Platelet Testing Guides Prasugrel-to-Clopidogrel Switch Post-ACS

September 08, 2017

BARCELONA, SPAIN — A new "deescalation" regimen of dual antiplatelet therapy post-ACS—which involves switching from prasugrel (Effient, Lilly/Daiichi-Sankyo) to clopidogrel in certain patients guided by a platelet-function test—has been shown to be noninferior to long-term prasugrel treatment[1].

"This is a more differentiated way of treating ACS patients with a scientifically validated alternative regimen that is more affordable and may lessen bleeding risks compared with extended treatment with a more potent antiplatelet agent," Dr Dirk Sibbing (Ludwig-Maximilians-University, Munich, Germany) told theheart.org | Medscape Cardiology.

Sibbing is lead investigator of the TROPICAL-ACS trial, which was presented at the recent European Society of Cardiology (ESC) 2017 Congress and simultaneously published online in the Lancet.

Current guidelines recommend use of the more potent antiplatelet agents prasugrel or ticagrelor (Brilinta/Brilique, AstraZeneca) on top of aspirin for 1 year after ACS, he explained.

"But results show that the anti-ischemic benefits from such therapy occur very early on, while the bleeding risk increases over the long term," he said. "So a sensible option would be to use a potent antiplatelet therapy in the acute phase, then switch to a less potent agent (ie, clopidogrel) for the longer term."

He notes, however, that clopidogrel has a large interpatient variability in platelet inhibition, with some patients still having high platelet reactivity when taking this agent.

"So we developed an algorithm whereby all patients receive prasugrel for 1 week and are then switched to clopidogrel for 1 week. They then undergo one single platelet-function test and if they are showing good platelet inhibition on clopidogrel they continue on that drug for the long term. If the platelet test shows high platelet reactivity on clopidogrel they are switched back to prasugrel for the chronic phase."

Sibbing explained that the decision to give prasugrel for just 1 week at the start was based on data showing that platelets only survive for around 7 to 10 days, "so the platelets that have seen the ACS and are thus in an activated state will have gone after about a week."

"Patients just have to come back once at 2 weeks postdischarge for their platelet-function test and then their medication is fixed for the following year."

Sibbing reported that a large US registry study—TRANSLATE ACS—has shown that 25% of ACS patients don't complete 1 year of prasugrel or ticagrelor after ACS in clinical practice.

"This is because of either bleeding concerns or economic issues," he said. "These drugs are expensive, whereas clopidogrel is now available generically and is much cheaper. This figure of 25% who do not complete 1 year of prasugrel/ticagrelor will be much higher in less affluent regions of world, where there is simply not the funding to use these expensive drugs."

As a result, many patients are switched over to clopidogrel anyway or stop taking any agent at all, he noted. "But this is being done in a haphazard, nonscientific way. Now we have some solid scientific data to show a safe and effective way of deescalating therapy."

In the Lancet paper, the researchers conclude: "Based on all the available evidence, uniform and potent platelet inhibition in ACS patients probably remains standard of care, because TROPICAL-ACS did not show superiority of deescalation. Notwithstanding, alternative treatment concepts are desired for a significant proportion of patients in clinical practice.

"Our trial now supports the safety and efficacy of an early and guided deescalation of platelet inhibition in ACS patients as an alternative strategy that can be followed whenever necessary for medical or socioeconomic reasons," they write.

They add that "the regimen of guided treatment seems also practical beyond the framework of a randomized controlled trial, because patients in many countries worldwide typically have planned outpatient visits within the first weeks after an ACS."

For the TROPICAL-ACS trial, 2610 biomarker-positive ACS patients with successful PCI and a planned duration of dual antiplatelet treatment of 12 months were randomized to either treatment with prasugrel for 12 months (control group) or to the deescalation regimen described above.

In the deescalation group, 39% of patients were found to have high platelet reactivity on clopidogrel and so were switched back to prasugrel at the 2-week mark.

Results showed that the primary end point—net clinical benefit (cardiovascular death, MI, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) at 1 year—had occurred in 7% of patients in the guided deescalation group and in 9% of the control group. The hazard ratio was 0.81 (95% CI 0.62–1.06).

The result satisfied the noninferiority margins of 30% and the stricter secondary analysis of 10% margins. The P value for superiority was 0.12.

There was no increase in the combined risk of cardiovascular death, MI, or stroke in the deescalation group—3% in both groups—and there was a trend toward less bleeding in deescalation group, but this was not significant.

There were 64 BARC 2 or higher bleeding events (5%) in the deescalation group vs 79 events (6%) in the control group (HR 0.82, 95% CI 0.59–1.13; P=0.23).

Sibbing pointed out that a previous smaller study—the 600 patient TOPIC trial published earlier this year—looked at a similar approach but switched all patients from more potent antiplatelet agents to clopidogrel at 4 weeks. "Bleeding was reduced with this strategy, but the study was underpowered to look at ischemic events," he said.

"TROPICAL-ACS is much larger and has more power to detect ischemic end points. It was designed as a noninferiority trial to establish a suitable alternative concept for patients who are unsuitable for long-term potent platelet inhibition."

Subgroup analysis of the TROPICAL-ACS trial suggested more benefit of deescalation in STEMI patients and in those aged under 70 years. "These groups actually showed superiority of the primary end point with deescalation therapy," Sibbing noted.

The researchers suggest that these groups may have derived a net clinical benefit because they are characterized by fewer comorbidities and a lower frequency of multivessel disease when compared with NSTEMI and older patients.

Platelet-Function Testing

In an accompanying comment[2] in the Lancet, Dr Dominick J Angiolillo (University of Florida College of Medicine-Jacksonville) notes that platelet-function testing has struggled to find a space in routine clinical practice, but the TROPICAL-ACS trial could lead to its resurgence.

He points out that the strategy could be challenging to implement if patients cannot easily access centers that conduct platelet testing and the need to switch therapies twice in some cases could cause confusion. Multiple factors can contribute to variability in platelet-function testing results, so genetic testing might be a better option.

He also notes that the findings cannot be applied to elderly individuals, patients with a previous cerebrovascular event, and those with medically managed ACS, as these patients were excluded from the trial; and the findings may also not be able to be extrapolated to ticagrelor because its off-target effects are thought to contribute to its overall benefits.

But Angiolillo agrees with the TROPICAL-ACS researchers that the strategy of platelet-function testing–guided deescalation therapy might be useful in patients unsuitable for prolonged therapy with potent antiplatelet agents due to bleeding concerns and socioeconomic factors.

TROPICAL-ACS is an independent, investigator-initiated trial, with an academic sponsor (Klinikum der Universität München, Munich, Germany). The trial was financially supported by a research grant from Roche Diagnostics. Sibbing reports grants from Roche Diagnostics and Daiichi Sankyo during the conduct of the study; and personal fees from Bayer, Daiichi Sankyo, Eli Lilly, Roche Diagnostics, MSD, Pfizer, and AstraZeneca outside of the submitted work. Disclosures for the coauthors are listed in the paper. Angiollio has consulted and received honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and the Medicines Company; for participation in review activities from CeloNova and St Jude Medical; and institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry, Merck, Novartis, Osprey Medical, and Renal Guard Solutions, all outside of the area of work. In addition, he has received funding from the Scott R MacKenzie Foundation and the NIH/NCATS Clinical and Translational Science Award to the University of Florida.

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