SNOWMASS, COLO. – Think very carefully before extending the duration of dual antiplatelet therapy beyond 6 months in drug-eluting stent recipients with stable ischemic heart disease, Patrick T. O’Gara, MD, advised at the Annual Cardiovascular Conference at Snowmass.
Six months of dual antiplatelet therapy (DAPT) in this setting received a Class I recommendation in the 2016 American College of Cardiology/American Heart Association guideline focused update on DAPT duration (J Am Coll Cardiol. 2016 Sep 6;68[10]:1082-115). That’s a departure from previous guidelines, which recommended 12 months of DAPT. The shortened DAPT duration of 6 months is consistent with European Society of Cardiology recommendations.
In contrast, extending DAPT beyond the 6-month mark garnered a relatively weak Class IIb recommendation in the ACC/AHA focused update, meaning it “could be considered,” noted Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
Considerable enthusiasm for extending DAPT well beyond 6 months after drug-eluting stent implantation has been generated in some quarters by the positive results of the PEGASUS TIMI 54 trial. But Dr. O’Gara and the other members of the guideline writing committee had reservations about the study, which together with other concerning evidence led to the weak Class IIb recommendation.
PEGASUS TIMI 54 included 21,162 patients with stable ischemic heart disease 1-3 years after a myocardial infarction who were randomized to low-dose aspirin plus either placebo or ticagrelor (Brilinta) at 60 mg or 90 mg b.i.d. and followed prospectively for a median of 33 months (N Engl J Med. 2015 May 7;372[19]:1791-800).
The primary efficacy endpoint, a composite of cardiovascular death, MI, or stroke, occurred in 9.0% of placebo-treated patients, compared with 7.8% of patients on either ticagrelor regimen, for a statistically significant 15% relative risk reduction in the DAPT group.
But there is more to the study than first meets the eye.
“I think what we as practitioners sometimes lose track of is that the investigators in this particular trial were very careful to enroll patients with stable ischemic heart disease who were at high risk of ischemic events over the next 3-5 years,” Dr. O’Gara noted. “These were patients who were generally older, patients with diabetes, chronic kidney disease, multivessel coronary disease, or who had had a second MI.”
Thus, the deck was stacked in favor of obtaining a result showing maximum efficacy. Yet, for every 10,000 patients treated with ticagrelor at 90 mg b.i.d., there were only 40 fewer cardiovascular events per year, compared with placebo. And that came at a cost of 41 more TIMI major bleeding events.
“That’s a wash at 90 mg,” the cardiologist said.
At 60 mg b.i.d. – the dose ultimately approved by the Food and Drug Administration – there were 42 fewer primary cardiovascular events per year per 10,000 treated patients, a benefit that came at the expense of 31 more TIMI major bleeding events.
“These are really razor thin margins, and I would encourage you to make a risk-benefit assessment of the trade-off between ischemia and bleeding in your decision-making,” Dr. O’Gara said.
The ACC/AHA guideline writing committee also took into account a meta-analysis of six randomized clinical trials totaling more than 33,000 high-risk patients post-MI who were assigned to more than 1 year of DAPT or aspirin alone. Extended DAPT brought a 22% reduction in the relative risk of major adverse cardiovascular events, but this was accompanied with a 73% increase in the risk of major bleeding (Eur Heart J. 2016 Jan 21;37[4]:390-9).
Turning to DAPT duration post-PCI in patients with an acute coronary syndrome, Dr. O’Gara noted that the 2016 ACC/AHA guideline focused update gave a Class I indication for 12 months of DAPT in recipients of a drug-eluting stent, but a weaker IIb recommendation for consideration of extending DAPT beyond that point – provided the patient was not at high bleeding risk and didn’t have significant bleeding during the first 12 months on DAPT.
“I think there’s a lot of individual and institutional variation with respect to this kind of decision-making, and I don’t think our guidelines are meant to be proscriptive, because our patients are quite nuanced,” the cardiologist observed.
The question physicians always have to ask in considering extended DAPT is, “How many ischemic events am I going to prevent at the expense of how many bleeding events?”
The investigators in the landmark DAPT study of extended therapy have analyzed their data in a fashion that has enabled them to develop a risk scoring system, known as the DAPT prediction rule, which is readily calculated based on factors including age, presence of diabetes, heart failure, and the size of the treated vessel.
For patients with a high DAPT score, assignment to an additional 18 months of DAPT after the initial 12 months of dual therapy was associated with a net 1.67% reduction in adverse events – both ischemic and bleeding – compared with the rate in patients who stopped DAPT at 12 months. For those with a low DAPT score, extended dual antiplatelet therapy resulted in a 1.03% net increase in adverse events (JAMA. 2016 Apr 26;315[16]:1735-49).
“I should warn you that the discriminatory power of this particular score is relatively modest,” Dr. O’Gara noted. “The C-statistic is not higher than about 0.7. But I do think that the DAPT score meets the sniff test biologically and clinically. It’s a real good first step. I do think this particular score needs to be validated externally in other populations going forward.”
Dr. O’Gara reported having no financial conflicts of interest.