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THEMIS: Ticagrelor-aspirin DAPT may benefit selected patients with diabetes, stable CAD
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PARIS — Ticagrelor added to low-dose aspirin reduced the incidence of ischemic events in patients with stable CAD and diabetes without a history of MI or stroke, but increased major bleeding compared with aspirin alone, according to results of the THEMIS trial presented at the European Society of Cardiology Congress.
Moreover, in the THEMIS-PCI prespecified subgroup analysis looking at patients with a history of PCI, dual antiplatelet therapy with ticagrelor (Brilinta, AstraZeneca) and aspirin reduced CV death, MI and stroke, although with increased bleeding.
Taken together, the results suggest that a strategy of long-term DAPT with ticagrelor and aspirin may be beneficial in selected patients at low risk for bleeding but with high risk for ischemic events, and in those who have undergone previous PCI, particularly with drug-eluting stents, the THEMIS investigators concluded.
Diabetes and stable CAD population
THEMIS was a randomized, double-blind trial that investigated whether ticagrelor added to aspirin would improve outcomes compared with aspirin alone in patients with CAD (history of PCI, CABG or angiographic stenosis 50%) and type 2 diabetes who were receiving hyperglycemic medications for at least 6 months, but no history of MI or stroke.
In total, 19,220 patients in 42 countries were randomly assigned to receive twice-daily ticagrelor 90 mg or matching placebo, in addition to aspirin 75 mg to 150 mg. The median age was 66 years and 31% were women.
Over a median follow-up of 39.9 months, the primary efficacy outcome — a composite of CV death, MI or stroke — occurred in 7.7% of patients assigned ticagrelor vs. 8.5% assigned placebo (HR = 0.9; 95% CI, 0.81-0.99).
However, the primary safety outcome — TIMI major bleeding — was higher with ticagrelor treatment, at 2.2% vs. 1% (HR = 2.32; 95% CI, 1.82-2.94). Patients assigned ticagrelor also had a higher incidence of PLATO major bleeding (3.2% vs. 1.5%; HR = 2.41; 95% CI, 1.98-2.93), BARC 3, 4 or 5 bleeding (3.6% vs. 1.7%; HR = 2.36; 95% CI, 1.96-2.84) and intracranial hemorrhage (0.7% vs. 0.5%; HR = 1.71; 95% CI, 1.18-2.48).
Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, professor of medicine at Harvard Medical School and Cardiology Today Editorial Board Member, noted at a press conference that the excess was related to traumatic subdural hematomas, rather than spontaneous or procedural intracranial hemorrhage.
The incidence of fatal bleeding was not significantly different (0.2% vs. 0.1%; HR = 1.9; 95% CI, 0.87-4.15).
The researchers also analyzed the incidence of an exploratory composite outcome of irreversible harm, defined as death from any cause, MI, stroke, fatal bleeding or intracranial hemorrhage, which occurred in 10.1% of the ticagrelor group vs. 10.8% of the placebo group (HR = 0.93; 95% CI, 0.86-1.02).
Patients assigned ticagrelor had a higher rate of permanent treatment discontinuation compared with those assigned placebo (34.5% vs. 25.4%).
During enrollment, the initial 90 mg ticagrelor dose was reduced to 60 mg twice daily due to emerging data on tolerability from the PEGASUS-TIMI 54 trial, according to Bhatt. About three-quarters of patients were enrolled before dose reduction.
The THEMIS data were published simultaneously in The New England Journal of Medicine.
PCI population
THEMIS-PCI was a prespecified subgroup analysis in patients with stable CAD and diabetes who had previous PCI. This analysis focused on 11,154 patients (58% of the THEMIS population) who had a history of PCI.
During follow-up, the primary efficacy outcome occurred in 7.3% of the ticagrelor group vs. 8.6% of the placebo group (HR = 0.85; 95% CI, 0.74-0.97). However, when the researchers restricted their analysis to patients without a history of PCI, the reduction in ischemic events was not observed (P =.76; P for interaction = .16), P. Gabriel Steg, MD, FESC, director of the coronary care unit in the cardiology department at Hôpital Bichat, Paris, professor of cardiology at the Université Paris – Diderot, said during a press conference.
