Key antiplatelet presentation yields more questions than answers

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 - clinical trial

The cardiology community often has debated how long we need to treat patients with dual antiplatelet therapy (DAPT) with aspirin and an ADP receptor blocker such as clopidogrel, prasugrel, or ticagrelor after stenting. The DAPT study sought to answer that question by following nearly 10,000 patients who had drug-eluting stents (DES) implanted and were on DAPT for a year. After the first year, patients who were free of adverse events were randomized to two groups: half stayed on DAPT for a 30-month period and the others were given a placebo. Both groups received daily aspirin.

The results presented Nov. 15 at the American Heart Association conference showed that patients on long-term DAPT had less MI and stent thrombosis compared with patients who were on DAPT for the standard 12-month period.

Despite these findings demonstrating a clear antithrombotic benefit, questions remain. Importantly, among 22,866 patients treated with DES who were enrolled, less than half were randomized at the 12–month time point. However, over half of the patients not randomized were eligible for randomization; 5,808 withdrew consent for unclear reasons. Among the 5,261 not eligible for randomization, 2,638 had events in the first 12 months. Most of the patients ultimately randomized were not troponin-positive acute coronary syndrome patients. Not surprisingly, this group would be expected to have a lower incidence of stent thrombosis than patients with STEMI or NSTEMI.

It’s likely that the treating physicians assessed thrombosis risk and excluded the patients from the randomization whom they perceived were at highest risk of thrombosis. Similarly, for patients they felt were at the lowest risk for cardiac events or the most risk for bleeding, they stopped the drug altogether.  

Additionally, the discussion portion of the manuscript and the accompanying editorial failed to take into account the role that blood vulnerability plays in thrombosis. There was no assessment of patient thrombogenicity or assessment of antiplatelet effect of clopidogrel or prasugrel.

At the beginning of the study, two thirds of patients were treated with clopidogrel and one third were on prasugrel. Clopidogrel has been shown to have unpredictable antiplatelet effects and patients with high platelet reactivity during clopidogrel have a higher risk for long-term thrombotic events including stent thrombosis.

At the end of the study period, patients treated with prasugrel had significantly lower incidences of thrombotic event occurrences compared to patients treated with clopidogrel (p for interaction 0.03) and had a similar rate of bleeding events (p for interaction 0.77). These observations again support the importance of measuring platelet function and selectively treating patients with high-platelet reactivity on clopidogrel with prasugrel. The latter strategy may have further improved patient outcomes.  

Another interesting observation was the greater incidence of stent thrombosis and major adverse events in patients who were on prasugrel at the start of the study and randomized to placebo as compared to patients who were earlier on clopidogrel and randomized to placebo. It is likely that the former group of patients was of high risk.  

There is no established relation of duration post-PCI to attenuation of the individual patient’s prothrombotic risk. Therefore, the DAPT study used an arbitrary cutoff of 30 months or 12 months without any assessment of intrinsic thrombogenicity. Perhaps a better strategy to improve patient outcomes would employ methods to understand why patients experience thrombosis and bleeding while on the drug. We are really no closer to answering these key questions even after the DAPT results were shared.

What lies ahead: Testing and treatment

An important takeaway from the DAPT study and a consideration for future research is the potential signal for higher mortality for nonselective prolonged DAPT. The cause of noncardiovascular death needs to be studied in more detail.

A personalized assessment of the propensity for thrombosis in the individual patient may improve the identification of patients for prolonged DAPT. Point-of-care genetic and platelet function testing devices are available.

Thrombelastography (TEG) has been widely used to assess global hemostasis as well as antiplatelet therapy effect.  Conventional TEG is a labor-intensive and time-consuming method. Our team presented validation study results for the new CORA (TEG 6S) point-of-care