Loading Dose Smooths Switch From Ticagrelor to Clopidogrel After PCI: SWAP-4

ORLANDO, FL—Patients with coronary artery disease who need to switch from ticagrelor to clopidogrel after PCI should receive a loading dose of 600 mg clopidogrel between 12 and 24 hours following ticagrelor discontinuation, according to results from a randomized, pharmacodynamic study.

Findings from the SWAP-4 study should help patients safely de-escalate without experiencing the spike in platelet reactivity likely caused by drug-drug interaction, investigators say.

To TCTMD, senior author Dominick Angiolillo, MD, PhD (University of Florida College of Medicine-Jacksonville), emphasized that “the purpose of the study is not to endorse de-escalation of therapy.”

Instead, “since this is occurring in clinical practice, we found it important to provide recommendations that if there is a need to de-escalate, [what would be] the best way to do it,” he said.

SWAP-4’s results were presented last week as a poster at the American College of Cardiology 2018 Scientific Session and simultaneously published in Circulation.

The past year has seen a flurry of research looking at the clinical outcomes associated with switching antiplatelet agents in patients whose therapy is “de-escalated”—usually this happens because of bleeding, but it can also be for economic reasons. Investigators in the field have stopped short of recommending the practice but collaborated on a consensus document published in October to give clinicians some guidelines for situations they will inevitably face in practice.

Dirk Sibbing, MD (Ludwig Maximilian University of Munich, Germany), who was not involved with SWAP-4 but was one of the co-authors on the consensus document, said the new data provide “solid evidence” to support a clinical protocol of switching patients from ticagrelor to clopidogrel with a loading dose of the latter. “Of course, you have to decide in [patients at high bleeding risk] if they can handle a loading dose, so it's not a ‘must’ to do it, but I think it's something you should strongly reconsider whenever it is possible,” he said.

Testing Platelet Reactivity Three Ways

For the study, Angiolillo along with Francesco Franchi, MD (University of Florida College of Medicine-Jacksonville), and colleagues enrolled 80 patients with CAD who had been on maintenance therapy with aspirin and clopidogrel for at least 30 days and agreed to switch to ticagrelor using a 7-day run-in phase (ticagrelor 180-mg loading dose followed by a 90-mg twice daily maintenance dose). Patients were then randomized to one of four study groups:

• Group A: clopidogrel 600-mg loading dose 24 hours after last dose of ticagrelor, followed by 75-mg/day maintenance dose
• Group B: clopidogrel 600-mg loading dose 12 hours after last dose of ticagrelor, followed by 75-mg/day maintenance dose
• Group C: clopidogrel 75-mg/day maintenance dose 24 hours after last dose of ticagrelor
• Group D: continue ticagrelor 90-mg twice daily maintenance dose

Pharmacodynamic testing was done at baseline; post run-in; and at 2, 24, 48, and 72 hours and 10 days using three different assays: VerifyNow (Accriva) to measure P2Y12 reaction units (PRUs), whole blood vasodilator-stimulated phosphoprotein to measure platelet reactivity index (PRI), and light transmittance aggregometry to look at maximal platelet aggregation (MPA).

During the run-in phase, after all of the patients had switched from aspirin and clopidogrel to ticagrelor, platelet reactivity was reduced from baseline as measured by the three different pharmacodynamic assays (P < 0.001). Then, following randomization, platelet reactivity remained lower in Group D patients who continued on ticagrelor compared with in the three cohorts randomized to clopidogrel (P < 0.001).

At 48 hours, PRU levels were similar between patients in Group A and Group C (P = 0.66) but lower in Group B than Group C (P = 0.024), and similar findings were seen with PRI. Compared with Group C, MPA levels were lower in both Group A (P = 0.041) and Group B (P = 0.028). None of the tests showed any differences between either of the two groups (A and B) that received loading doses.

Notably, patients in Group C who did not receive loading doses saw platelet reactivity rise from baseline, a shift that was apparent at 24 hours and reached statistical significance at the 48-hour mark, dipping slightly after 72 hours but remaining statistically higher through 10 days.

Almost one-quarter of patients were carriers of a CYP2C19 loss-of-function allele, but no interaction was observed between this status and the effects of treatment group on measures of platelet reactivity throughout the study.

Takeaway: Don’t Skip the Loading Dose

“The results of our study show that when switching from ticagrelor to a standard maintenance dose of 75 mg of clopidogrel, we have a greater increase in platelet reactivity which can be mitigated with the administration of a 600-mg loading dose,” Angiolillo summarized. “The study also evaluated what was the optimal timing of administration of the loading dose, and we essentially did not see any differences between giving this 12 or 24 hours after the last maintenance dose of ticagrelor. Nevertheless, we did see that even with the 600-mg loading dose, there was a potential for the drug-drug interaction, but it was not to the extent observed with the 75-mg [maintenance dose].”

While this was not a study of clinical outcomes, it is known that increased platelet reactivity should be avoided in high-risk patients, he said. “So the first clinical message is, if you are going to do a de-escalation, . . . try to avoid this if at all possible immediately after the PCI period and try to delay, because the patients are obviously more vulnerable and more prone to thrombotic complications in the peri-PCI period.”

Also, always give a loading dose of 600-mg clopidogrel, Angiolillo stressed. It “doesn't matter if you give it at 12 hours or 24 hours, whatever is most convenient for the patient,” he advised.

For patients with bleeding complications, “do what you believe is best . . . for the patient,” he said. “In our consensus document, we recommend in the setting of bleeding to just go to the maintenance dose.”

Sibbing agreed with all of Angiolillo’s recommendations, saying, “Although this loading dose cannot fully compensate, it seems to bring patients into a safer haven in terms of the levels of platelet reactivity.”

This topic is one “that affects so many patients all over the world,” Sibbing added. “If you look at the rates of ACS patients in the US and beyond, this is really a topic of research that can affect most of the patients, and this is also in my opinion why more research is needed here, specifically on a clinical level.”

The publication of SWAP-4 helps explain the mechanisms of drug effects, said Sibbing. But he called for more trials in the vein of TROPICAL-ACS—his own study—and also TOPIC, which looked at guided and unguided de-escalation therapy strategies, respectively. Sibbing also pointed to the recently presented PHARMCLO results, which could support a genotyping-based antiplatelet strategy, as well as to ongoing studies like TAILOR-PCI and POPular Genetics, which could do the same.

“These trials will be important and may pave the way toward more personalized treatment in ACS patients,” he concluded.