Dual Antiplatelet Therapy—Good Option in High Risk Diabetes Patients

Study finds ticagrelor plus aspirin more effective in reducing ischemic cardiovascular events in patients with type 2 diabetes provided there is no heightened concern for excessive bleeding.

with Deepak L. Bhatt, MD, MPH, and Michael Bush, MD

In patients with stable coronary artery disease and type 2 diabetes who have no history of myocardial infarction (MI) or stroke, you may be able to lower their incidence of ischemic events with dual treatment of antiplatelet therapy—consisting of ticagrelor and aspirin,1 according to researchers from Brigham and Women’s Hospital Heart and Vascular Center in Boston, Massachusetts.

While the benefit of the combination treatment in preventing ischemic events is a positive outcome, the findings are tempered by a higher risk of major bleeding incidents when compared to participants receiving the aspirin alone.1

Patients with diabetes and CVD may benefit from combination anticlotting therapy.

Combination Therapy Proves Beneficial for Some Patients

“The trial results support a new option for managing high-risk patients with diabetes and extends the populations in which dual antiplatelet therapy is known to be beneficial—namely acute coronary syndromes (ACS), prior MI, and recent coronary stenting,” says corresponding author Deepak L. Bhatt, MD, MPH, who is executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital Heart and Vascular Center, in Boston, Massachusetts.

“Thus, in carefully selected patients with diabetes and stable coronary artery disease, who have a history of previous coronary stenting and have presumably tolerated dual antiplatelet therapy (DAPT) in the past without bleeding complications, the combination of ticagrelor plus low-dose aspirin should be considered,” Dr Bhatt told EndocrineWeb. He is also a professor of medicine at Harvard Medical School.

Platelet-mediated thrombosis is a “major mechanism contributing to ischemic events”—especially among patients with diabetes, which increases the risk of platelet activation.2 Treatment with aspirin alone, currently the standard therapy, “may not provide fully effective antithrombotic protection,”1 says Dr. Bhatt.

Previous studies have shown that ticagrelor—a reversible antagonist of the platelet P2Y12 receptor—can provide more consistent platelet inhibition, compared to either aspirin or clopidogrel.3 Moreover, when added to aspirin, ticagrelor has been shown to protect against cardiovascular events in patients with ACS and high-risk patients with previous MI.3,4

The authors describe the relative benefit of ticagrelor in these patients as “consistent,” regardless of whether the individual has diabetes or not.1 Findings from prior research targeting the benefits of ticagrelor in patients with diabetes and ACS or previous MI has revealed that those with diabetes may have a “large absolute benefit” from the addition of ticagrelor to aspirin. 6,7

“While the use of DAPT is known to improve outcomes in patients with ACS, prior MI, or recent coronary stenting,” says Dr Bhatt, “what was unknown is whether patients with diabetes and stable CAD—a group generally believed to be at high ischemic risk—would benefit from initiation of long-term DAPT with low-dose aspirin plus ticagrelor vs low-dose aspirin plus placebo.” These findings confirm the merits of considering this combination in suitable patients.

Combination Therapy Well Tolerated Benefit in High Risk Patients

The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS),1 was a phase 3b randomized trial designed to evaluate the efficacy and safety of ticagrelor in people with diagnosed diabetes.

The study was conducted at 1315 sites in 42 countries, enrolling 19,220 patients, ages ≥ 50 years (median age 66.0 [61.0-72.0], 31.4% female), 9619 were randomized to receive ticagrelor plus low-dose aspirin or ticagrelor plus placebo (n = 9619 and 9601 respectively). This was “the largest trial of individuals with diabetes to date,” he says.

To be considered as having “stable” CAD, patients were required to meet at least one of several criteria: a history of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG); or documentation of angiographic stenosis of ≥ 50% in at least one coronary artery.1

At the start of the trial, patients in the ticagrelor group were assigned to receive a 90-mg dose twice daily. However, the dose was reduced to 60 mg twice daily for those enrolled in the first three months and participants thereafter were given the lower ticagrelor dose, following data from another trial of ticagrelor, in which a 60-mg dose provided similar platelet inhibition but with better tolerability.8-10

The primary efficacy outcome of the THEMIS trial consisted of a composite MACE of cardiovascular death, MI, and stroke, while secondary efficacy outcomes reflected cardiovascular death, MI, ischemic stroke, and all-cause mortality; the primary safety outcome was major bleeding (as defined by the TIMI classification).10

The baseline characteristics (eg, demographics, geographic region, medical history, and comorbidities) of the overall patient cohort were “well balanced” between the 2 groups:

  • 58.0% of the patients had undergone PCI (with or without stent placement)
  • 21.8% had undergone CABG but not PCI
  • 7.0% had undergone both PCI and CABG
  • 20.2% had no history of coronary revascularization and had received only medical treatment.
  • Approximately 25.5% reported having had diabetes-related complications.
  • ≥ 50% were taking metformin
  • ≥ 20% were receiving insulin

Of the patients overall, 73.9% had enrolled prior to the reduction in the ticagrelor dose, while 26.1% were enrolled after dose reduction.

Consistent, Significant Reductions in CV Events with Dual Therapy

The addition of ticagrelor was found to be superior to placebo meeting the primary composite efficacy outcome, which occurred in 7.7% vs 8.5% of patients who received only aspirin—driven by the lower incidence of MI and stroke in the combination treatment group. The corresponding Kaplan-Meier rates were 6.9% and 7.6%, respectively, at 36 months (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.81 - 0.99; P = 0.04).

