BRILINTA (Page 6 of 8)

14.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction

THEMIS

The THEMIS study (NCT01991795) was a double-blind, parallel group, study in which 19,220 patients with CAD and Type 2 Diabetes Mellitus (T2DM) but no history of MI or stroke were randomized to twice daily BRILINTA or placebo, on a background of 75-150 mg of aspirin. The primary endpoint was the composite of first occurrence of CV death, MI, and stroke. CV death, MI, ischemic stroke, and all-cause death were assessed as secondary endpoints.

Patients were eligible to participate if they were ≥ 50 years old with CAD, defined as a history of PCI or CABG, or angiographic evidence of ≥ 50% lumen stenosis of at least 1 coronary artery and T2DM treated for at least 6 months with glucose-lowering medication. Patients with previous intracerebral hemorrhage, gastrointestinal bleeding within the past 6 months, known bleeding diathesis, and coagulation disorder were excluded. Patients taking anticoagulants or ADP receptor antagonists were excluded from participating, and patients who developed an indication for those medications during the trial were discontinued from study drug.

Patients were treated for a median of 33 months and up to 58 months.

Patients were predominantly male (69%) with a mean age of 66 years. At baseline, 80% had a history of coronary artery revascularization; 58% had undergone PCI, 29% had undergone a CABG and 7% had undergone both. The proportion of patients studied in the US was 12%. Patients in THEMIS had established CAD and other risk factors that put them at higher cardiovascular risk.

BRILINTA was superior to placebo in reducing the incidence of CV death, MI, or stroke. The effect on the composite endpoint was driven by the individual components MI and stroke; see Table 9.

Table 9 — Primary composite endpoint, primary endpoint components, and secondary endpoints (THEMIS)
*
Primary endpoint
The event rate for the components CV death, MI and stroke are calculated from the actual number of first events for each component.
BRILINTA N=9619

Placebo N=9601

HR (95% CI)

p -value

Events / 1000 patient years

Events / 1000 patient years

Time to first CV death, MI, or stroke *

24

27

0.90 (0.81, 0.99)

0.04

CV death

12

11

1.02 (0.88, 1.18)

Myocardial infarction

9

11

0.84 (0.71, 0.98)

Stroke

6

7

0.82 (0.67, 0.99)

Secondary endpoints

CV death

12

11

1.02 (0.88, 1.18)

Myocardial infarction

9

11

0.84 (0.71, 0.98)

Ischemic stroke

5

6

0.80 (0.64, 0.99)

All-cause death

18

19

0.98 (0.87, 1.10)

CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; MI = Myocardial infarction.

The Kaplan-Meier curve (Figure 15) shows time to first occurrence of the primary composite endpoint of CV death, MI, or stroke.

Figure 15 — Time to First Occurrence of CV death, MI or Stroke (THEMIS)

figure_15
(click image for full-size original)

T = Ticagrelor; P = Placebo; N = Number of patients.

The treatment effect of BRILINTA appeared similar across patient subgroups, see Figure 16.

Figure 16 – Subgroup analyses of ticagrelor (THEMIS)

figure_16
(click image for full-size original)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

14.3Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

THALES

The THALES study (NCT03354429) was a 11016-patient, randomized, double-blind, parallel-group study of BRILINTA 90 mg twice daily versus placebo in patients with acute ischemic stroke or transient ischemic attack (TIA). The primary endpoint was the first occurrence of the composite of stroke and death up to 30 days. Ischemic stroke was assessed as one of the secondary endpoints.

Patients were eligible to participate if they were ≥40 years old, with non-cardioembolic acute ischemic stroke (NIHSS score ≤5) or high-risk TIA (defined as ABCD2 score ≥6 or ipsilateral atherosclerotic stenosis ≥50% in the internal carotid or an intracranial artery). Patients who received thrombolysis or thrombectomy within 24 hours prior to randomization were not eligible.

Patients were randomized within 24 hours of onset of an acute ischemic stroke or TIA to receive 30 days of either BRILINTA (90 mg twice daily, with an initial loading dose of 180 mg) or placebo, on a background of aspirin initially 300-325 mg then 75-100 mg daily. The median treatment duration was 31 days.

BRILINTA was superior to placebo in reducing the rate of the primary endpoint (composite of stroke and death), corresponding to a relative risk reduction (RRR) of 17% and an absolute risk reduction (ARR) of 1.1% (Table 10). The effect was driven primarily by a significant reduction in the stroke component of the primary endpoint (19% RRR, 1.1% ARR).

Table 10 — Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoint (THALES)
*
The number of patients with the event of interest. In the time to first stroke, patients who died are censored at the time of death.
BRILINTA N=5523

Placebo N=5493

HR (95% CI)

p -value

n (patients

with event)

KM%

n (patients

with event)

KM%

Time to first Stroke or Death

303

5.4%

362

6.5%

0.83 (0.71, 0.96)

0.015

Time to first Stroke *

284

5.1%

347

6.3%

0.81 (0.69, 0.95)

Time to Death *

36

0.6%

27

0.5%

1.33 (0.81, 2.19)

Secondary Endpoint

Time to first Ischemic Stroke

276

5.0%

345

6.2%

0.79 (0.68, 0.93)

0.004

CI = Confidence interval; HR = Hazard ratio; KM = Kaplan-Meier percentage calculated at 30 days; N = Number of patients

The Kaplan-Meier curve (Figure 17) shows the time to first occurrence of the primary composite endpoint of stroke and death.

Figure 17 – Time to First Occurrence of Stroke or Death (THALES)

figure_17
(click image for full-size original)

KM%: Kaplan-Meier percentage evaluated at Day 30; T=Ticagrelor; P=placebo; N=Number of patients

BRILINTA’s treatment effect on stroke and on death accrued over the first 10 days and was sustained at 30 days. Although not studied, this suggests that shorter treatment could result in similar benefit and reduced bleeding risk.

The treatment effect of BRILINTA was generally consistent across pre-defined subgroups (Figure 18).

Figure 18 — Subgroup analyses of ticagrelor 90 mg (THALES)

figure_18
(click image for full-size original)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

At Day 30, there was an absolute reduction of 1.2% (95% CI: -2.1%, -0.3%) in the incidence of non-hemorrhagic stroke and death (excluding fatal bleed) favoring ticagrelor (294 events: 5.3%) over placebo (359 events: 6.5%) in the intention-to-treat population. In the same population, there was an absolute increase of 0.4% (95% CI: 0.2%, 0.6%) in the incidence of GUSTO severe bleeding unfavorable to ticagrelor arm (28 events: 0.5%) compared to the placebo arm (7 events: 0.1%).

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