Guiding DAPT Based on Genes or Platelet Tests Still ‘Tempting’

Despite no slam-dunk evidence supporting the use of guided dual antiplatelet therapy (DAPT) strategies, either with platelet function or genotype testing, a new review paper argues that there’s still hope that some patients will see benefit from use of these tests.

The concept of guided DAPT is founded on the idea that such testing can identify patients who might be at high risk of thrombotic events due to high platelet reactivity (HPR) or CYP2C19 loss-of-function alleles and might need escalated therapy. Patients at high risk of bleeding, on the other hand, could be identified as needing their drug dosages scaled back.

Yet, decades of studies haven’t provided conclusive evidence to justify bringing these often-expensive tests into routine clinical use. POPULAR GENETICS showed that guided DAPT escalation was noninferior to a blanket approach of giving prasugrel or ticagrelor to all, with regard to thrombotic events, but the larger TAILOR-PCI trial did not show that using a genotype-guided oral P2Y12 inhibitor strategy compared with conventional clopidogrel treatment decreased the risk of ischemic events at 12 months. As for platelet function testing, studies like ARCTIC and ANTARCTIC showed no benefits, and TROPICAL-ACS demonstrated that guided DAPT was noninferior to 12 months of prasugrel regarding net clinical events but offered no bleeding advantage.

“Customizing DAPT, both in terms of selection and duration, aligns with the current trend towards precision medicine,” senior author Davide Capodanno, MD, PhD (University of Catania, Italy), told TCTMD in an email. “Platelet function and genotype tests are imperfect tools, with mixed results in the literature, and their results probably miss the contribution of antiplatelet resistance coming from other factors such as age, body weight, chronic kidney disease, and diabetes.”

Several studies in this space show that “there are indeed good candidates to de-escalation and escalation out there,” Capodanno continued, adding that a renewed focus on finding these specific patients is warranted.

Commenting on the paper for TCTMD, Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York), said the studies to date leave practicing clinicians in a bind. “We are now in this abyss of understanding how we put to use all of the data that's there on platelet function testing and genotyping.” She argued that all the trials in this space so far have been “woefully underpowered,” saying this has led to “a miss for pretty much all of them in terms of making an important impact.”

Existing Data

Current US guidelines do not mention guided DAPT strategies. But European guidelines, which have included them since 2017, recommend using platelet function and genotype testing to guide decisions on timing of cardiac surgery in patients with CAD who have recently received P2Y12 inhibitors (class IIb, level of evidence B) and to guide de-escalation of P2Y12 inhibitors, especially for those with ACS who are not suitable for 12 months of DAPT with prasugrel or ticagrelor (class IIb, level of evidence B).

The review paper, published last week in Circulation: Cardiovascular Interventions, with first author Nicola Ammirabile, MD (University of Catania), offers an updated summary of the existing evidence for guided DAPT after PCI.

Platelet function testing studies date back the farthest, with most failing to show benefits compared with standard care. TROPICAL-ACS and PATH-PCI were notable exceptions, the authors write, but the former used a guided approach that is “difficult to replicated in clinical practice” and the latter used an assay that it not widely available and is less validated than others.

TAILOR-PCI had been widely expected to cement the benefits of genotyping to guide DAPT following positive data from PHARMCLO and a smaller Middle East study, as well as the noninferiority finding seen with POPULAR GENETICS. But some observers believe the non-statistically significant 34% reduction in the composite of cardiovascular death, MI, stroke, definite or probable stent thrombosis, and severe recurrent ischemia with a genotype-guided strategy among patients with a CYP2C19 loss-of-function allele compared with conventional clopidogrel therapy might have been more persuasive if the study was better-powered.

Meta-analyses generally “suggest that the guided strategies may significantly reduce the risk of MACE compared with standard DAPT, with little or no influence on the risk of bleeding,” the authors write.

They also highlight the fact that no studies have compared platelet function and genotype testing head-to-head to gauge whether one is superior to the other. “Importantly, one should bear in mind that while the platelet function testing evaluates the downstream effects on platelet inhibition arising from mechanisms associated with HPR, genotype represents only a single facet among several factors contributing to HPR,” Ammirabile and colleagues note, adding that these comparisons are needed.

Guided DAPT is “tempting,” the authors conclude. The evidence, in total, shows that “these approaches seem to reduce the risk of ischemic events especially in younger patients with ACS (ie, prompting de-escalation of DAPT), with little or no effect on the risk of bleeding. The current body of evidence is weaker in chronic coronary syndrome/ (ie, prompting escalation of DAPT), although some benefit in younger patients cannot be excluded.”

Future Directions

Mehran agreed that guided DAPT strategies can be “extremely useful” in certain patient groups and argued that future machine-learning models might be able to help bring platelet function and genotype testing into the forefront. For example, she said, a model like xDAPT, which does not currently include genotype or platelet function testing data, could be even “richer” with these included.

While no ongoing studies of platelet function testing are known, Capodanno said trials of genotype testing like GUARANTEE, DAN-DAPT, and ADEN “will contribute to define the role and impact of the genetic information on decision-making and cardiac outcomes.”

Assuming these are positive trials and tests become more accessible, faster, and easier to perform, “there could be chance for broader use in the future,” he continued. “We should also define the right reaction to the result of these tests: de-escalation of noncarriers? Escalation of carriers? Both? This is pretty heterogeneous across trials, and a possible reason for their divergent results.”

Most importantly, Capodanno urged “simplification” with regard to implementing and investigating guided DAPT strategies going forward.