There was no significant between-group difference in the incidence of cardiovascular death (a secondary efficacy outcome); however, there were fewer MIs and fewer ischemic strokes in the ticagrelor group, compared to the placebo group. The number needed to treat to prevent one primary event at 36 months was 138, and the treatment effect was found to be consistent over time. A prespecified sensitivity analysis that accounted for the reduction in the ticagrelor dose during the trial found results consistent with those of the primary analysis.

“In the overall THEMIS trial there was a statistically significant 10% reduction in the primary efficacy endpoint, which was the rate of cardiovascular death, MI, or stroke,” Dr Bhatt told EndocrineWeb. “There were consistent and significant reductions in MI, including ST-elevation MI (STEMI), ischemic stroke and amputations or acute limb ischemia.”

Most Bleeding Events in the Ticagrelor Group Were Caused by Falls

Although the ticagrelor group showed superior efficacy outcomes, the safety of this drug fell short with a higher frequency of TIMI major bleeding found in the ticagrelor vs the placebo group (2.2% vs 1.0%; HR, 2.32 [5% CI, 1.82 to 2.94] P < 0.001). The number needed to treat at 36 months (ie, for one major bleeding event) was 93, as calculated in the modified ITT population of 19,220 patients.

Other serious adverse events occurred with slightly less frequency in the cohort receiving ticagrelor combination therapy than with aspirin alone (31.9% vs 33.7%), but certain “adverse events of interest” occurred more frequently with ticagrelor than with placebo—particularly dyspnea (21.4% vs 7.3%).

No significant difference was found between the two groups in the incidence of fatal bleeding episodes, although the number of events was higher in the ticagrelor group.

On the other hand, intracranial hemorrhage occurred more often in patients taking the ticagrelor and aspirin than those in the placebo arm (0.7% vs 0.5%; HR, 1.71 [95% CI, 1.18 - 2.48] P = 0.005)—a difference driven by traumatic intracranial hemorrhages (41 vs.16 events). The authors emphasize that there was no significant between-group difference in the number of spontaneous or procedural events (28 vs 27, and 1 vs 3, respectively).

Dr Bhatt says that there was a “statistically significant increase in major bleeding in THEMIS, including a small but statistically significant 0.2% excess intracranial bleeding with DAPT.” However, these bleeding events consisted largely of traumatic subdural hematomas, mostly from falls.

Ticagrelor Performed Best in Patients with Previous PCI

Dr Bhatt also discussed findings of the THEMIS-PCI trial,12 “which was designed prospectively to examine those patients who specifically had a history of previous PCI.” This trial consisted of 58% of patients from the overall THEMIS trial who had a previous percutaneous coronary intervention (PCI) prior to enrollment (n=11,154). Patients were followed for a median of 3.3 years (IQR 2.8-3.8).

In this population, the benefit conferred by ticagrelor found in the overall trial was “amplified,” with a 15% reduction in the primary efficacy endpoint and no signal of excess intracranial bleeds (31 vs 33 events), he says. Moreover, although major bleeding was still significantly increased, the excess bleeding was not as great as that seen in the THEMIS patients without a history of PCI.

“Thus, in carefully selected patients with diabetes and stable CAD who have a history of previous coronary stenting an have presumably tolerated DAPT in the past without bleeding complications, the combination of ticagrelor plus low-dose aspirin should be considered,” confirms Dr. Bhatt.

Consider Risk of Cardiovascular Events vs Bleeding on a Case-by-Case Basis

Michael Bush, MD, FACE, clinical chief of endocrinology at Cedars-Sinai Medical Center, in Los Angeles, California, says: “any study trying to deal with reducing cardiovascular disease in diabetes patient is important because of their higher incidence of heart attack and cardiovascular events.”

The study makes an important contribution to the field because of its large size and because it “focused on a high-risk group of people with diabetes and stable cardiovascular disease with the purpose of determining how to prevent high-risk outcomes in this group,” he says.

Dr. Bush, also a clinical associate professor at the Geffen School of Medicine at the University of California in Los Angeles, offers this take-home message for practitioners.

“This study showed that for antiplatelet and anticoagulant use in patients with diabetes, it is essential to look at individual patients and weigh their risk factors for both cardiovascular events and bleedings. Individual doctors must make the best choice for individual patients on a case-by-case basis,” he tells EndocrineWeb.

Make Sure Patients Are Not At Elevated Risk of Bleeding

Dr. Bhatt says that he and his colleagues are “assessing how generalizable the results of THEMIS and THEMIS-PCI may be. Our initial results suggest that there are many patients such as those in THEMIS-PCI who may benefit from this strategy of more intense anti-thrombotic therapy than just aspirin alone.”

However, he cautions, “the key is making sure that patients are not at elevated risk of bleeding, in which case this strategy of more intense and prolonged anti-thrombotic therapy can backfire.”

On the other hand, in patients at low bleeding risk, “this approach may provide a substantial reduction in ischemic events involving the heart, brain, and peripheral circulation as well.” The best candidates for this approach, he suggests, are patients with prior PCI because “they would have, of course, already been exposed to a period of DAPT previously at the time of stenting.”

Moreover, “contemporary data show that patients with diabetes and stable CAD, but without a history of MI, are the same level of ischemic risk as patients with a history of prior MI but without diabetes—thus, there is a large unmet clinical need in these patients,” he concludes.

Dr. Bhatt reports research funding from AstraZeneca was granted to Brigham and Women’s Hospital to support two trials: THEMIS and THEMIS-PCI. Dr. Bush has no relevant disclosures.

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