. The mean duration of clopidogrel use was 270 days, with 45% of patients receiving the drug for 6 months, 14% for 6 months to 1 year, and 41% for longer than 1 year.

Death, MI Highest Within 90 Days

At the time of clopidogrel cessation, 411 patients remained event-free. At a mean follow-up of 543 days after discontinuation, the primary endpoint of all-cause death and MI had occurred in 29.7% of patients.

The overall incidence rate of death or MI was 0.54 per 1,000 person-days of follow-up (95% CI 0.45-0.64). However, these events were concentrated within the first 90 days, yielding a 2.6-fold increase compared with the periods from 91 to 365 days after discontinuation and from 1 to 2 years. A similar pattern was seen for the individual endpoint of death (table 1).

Table 1. Outcomes After Clopidogrel Cessation

In addition, approximately 42% to 60% of adverse events in the first year after cessation of clopidogrel occurred within the first 90 days, regardless of the duration of therapy. The higher early risk of death or MI was consistent across multiple subgroups including stent type (DES vs. BMS), stent diameter (≤ 3.0 mm vs. > 3.0 mm), diabetes status, and study period (2000-2004 vs. 2005-2009).

In sensitivity analyses, results were similar after removing patients with a bleeding event leading to clopidogrel cessation or a history of gastrointestinal bleeding. Incidence rates of death or MI were also comparable after exclusion of patients who received fewer than 30 days of clopidogrel; such patients may have been noncompliant and thus at greater risk for adverse events.

In the full 603-patient cohort, a longer course of dual antiplatelet therapy was associated with a lower cumulative rate of long-term death or MI. More than 2 years of clopidogrel halved the risk compared with less than 6 months of the therapy (adjusted HR 0.48; 95% 0.33-0.70; P < 0.001).

The phenomenon of a spike in adverse events within the first few months after clopidogrel cessation is “very poorly characterized,” Dr. Brar told TCTMD in a telephone interview, noting that there have been a few reports of its occurrence in medically treated ACS patients and, with a less pronounced effect, in the general PCI population. But this is the first study in PCI-treated SVG patients, he noted.

“We tried to overcome the limitations of prior studies by looking at patients who were treated long term, and also by addressing confounding issues, such as noncompliance or a bleeding event that would lead to cessation of one or more antiplatelet drugs and may also heighten the risk of heart attack or death,” he said.

Platelets on the Rebound?

Dr. Brar was reluctant to attribute the temporal pattern of clinical events to a so-called rebound of platelet reactivity following clopidogrel cessation. “The fact that you see this phenomenon consistently, whether clopidogrel has been given for 6 months or 2 years, raises the possibility that [rebound] could be one of the mechanisms. But that’s going to require more research to elucidate.

“I subscribe more to the concept that [vein graft] patients have extensive, severe multivessel disease and that dual antiplatelet therapy is probably protective not only at the site of PCI but throughout the coronary tree,” he said.

One next step may be to perform serial platelet function testing around the time of clopidogrel discontinuation, Dr. Brar suggested. “Some data [show] increased platelet reactivity for the first several weeks, and that [the spike] doesn’t normalize for about 3 months—which is pretty close to that 90-day window [of increased events] that we observed,” he noted.

If platelet rebound were confirmed, Dr. Brar said, tapering the clopidogrel dose might be one coping strategy. Another open question is whether the newer antiplatelet agents such as prasugrel and ticagrelor also are subject to the same phenomenon, he observed.

In a telephone interview with TCTMD, Emmanouil S. Brilakis, MD, PhD, of the University of Texas Southwestern Medical School at Dallas (Dallas, TX), said it makes sense that, after stopping clopidogrel, platelet reactivity and thus the odds of adverse events increase, especially among already high-risk SVG patients.

However, Dr. Brilakis pointed out that due to the observational nature of the study, the reasons for clopidogrel discontinuation are unavailable. Cessation could have been prompted by illness or impending surgery—or simply because the patient was doing fine, he said.

Extended Therapy 

Current guidelines regarding the duration of dual antiplatelet therapy do not adequately address the SVG population, Dr. Brar noted, and there are few data to inform a decision. But, overall, the current findings point to the importance of long-term therapy, he said. In fact, because event rates for this group are arguably higher than for any other PCI population, “even indefinite therapy would be worthy of consideration,” he added.

“[I]t may be a good idea to give a minimum of 12 months of dual antiplatelet therapy after vein graft intervention, which most [centers] currently do even with BMS implantation,” Dr. Brilakis suggested. “And in patients who tolerate clopidogrel well over the first year, you may consider continuing [the drug] for a little longer. . . . This paper gives us a little more ammunition to do this.”

Meanwhile, the current findings suggest that when vein graft patients are taken off clopidogrel, physicians need to be extra vigilant over the following few months, said Dr. Brar. They also need to make sure their patients continue to take aspirin, Dr. Brilakis added.
 

Note: Several study coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

Related Stories:

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• ISAR-CABG Published: DES Preferred for Saphenous Vein Graft Lesions
• Stenting With DES Helps Stave Off Aggressive Disease in SVGs