PHARMCLO: Biggest Genotyping Trial to Date Suggests Better Outcomes After ACS, With Caveats
Several experts were disappointed that the trial was stopped early due to a regulatory issue, but remain hopeful that another study can be done.
ORLANDO, FL—The largest randomized trial to date testing bedside genotyping to guide antiplatelet therapy decisions shows that such an approach is feasible and may reduce the risk of ischemic events and bleeding. Investigators say, however, that the trial’s early halt for regulatory reasons left it underpowered and as such the findings shouldn’t have an impact on guidelines.
Presenting results of the PHARMCLO study as a late-breaking clinical trial at the American College of Cardiology 2018 Scientific Session the day after pharmacogenomic testing was shown to influence prescriber behavior in the ADAPT study, Diego Ardissino, MD (Azienda Ospedaliero-Universitaria di Parma, Italy), told TCTMD that with the current evidence, “we cannot conclude that this is really something that we should bring into everyday clinical practice.”
For the study, which was simultaneously published in the Journal of the American College of Cardiology, Ardissino along with Francesca Maria Notarangelo, MD (Azienda Ospedaliero-Universitaria di Parma), and colleagues intended to randomize 3,600 Italian patients with ACS beginning in June 2013 to undergo bedside genotyping or usual care and determine the effect on clinical outcomes over a year. After 888 patients were enrolled, regulators prematurely closed the study in February 2015 due to a “lack of in vitro diagnosis certification” for the genotyping instrument used, Ardissino explained.
Compared with those in the standard care arm, patients in the pharmacogenomic arm were less likely to received clopidogrel (43.3% vs 50.7%) and more likely to be prescribed prasugrel or ticagrelor (50.2% vs 41.1%; P = 0.02 overall).
At 1 year, patients who underwent genotyping were half as likely to have a primary composite endpoint event (cardiovascular death, nonfatal MI, nonfatal stroke, or BARC 3-5 major bleeding) compared with patients receiving usual care (15.9% vs 25.9%; HR 0.58; 95% CI 0.43-0.78). This was driven by a reduction in nonfatal MI in the genotype group (4.6% vs 10.7%; HR 0.42; 95% CI 0.25-0.70); there were no significant differences in any of the other individual endpoints. The results were maintained among only patients on clopidogrel (24.7% vs 35.4%; HR 0.68; 95% CI 0.47-0.97).
The mean patient age among the enrolled study population was 70.9 years and more than one-quarter of patients were older than 80 years. Additionally, 21.5% reported a previous MI, 27.5% were hospitalized for STEMI, and 96.3% underwent coronary angiography.
High-risk Population Sought After
Discussing the findings after their presentation, panelist Glenn Levine, MD (Baylor College of Medicine, Houston, TX), said he was “very much gratified” to see such a study undertaken given that both US and European guidelines classify genetic testing with a class III recommendation due to the lack of outcomes data.
But given the power of the study, Levine said he was surprised by the magnitude of benefit observed between the study arms in terms of the primary endpoint. “In PLATO and TRITON, in which all the patients were randomized to a different therapy, there was only a 2% absolute difference between the groups, and in all the studies of point-of-care platelet inhibition and tailored therapy, there was actually no benefit,” Levine noted. “So your 8% absolute reduction is striking [given] these other studies.”
Not dismissing the role of chance in their results, Ardissino said the fact that more patients in the pharmacogenomic arm received ticagrelor could have influenced the findings. But it’s also possible that “we simply underestimated the effect size,” he commented. “When you go into personalized medicine, the effect size is much larger than what we are used to.”
Also commenting during the late-breaking clinical trials session, J. Dawn Abbott, MD (Brown University, Providence, RI), said it is “very unfortunate that the trial had to be stopped early due to a regulatory issue.” One thing of note with PHARMCLO, she observed, “is the inclusion of a broad population of patients that are normally not included in randomized trials, in particular the elderly. I wonder if some of the findings are due to that fact, and that these patients may be overtreated or their risk of bleeding or ischemic events not assessed appropriately.”
Ardissino agreed, adding that his team originally set out to enroll a high-risk population because with this group it “is more likely that the genetic data will improve your clinical judgement and therefore the selection of antiplatelet therapy.”
Robert DiDomenico, PharmD (The University of Illinois at Chicago), who was not involved with the study, told TCTMD that the because the study was stopped early and was underpowered to look at clinical events, the PHARMCLO data disappointingly leaves unanswered some important questions: “Do we have enough evidence? Is this strong enough or compelling enough based on the small sample size?”
The “naysayers for personalized medicine” are going to point to this study and the lack of other evidence to support their platform, he added. Still, “I think it's probably the strongest evidence so far to suggest that personalizing therapy actually makes a difference in outcomes.”
Several ongoing trials with findings expected in 2020 will hopefully give a bit more confirmation, Ardissino said.
A concern DiDomenico has now is increasing the use of genotyping of this kind in the United States, where it is “very center-specific” at the moment with only a “couple dozen” institutions conducting this kind of testing on a regular basis today, he said.
His institution has been conducting genotyping for clopidogrel, warfarin, and “a variety of other things” for about 10-15 years now, he said. However, “pharmacists have been the ones to really adapt it and learn the science, and the physicians have been a little slow.” It’s also possible that physicians have thought the information was interesting, but felt there was little they could do with it given there were previously few P2Y12 inhibitor options other than clopidogrel.
But with new data released in the past 6-8 months and the fact that “it’s becoming a little easier to use [prasugrel and ticagrelor] from an insurance perspective,” DiDomenico said, many physicians have now “really caught onto this” and are “jumping in the deep end, so to speak.”
Notarangelo FM, Maglietta G, Bevilacqua P, et al. Pharmacogenomic approach to selecting antiplatelet therapy in acute coronary syndromes: PHARMCLO trial. J Am Coll Cardiol. 2018;Epub ahead of print.
- This scientific project was approved by the Health Authority of Regione Emilia Romagna and was supported by “Programma di Ricerca Regione – Università, Regione Emilia Romagna, bando 2010–2012– Area 2 Ricerca per il Governo clinico”.
- Notarangelo, Ardissino, and DiDomenico report no relevant conflicts of interest.