When Moving From DAPT to Monotherapy After PCI, the P2Y12 Inhibitor Matters

The efficacy of P2Y12 monotherapy depends on the type of drug used after discontinuation of dual antiplatelet therapy (DAPT) for post-PCI patients, according to a new patient-level meta-analysis.

Specifically, ticagrelor was noninferior to continued DAPT for the primary composite endpoint of all-cause mortality, MI, or stroke and superior for major bleeding and net adverse clinical events (NACE) across six randomized trials. But while clopidogrel reduced bleeding, it did not meet noninferiority criteria compared to DAPT regarding the primary composite endpoint.

“These findings suggest that ticagrelor monotherapy was similarly effective and safer than DAPT and that clopidogrel was not noninferior to DAPT for ischemic protection, but the current evidence base is inadequate and further trials are needed,” write Marco Valgimigli, MD, PhD (Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland), and colleagues.

Several studies have now highlighted the safety and feasibility of monotherapy after a short course of DAPT in patients following PCI. A prior meta-analysis demonstrating the advantages of P2Y12 inhibitor monotherapy over aspirin for secondary prevention did not discriminate between clopidogrel and more potent drugs like ticagrelor and prasugrel, but the former—which is subject to ineffectiveness in patients with clopidogrel resistance—was only used in 22.2% of the cohort.

Commenting on the new meta-analysis for TCTMD, Arman Qamar, MD (NorthShore University Health System, Evanston, IL), called it a “major step forward” for the field. Building on the success of the TWILIGHT trial–which was included here and originally proved the feasibility of using ticagrelor monotherapy after a short course of DAPT post-PCI—he said this study “adds more power; the more patient population you have, the more generalizability increases.”

Ticagrelor Noninferior

For the study, published online yesterday in JAMA Cardiology, Valgimigli and colleagues pooled data from six contemporary randomized trials comprising 25,960 patients (mean age 64-67 years; 23% female; 64% ACS) undergoing PCI who were randomized to continued DAPT or a short course of DAPT followed by P2Y12 inhibitor monotherapy (median treatment duration 334 days):

• TWILIGHT
• GLASSY
• STOPDAPT-2
• SMART-CHOICE
• TICO
• STOPDAPT-2 ACS

A total of 24,394 patients were included in the per-protocol analysis, including 12,403 receiving DAPT as well as 8,292, 3,654, and 45 receiving ticagrelor, clopidogrel, and prasugrel monotherapy, respectively. Given how few patients received prasugrel, that drug was not studied in the meta-analysis. Importantly, while the trials looking at ticagrelor monotherapy were conducted across Asia, Europe, and North America, those studying clopidogrel monotherapy were only performed in Asia.

Overall, ticagrelor monotherapy met noninferiority criteria compared with DAPT for the primary composite endpoint (3.0% vs 3.46%; HR 0.89; 95% CI 0.74-1.06; P for noninferiority = 0.004), but the same was not seen for clopidogrel monotherapy (2.76% vs 2.07%; HR 1.37; 95% CI 1.01-1.87; P for noninferiority > 0.99). Notably, the clopidogrel finding was driven by increased rates of noncardiovascular death.

Compared with DAPT, both ticagrelor (0.94% vs 2.0%; HR 0.47; 95% CI 0.36-0.62) and clopidogrel monotherapy (0.59% vs 1.20%; HR 0.49; 95% CI 0.30-0.81) were associated with a lower risk of major bleeding. Also, the risk of NACE—a composite of all-cause death, MI, stroke, and BARC 3 or 5 bleeding—was lower with ticagrelor (3.84% vs 5.25%; HR 0.74; 95% CI 0.64-0.86) but not clopidogrel monotherapy (3.29% vs 3.28%; HR 1.00; 95% CI 0.78-1.28).

Multivariate analyses confirmed an interaction between P2Y12 inhibitor type and the primary composite endpoint as well as for the composite of death or MI, all-cause death alone, and NACE. Additionally, several sensitivity analyses confirmed the main findings.

When the researchers performed an analysis excluding STOPDAPT-2 ACS, which was identified as driving much of the observed risk for clopidogrel, the risk associated with clopidogrel monotherapy compared with DAPT regarding the primary composite endpoint decreased (HR 1.13; 95% CI 0.77-1.65).

“Our patient-level meta-analysis provides evidence that aspirin discontinuation 1 to 3 months after PCI followed by ticagrelor monotherapy was safer than and at least as effective as standard DAPT,” the authors write. “The residual possibility of a small risk needs to be interpreted against the 53% relative reduction of major bleeding and 26% relative reduction of NACE. In addition, we observed a nominally significant 28% lower risk of mortality with ticagrelor monotherapy. The mortality benefit might be related to the substantial reduction in major bleeding.”

Regarding the role of high platelet reactivity in their findings, Valgimigli and colleagues say the lack of pharmacodynamic or genetic data in their study prevents the drawing of any conclusions. However, they note the higher prevalence of CYP2C19 loss-of-function alleles in some Asian patients which can limit the effectiveness of clopidogrel. Still, they write, “East Asian populations have a lower incidence of ischemic heart disease and a decreased risk of post-PCI atherothrombotic complications compared with white populations.”

More Data Needed for Clopidogrel, Prasugrel

Qamar noted two main challenges with using ticagrelor monotherapy: high cost—as much as $600 co-pays—and the drug’s twice-daily regimen. Because of these hurdles, generic, once-daily clopidogrel seems more appealing for many patients and physicians, he said.

While it’s clear that clopidogrel cuts the risk of bleeding for most patients, “if that bleeding prevention is coming at a risk for increasing thrombotic risk, then that is unacceptable,” Qamar said, adding that the meta-analysis clearly shows that ticagrelor has the upper hand when it comes to ischemic risk, bleeding, and NACE combined. However, he did note the limitation of the clopidogrel analysis being completed only in East Asian patients, challenging the generalizability of the findings.

“Based on this data, I think the question is: how does this field move forward?” he said. “If I have to do abbreviated duration of dual antiplatelet therapy, I personally would feel more comfortable using ticagrelor compared to clopidogrel. I am not saying that this particular meta-analysis suggests that clopidogrel should never be used or should not be used when it comes to P2Y12 monotherapy—it should be.”

Qamar called for a trial like TWILIGHT but comparing clopidogrel monotherapy with continued DAPT conducted in North America, Europe, and South America. Additionally, he said, more knowledge is needed for prasugrel given that it’s available as a low-cost generic.

Overall, physicians need to move to more of a personalized medicine approach when prescribing dual antiplatelet therapy, according to Qamar.

“One size does not fit all,” he said. “Of course, the stent technology, IVUS, and everything is great, and we have been able to cut down on the duration of antiplatelet therapy, but we should decide that tailoring on a case-by-case basis. If a patient got stenting in the setting of MI, if it's a bifurcation PCI, left main PCI, if the presentation was something like in-stent restenosis or cardiogenic shock, then favor using a longer duration of dual antiplatelet therapy with a potent agent, preferably ticagrelor or prasugrel.”