Patients assigned ticagrelor or placebo had similar rates of CV death (3.1% vs. 3.3%; HR = 0.96; 95% CI, 0.78-1.18) and all-cause death (5.1% vs. 5.8%; HR = 0.88; 9% CI, 0.75-1.03).
TIMI major bleeding occurred in 2% of patients assigned ticagrelor vs. 1.1% of patients assigned placebo (HR = 1.03; 95% CI, 1.48-2.76). Rates of fatal bleeding (0.1% vs. 0.1%; HR = 1.13; 95% CI, 0.36-3.5) and intracranial hemorrhage (0.6% vs. 0.6%; HR = 1.21; 95% CI, 0.74-1.97) were not significantly different, according to the results.
The THEMIS-PCI researchers also examined net clinical benefit, defined as all-cause death, MI, stroke, fatal bleeding or intracranial hemorrhage, and found that ticagrelor improved net clinical benefit in those with a history of PCI (9.3% vs. 11%; HR = 0.85; 95% CI, 0.75-0.95), but there was no improvement in patients who did not undergo PCI (P for interaction = .012).
According to the researchers, this benefit was present regardless of time since PCI.
Moreover, in a prespecified analysis that looked at patients with previous drug-eluting stent implantation, in particular, the primary efficacy endpoint was higher in those who received placebo (6.9% vs. 8.6%; HR = 0.79; 95% CI, 0.67-0.94).
“This suggests that long-term therapy with ticagrelor in addition to aspirin is a new option for patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischemic risk and low bleeding risk,” Steg said during the press conference.
The THEMIS-PCI data were published simultaneously in The Lancet.
Patient identification
Speaking with Cardiology Today, Bhatt said “it is important to identify patients in whom the magnitude of benefit and net clinical benefit justify the actual clinical use.
“We think we found that with the THEMIS-PCI population. In those patients with diabetes and stable CAD who specifically had a history of previous PCI and presumably had been on DAPT before and tolerated it without bleeding or other issues, that appears to be the ideal population to consider the initiation of ticagrelor on top of aspirin or, potentially, though not directly studied in our trial, continuation of DAPT if they’re already on it.”
In a related editorial published in NEJM, Eric R. Bates, MD, professor of internal medicine at the University of Michigan, noted that THEMIS and the overall PARTHENON program have made great strides in research on antiplatelet therapy and atherothrombosis.
“It may be possible to identify individual patients who have an increased risk of thrombotic events and a reduced risk of bleeding for whom this trade-off may be advantageous. But for most patients with type 2 diabetes and known coronary disease who fit the THEMIS enrollment criteria, the addition of ticagrelor to aspirin is not recommended,” Bates wrote. – by Katie Kalvaitis
References:
Bhatt DL, et al. Hot Line Session 1. Presented at: European Society of Cardiology Congress; Aug. 31-Sept. 4, 2019; Paris.
Bates ER. N Engl J Med. 2019;doi:10.1056/NEJMe1910813.
Bhatt DL, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)31887-2.
Steg PG, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908077.
Disclosures: THEMIS and THEMIS-PCI were funded by AstraZeneca. Bhatt reports he received research finding from AstraZeneca; see the full study for Bhatt’s other relevant financial disclosures. Steg reports he has research contracts with AstraZeneca, Amarin, Bayer, Sanofi and Servier, and other ties with Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi and Servier.
Perspective
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Richard Becker, MD
The history of ticagrelor spans over 2 decades with a focused goal to develop a drug that targets the platelet P2Y12 receptor, activated by ADP. The initial construct was treatment on a background of aspirin, a standard of care, always being mindful of safety. That led to a series of investigations and, a decade ago, the PLATO trial (Wallentin L, et al. N Engl J Med. 2009;doi:10.1056/NEJMoa0904327).
The PLATO population included patients with ACS, with or without STEMI, in a head-to-head comparison with clopidogrel, both on a background of aspirin. PLATO showed a reduction in CV death, MI or stroke with ticagrelor with no increase in overall major bleeding, but an increase in non-procedure-related bleeding.
