AT ACC 15
SAN DIEGO (FRONTLINE MEDICAL NEWS) – The idea that patients with established coronary disease can derive important, secondary-prevention benefit from prolonged dual-antiplatelet therapy received a major boost with the results of a major, international, controlled trial with more than 21,000 patients.
Results from the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) showed putting post-myocardial infarction patients on dual-antiplatelet therapy (DAPT) with aspirin and the thienopyridine ticagrelor (Brilinta) for a median of 33 months cut the combined incidence of cardiovascular death, MI, or stroke by a relative 15%, compared with patients on aspirin alone as well as the other standard treatments used for post-MI patients, Dr. Marc S. Sabatine reported at the annual meeting of the American College of Cardiology.
The findings added to the growing body of evidence that long-term – and possibly lifelong – DAPT is a key part of secondary prevention. Last year, results from the DAPT (Dual Antiplatelet Therapy) trial ( N. Engl. J. Med. 2014;371:2155-66 ) supplied evidence for this in acute coronary syndrome patients who had undergone percutaneous coronary intervention (PCI). The PEGASUS-TIMI 54 trial did not require that enrolled post-MI patients had undergone PCI, but the reality is that this is the way most MI patients get managed, and in PEGASUS-TIMI 54 roughly 83% of the patients had a PCI history.
The new findings also highlighted the risk-benefit trade-off that DAPT means for patients. In PEGASUS-TIMI 54 the increased incidence of major bleeding events roughly matched the decreased rate of major cardiovascular events prevented. But while the incidence of bleeds categorized as TIMI major bleeds more than doubled in the patients randomized to DAPT compared with those on aspirin only, the prolonged treatment with ticagrelor did not result in an increase in fatal bleeds or in intracranial hemorrhages, the two most feared types of TIMI major bleeds.
“I’d much rather prevent cardiovascular deaths, MIs, and strokes even at the expense of causing reversible, nonfatal bleeding events,” said Dr. Sabatine, professor of medicine at Harvard Medical School in Boston and chairman of the TIMI Study Group at Brigham and Women’s Hospital.
Another notable adverse effect from ticagrelor treatment was a roughly threefold increased incidence of dyspnea, which led to drug discontinuation in 5%-7% of patients, depending on whether they received ticagrelor at 60 mg b.i.d. or 90 mg b.i.d. The study results showed a reduced rate of both bleeding and dyspnea in patients randomized to receive the 60-mg b.i.d. dosage, compared with those who received the 90-mg b.i.d. dosage, which is the standard ticagrelor dosage and the formulation now sold. At the same time, the efficacy of the 60-mg b.i.d. dosage for preventing ischemic events equaled that of the higher dosage. But as of today, it is impossible for a physician to prescribe a 60-mg formulation of ticagrelor because the manufacturer does not sell it.
Several cardiologists PEGASUS-TIMI 54 at the meeting said that they agreed with Dr. Sabatine and felt that the benefits from prolonged DAPT with ticagrelor outweighed the downside of an increased bleeding risk.
“I think that the benefit is greater than the risk. None of us wants to see patients experience bleeding, but I was encouraged that fatal bleeds and intracranial hemorrhages were no different,” commented Dr. Elliott M. Antman , a professor of medicine at Harvard.
“The benefits outweigh the bleeding risk, but I wouldn’t trivialize the bleeding risk. Assessing a patient’s bleeding risk is really important,” commented Dr. Robert Harrington , professor of medicine at Stanford (Calif.) University.
But others at the meeting said that the elevated bleeding risk gave them pause. “There clearly is a price to be paid even if extended-duration DAPT reduces MI and stent thrombosis. I believe only the highest risk patients – those with acute coronary syndrome and ST-elevation MI – are the ones for whom I’d even consider it. Unless we can reduce bleeding risk, maybe with even lower doses [of ticagrelor], stopping aspirin, or using a reversal agent, we will be causing bleeds that are very relevant to patients,” commented Dr. Ajay J. Kirtane , an interventional cardiologist at Columbia University in New York.
Dr. Kirtane also questioned whether TIMI major bleeds was the appropriate measure of bleeding risk in the context of a study like PEGASUS-TIMI 54. “Historically, TIMI major bleeding was derived from studies of acute heart attack patients getting fibrinolytic therapy. That is a very different population from this one. In my mind, the combination of TIMI major and minor bleeding would be more encompassing, and for patients the bleeding risks of these therapies are real and have been associated with bad sequelae,” he said in an interview.
When placed in the context of prior reports the new findings also raise the possibility that the generic, and hence much cheaper, thienopyridine clopidogrel might provide roughly the same long-term benefit as more expensive ticagrelor, especially for patients without a genetic profile that makes them poor clopidogrel metabolizers. This may be an attractive option for patients who have a problem paying for ticagrelor long term.
“I’d rather prescribe a patient a cheaper medication that might be a bit less effective than create an economic hardship,” Dr. Harrington said in an interview. The results from the DAPT trial, which included some post-PCI patients who received long-term DAPT with clopidogrel plus aspirin “give you a certain comfort” with the idea of substituting clopidogrel for ticagrelor when affordability is a major concern, Dr. Harrington noted.
PEGASUS-TIMI 54 enrolled 21, 162 patients who were 1-3 years out from a prior myocardial infarction at 1,161 sites in 31 countries. Enrolled patients also had to be at least 50 years old, and have at least one additional risk factor for ischemic events such as age 65 years or older, diabetes, multivessel coronary artery disease, or chronic renal dysfunction. The enrolled patients averaged 1.7 years out from their index MI. Randomization assigned patients to treatment with 90 mg ticagrelor b.i.d., 60 mg ticagrelor b.i.d., or placebo, and all patients also received daily treatment with 75-150 mg aspirin.
After a median follow-up of 33 months on treatment, the combined rate of cardiovascular death, myocardial infarction, or stroke – the study’s primary endpoint – occurred in 7.85% of patients on the 90-mg ticagrelor dosage, 7.77% of those on the 60-mg dosage, and in 9.04% of patients on placebo receiving aspirin only, statistically significant differences for the study’s primary endpoint for each of the two ticagrelor dosages. Concurrent with the report at the meeting the results also appeared online ( N. Engl. J. Med. 2015; [doi:10.1056/nejmoa1500857] ). This translated into hazard ratios of 0.85 for the 90 mg dosage and 0.84 for the 60 mg dosage compared with placebo.
The study’s primary safety outcome was the incidence of TIMI major bleeding events, which occurred in 2.60% of patients on the higher ticagrelor dosage, 2.30% of those on the 60 mg dosage, and in 1.06% of those on placebo, which converted into hazard ratios of 2.69 for the 90-mg dosage and 2.32 for the lower dosage for TIMI major bleeds compared with aspirin alone.
On Twitter @mitchelzoler
