Next Gen Innovators

Next Gen Innovators

January 21, 2019
4 min read

Off-label use of newer P2Y12 inhibitors common in stable ischemic heart disease

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact

Jay Giri
Jay Giri

More than one-third of patients without ACS who underwent PCI were prescribed prasugrel or ticagrelor between 2009 and 2016, but data are limited on their benefits in stable ischemic heart disease, according to a research letter published in Circulation: Cardiovascular Interventions.

“We have observed in our clinical practice that patients with stable ischemic heart disease who undergo PCI are sometimes prescribed prasugrel or ticagrelor, despite no guidelines or clinical trial evidence supporting the use of these drugs outside of ACS. We thus wanted to look into how commonly prasugrel and ticagrelor were being prescribed off-label for stable ischemic heart disease patients receiving elective PCI,” Elias J. Dayoub, MD, MPP, from the Corporal Michael J. Crescenz VA Medical Center and fellow in the National Clinician Scholars Program and associate fellow at the Leonard Davis Institute of Health Economics at the Perelman School of Medicine at the University of Pennsylvania, wrote in an email to Cardiology Today’s Intervention.

Increased use in stable ischemic heart disease

Using data from OptumInsight Clinformatics Data Mart, a U.S. commercial health insurance database, Dayoub and colleagues analyzed claims data from 42,683 adults younger than 64 years who filled a P2Y12 inhibitor prescription within 30 days after PCI.

Of these patients, 16% did not have an ACS indication for PCI. Among patients without ACS, those filling a clopidogrel prescription decreased from 99% to 66% after PCI from 2009 to 2016. In contrast, patients without ACS who filled a prasugrel (Effient, Daiichi Sankyo/Eli Lilly) or ticagrelor (Brilinta, AstraZeneca) prescription increased from 1% to 34%, according to the data.

A similar trend was observed among patients with ACS, with the proportion of patients filling a clopidogrel prescription decreasing from 98% to 52% and the proportion of patients filling a prasugrel or ticagrelor prescription increasing from 2% to 48% during the study period.

“We were surprised to find that, by 2016, more than 1 in 3 patients undergoing elective PCI were prescribed prasugrel or ticagrelor, given there is no strong evidence to support the use of prasugrel or ticagrelor in patients with stable ischemic heart disease,” Dayoub said.

Jay S. Giri, MD, MPH, director of peripheral intervention and assistant professor of medicine at the Hospital of the University of Pennsylvania, was a fellow researcher on the study. He noted that he was less surprised to see a substantial and increasing proportion of patients receiving these potent antiplatelet agents in stable CAD before the completion of trials in this setting.

“There will be some who state that this is all a consequence of marketing, and I’m sure that has some influence. But in reality, I bet the rationale underlying this finding is more complex,” Giri, who is also a Cardiology Today Next Gen Innovator, wrote in an email to Cardiology Today’s Intervention. “There are a number of reasons a cardiologist may choose these agents over clopidogrel in stable CAD. These might include: abnormal clopidogrel metabolism, which can be assessed with a genetic test; complicated anatomical features such as long stent length, use of atherectomy and bifurcation stenting; or a stent in a location that represents a catastrophic risk if stent thrombosis were to occur. For example, I recently placed a left main coronary artery stent in a patient who was an intermediate clopidogrel metabolizer. I doubt there are many practitioners out there who would feel comfortable using clopidogrel as their preferred P2Y12 inhibitor in this clinical circumstance regardless of the current absence of randomized trial data justifying more potent antiplatelet therapy for this patient.”

This study was not without limitations, including its retrospective design and use of administrative claims, according to the researchers. Primary clinical data were also unavailable, as were detailed anatomic data and phenotypic or genotypic assessment of platelet reactivity. The study population also only included commercially insured patients and excluded elderly patients.

Concerns for clinical practice

Dayoub, Giri and colleagues previously performed a study of adherence in patients prescribed prasugrel or ticagrelor vs. clopidogrel.

“Our past study found PCI patients prescribed prasugrel or ticagrelor, when compared with clopidogrel, have lower rates of adherence and experience higher out-of-pocket costs; thus, we recommend physicians be judicious when prescribing these newer antiplatelet agents for off-label indications,” Dayoub said.

Potential drivers for increased use of prasugrel and ticagrelor include increasing physician comfort with these medications and extension of trial results in patients with ACS to those with stable ischemic heart disease, but more information is necessary, the researchers noted.

“It would be helpful to identify what is driving off-label use of prasugrel and ticagrelor in stable ischemic heart disease. While we suspect clinicians may be selecting higher-risk patients to receive newer, more potent P2Y12 inhibitors, it is unclear if other factors are being considered when prescribing these agents off-label. Moreover, studies like the ongoing ALPHEUS trial will help determine the role of newer P2Y12 inhibitors for elective PCI, and perhaps provide the evidence to support their use in patients with stable ischemic heart disease,” Dayoub wrote in his email.

“Until we have good evidence to support the use of prasugrel or ticagrelor in stable ischemic heart disease, clinicians should be prudent in prescribing these medications off-label, especially given the cost and adherence implications that may exist for some patients.”

Giri also added that considering the whole patient is key to optimizing treatment.

“I think that interventional cardiologists should continue to individualize their decision making regarding antiplatelet therapy based on a patient’s unique risk/benefit ratio of bleeding to future ischemic events. However, I completely agree with Elias that an additional and equally important part of this personalized strategy must account for a patient’s ability to obtain and afford a potentially more expensive medication,” he told Cardiology Today’s Intervention. “While we as a CV community spend a lot of time trying to gain a more nuanced understanding of the former issue, in my experience comparatively little attention is given to the effect of patients’ unique pharmacoeconomic considerations on their risk of future clinical events.” – by Melissa Foster

For more information:

Elias J. Dayoub, MD, MPP, can be reached at; Twitter: @elias_dayoub.

Jay Giri, MD, MPH, can be reached at; Twitter: @jaygirimd.

Disclosures: The authors report no relevant financial disclosures.