At that time, the cardiology community felt fairly confident that for patients with unstable coronary disease, that the combination of aspirin and a P2Y12 inhibitor was optimal care and the data still support that approach.
In THEMIS, the question was around the efficacy and safety of ticagrelor in patients with stable CAD and diabetes, without prior MI or stroke. Do we need DAPT in those patients or would monotherapy be sufficient? The THEMIS trial investigated a highly prevalent patient population, one that is rapidly increasing in the era of obesity, inactivity and type 2 diabetes. This is a population for which we are still trying to define optimal therapy.
In the prespecified THEMIS-PCI cohort, the question of duration of DAPT in a patient who experienced a prior PCI with a stent is still open to discussion. Management guidelines reflect clinical trials, clinician experience and patient values and preferences. Thus, variability is common: 1 year, 18 months, 3 months?
The cardiology community has particular interest in the THEMIS- PCI pre-specified subgroup analysis of patients with prior PCI who received drug-eluting stents. The composite endpoint of CV death, MI or stroke was reduced with ticagrelor plus aspirin when compared with monotherapy, though with the signal of bleeding. One should never minimize the importance of bleeding; however, it is reassuring to see that the rates were not significantly different between groups for intracranial hemorrhage or fatal bleeding.
The primary message for clinicians is that patients with prior PCI at high ischemic risk and moderate to low bleeding risk, a strategy of aspirin 100 mg or less and ticagrelor 60 mg once daily offers benefit.
Perspective
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Richard Kovacs, MD, FACC
This was well done, well written, a good-sized trial and was adequately powered to draw a conclusion.
We continue to need more knowledge on who should be on DAPT and who shouldn’t be on DAPT to reduce risk. The challenge in general is that the size of the diabetes population is increasing. The interaction between cardiologists and diabetologists is also increasing with all of the overlap between the different therapies and the need to reduce risk in this particular population.
The NEJM editorial by Eric Bates, MD, really sums up THEMIS nicely. What we know is that we can reduce risk by inhibiting platelets with more potent antiplatelet therapies, or DAPT, in this instance. However, that reduction in CV risk comes with an increase in bleeding risk. What we have to decide, as clinicians with the patient in front of us, is how to inform the patient that we are going to reduce ischemic risk but that there is a downside risk of bleeding, and how to make that informed decision. Now we have another large sample of patients from a large trial where we further understand the equation.
I still think we need to understand how to have that conversation about bleeding risk with the patient, and to be able to better identify those at high bleeding risk and those at low bleeding risk so we can take advantage of the clinical benefits and minimize the clinical risk.
Perspective
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Robert A. Harrington, MD
These results are really interesting in the sense that we thought about that in the beginning. I’m also one of the study chairs along with Lars Wallentin, MD, PhD, for the original PLATO trial that’s now 10 years ago at this meeting that we presented the results of that, which was really the first trial that showed that ticagrelor improved clinical outcomes relative to standard therapy, This has been a long journey with ticagrelor. With this particular question, it was really asking — and we knew from the earlier studies that the group of patients who’ve had prior PCI, they may well be different than the group of patients with stable coronary disease but without prior PCI for a variety of biologic reasons that might be true. At the beginning when the trial was being planned, we very purposely said we really want to get a lot of patients who’ve had a prior PCI. It was one of the entry criteria, but we didn’t want to only get those patients. The overall trial enrolled over 19,000 patients, but the PCI subset is over 11,000 patients, so it’s a big subset. In the overall trial, there is a modest effect of the benefit of ticagrelor over placebo in patients with stable coronary disease, but in the group of patients with PCI, that’s where all the benefit is. In the group of patients without PCI, there does not appear to be a benefit, only risk. What it says is that if you’re somebody who’s had coronary disease defined by having had a prior coronary intervention, longer-term treatment with ticagrelor relative to coming off dual antiplatelet therapy at some point definitely looks beneficial. That’s big news. That’s a trial that can be implemented tomorrow because the drug is available.
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