Antiplatelet Resistance: The Problem of Nonresponders

NEW ORLEANS—Resistance to antiplatelet therapy is a common problem in patients with coronary artery disease (CAD). Strategies are emerging to help overcome resistance to clopidogrel (Plavix), and promising evidence suggests that novel antiplatelet agents will be less problematic, experts said at the American College of Cardiology annual meeting.

Clinically, antiplatelet resistance is defined as recurrent thrombosis while taking aspirin or clopidogrel.

Depending on the assay used, 5% to 10% of patients are resistant to aspirin, said Steven R. Steinhubl, MD, associate professor of medicine, University of Kentucky, Lexington. Aspirin-resistant patients with stable CAD have been shown to have a 5-fold increased risk of death in 2 years. Although platelet function testing can identify resistant patients, no evidence suggests that altering antiplatelet therapy (especially after angioplasty) based on test results will affect clinical outcomes. This presents a conundrum for clinicians, the speakers agreed.

Patients with resistance to clopidogrel also have an increased risk of recurrent cardiovascular (CV) events, thrombotic complications, and periprocedural myocardial damage during angioplasty. Adnan Kastrati, MD, of Deutsches Herzzentrum Muenchen, Munich, Germany, noted that in the EXCELSIOR (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate) study of 802 patients evaluated for clopidogrel response before elective angioplasty, those in the fourth quartile of platelet reactivity (>32%) had a 4-fold increase in major adverse cardiac events at 30 days compared with those in the first quartile (<4%).

David Antoniucci, MD, head of cardiology, Careggi Hospital, Florence, Italy, reported that in the RECLOSE (Low Responsiveness to Clopidogrel and Sirolimus- or Paclitaxel-Eluting Stent Thrombosis) trial of 804 patients receiving drug-eluting stents, after 6 months of using aspirin and clopidogrel, the clopidogrel nonresponders had a 3-fold increased risk for stent thrombosis compared with responders (8.6% vs 2.3%) and an even greater risk for CV events (8.6% vs 1.4%).

These findings suggest that faithful adherence to antiplatelet therapy with clopidogrel may not offer enough protection against late stent thrombosis, Dr Antoniucci suggested. He added that testing for clopidogrel responsiveness before stenting might have an important influence on the treatment plan. "Nonresponders might need alternative antiplatelet drugs or different dosages, or perhaps they should be treated with bare-metal stents or offered the opportunity for coronary bypass surgery," he said.

Overcoming Clopidogrel Resistance

Increasing the clopidogrel loading dose from 300 to 600 mg (though not from 600 to 900 mg) and increasing the maintenance dose to 150 mg/day can significantly improve platelet response to clopidogrel, according to recent studies. However, the clinical relevance of such a strategy is currently unknown, Dr Kastrati pointed out.

Paul Fefer, MD, of Sheba Medical Center, Tel Aviv, Israel, described good outcomes with clopidogrel "reloading" in a study of 200 patients with acute myocardial infarction. Patients received clopidogrel 300 mg as a loading dose, then 75 mg/day for maintenance. On day 4, the 15% of patients who were identified as nonresponders were reloaded with clopidogrel 600 mg and maintained on 150 mg/day for 1 month. Reloading significantly reduced platelet aggregation from 83% to 56%, Dr Fefer reported.

The Dual-Resistant Patient

Neal Kleiman, MD, director, Cardiac Catheterization Laboratory, Methodist DeBakey Heart Center, and professor of medicine, Weill Medical College of Cornell University, New York City, asked, "Does clopidogrel 'rescue' patients who are aspirin-resistant, or are many patients resistant to both drugs?"

His group evaluated 150 elective angioplasty patients and found 24% to be resistant to clopidogrel and 13% to be resistant to aspirin. Nearly half of the aspirin-resistant patients were also resistant to clopidogrel, compared with 20% of the aspirin-sensitive patients. Most dual resistance was seen in women and in diabetics; dual-resistant patients had more increases in creatine kinase MB enzymes.

"The findings suggest that 10% to 15% of the elective angioplasty population will have aspirin resistance, and about half of these patients will also be resistant to clopidogrel," Dr Kleiman said. "The meaning of this is unclear, but if you are concerned that your patient is not covered with aspirin, realize that he may not be covered with clopidogrel either. This makes a strong case for platelet function testing in some patients."

Should You Test for Platelet Function?

Although it is possible to identify nonresponders to clopidogrel and aspirin, Alan D. Michelson, MD, of the University of Massachusetts Medical School, Boston, said it is not currently appropriate. Before testing can be recommended outside of research trials, aspirin-dependent laboratory testing must be linked to clinical outcomes, especially considering the lack of an established treatment for aspirin resistance. The same holds true for clopidogrel, he said.

Key Points

• No evidence is available to show that altering antiplatelet therapy based on platelet function tests can affect clinical outcomes.
• Clopidogrel-resistant patients are at risk of recurrent CV events, thrombotic complications, and periprocedural myocardial damage during angioplasty.
• Antiplatelet therapy with clopidogrel may not protect against late stent thrombosis.
• Increasing the clopidogrel dose can improve platelet response, but the clinical benefits from it are still unknown.
• New agents in development show promising results and may offer new alternatives.

Nevertheless, the 2006 American College of Cardiology/American Heart Association guidelines recommend that in patients in whom subacute stent thrombosis may be catastrophic or lethal, platelet aggregation studies may be considered. And if <50% inhibition of platelet aggregation is demonstrated, consider increasing the maintenance dose of clopidogrel from 75 to 150 mg/day. Randomized trials are currently under way to evaluate the benefit of altering therapy in nonresponders.

Novel Antiplatelet Agents

Novel antiplatelet agents appear to have numerous advantages over clopidogrel and aspirin. The top 3 in development&#8212;prasugrel, cangrelor, and AZD 6140&#8212;all have a rapid onset of action, produce a high level of inhibition, and are not associated with resistance. Cangrelor and AZD 6140 are also rapidly reversible, said Dominick J. Angiolillo, MD, associate director of cardiovascular research, University of Florida, Jacksonville.

"So far, we see excellent degrees of platelet inhibition. We need to gather clinical experience to determine if more potent inhibition will be associated with better clinical outcomes," he said. The safety and efficacy of the new agents are being evaluated in adequately powered trials that compare them with clopidogrel.