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Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial

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@article{084949fad67642a3a03d0acac33f1f26,
title = "Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial",
abstract = "BACKGROUND: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor.METHODS: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50{\%} or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population).FINDINGS: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58{\%} of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3{\%}] of 5558 vs 480 [8·6{\%}] of 5596; HR 0·85 [95{\%} CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1{\%}] with ticagrelor vs 183 (3·3{\%}) with placebo; HR 0·96 [95{\%} CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1{\%}] vs 323 [5·8{\%}]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0{\%}) of 5536 patients receiving ticagrelor and 62 (1·1{\%}) of 5564 patients receiving placebo (HR 2·03 [95{\%} CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1{\%}) of 5536 patients with ticagrelor and 6 (0·1{\%}) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6{\%}) and 31 (0·6{\%}) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3{\%}) versus 617/5596 (11·0{\%}), HR=0·85, 95{\%} CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI.INTERPRETATION: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk.FUNDING: AstraZeneca.",
keywords = "Aged, Aspirin/therapeutic use, Cardiovascular Diseases/mortality, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease/complications, Coronary Stenosis/diagnostic imaging, Diabetes Mellitus, Type 2/complications, Double-Blind Method, Drug Therapy, Combination, Female, Hemorrhage/chemically induced, Humans, Hypoglycemic Agents/therapeutic use, Male, Middle Aged, Myocardial Infarction/epidemiology, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors/therapeutic use, Secondary Prevention, Stroke/epidemiology, Ticagrelor/therapeutic use",
author = "Bhatt, {Deepak L} and Steg, {Philippe Gabriel} and Mehta, {Shamir R} and Leiter, {Lawrence A} and Tabassome Simon and Kim Fox and Claes Held and Marielle Andersson and Anders Himmelmann and Wilhelm Ridderstr{\aa}le and Jersey Chen and Yang Song and Rafael Diaz and Shinya Goto and James, {Stefan K} and Ray, {Kausik K} and Parkhomenko, {Alexander N} and Kosiborod, {Mikhail N} and McGuire, {Darren K} and Harrington, {Robert A} and {THEMIS Steering Committee and Investigators}",
note = "Copyright {\circledC} 2019 Elsevier Ltd. All rights reserved.",
year = "2019",
month = "9",
day = "28",
doi = "10.1016/S0140-6736(19)31887-2",
language = "English",
volume = "394",
pages = "1169--1180",
journal = "Lancet",
issn = "0140-6736",
publisher = "The/Lancet Publishing Group",
number = "10204",

}

RIS

TY - JOUR

T1 - Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI)

T2 - a phase 3, placebo-controlled, randomised trial

AU - Bhatt, Deepak L

AU - Steg, Philippe Gabriel

AU - Mehta, Shamir R

AU - Leiter, Lawrence A

AU - Simon, Tabassome

AU - Fox, Kim

AU - Held, Claes

AU - Andersson, Marielle

AU - Himmelmann, Anders

AU - Ridderstråle, Wilhelm

AU - Chen, Jersey

AU - Song, Yang

AU - Diaz, Rafael

AU - Goto, Shinya

AU - James, Stefan K

AU - Ray, Kausik K

AU - Parkhomenko, Alexander N

AU - Kosiborod, Mikhail N

AU - McGuire, Darren K

AU - Harrington, Robert A

AU - THEMIS Steering Committee and Investigators

N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

PY - 2019/9/28

Y1 - 2019/9/28

N2 - BACKGROUND: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor.METHODS: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population).FINDINGS: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI.INTERPRETATION: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk.FUNDING: AstraZeneca.

AB - BACKGROUND: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor.METHODS: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population).FINDINGS: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI.INTERPRETATION: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk.FUNDING: AstraZeneca.

KW - Aged

KW - Aspirin/therapeutic use

KW - Cardiovascular Diseases/mortality

KW - Coronary Angiography

KW - Coronary Artery Bypass

KW - Coronary Artery Disease/complications

KW - Coronary Stenosis/diagnostic imaging

KW - Diabetes Mellitus, Type 2/complications

KW - Double-Blind Method

KW - Drug Therapy, Combination

KW - Female

KW - Hemorrhage/chemically induced

KW - Humans

KW - Hypoglycemic Agents/therapeutic use

KW - Male

KW - Middle Aged

KW - Myocardial Infarction/epidemiology

KW - Percutaneous Coronary Intervention

KW - Platelet Aggregation Inhibitors/therapeutic use

KW - Secondary Prevention

KW - Stroke/epidemiology

KW - Ticagrelor/therapeutic use

U2 - 10.1016/S0140-6736(19)31887-2

DO - 10.1016/S0140-6736(19)31887-2

M3 - Journal article

VL - 394

SP - 1169

EP - 1180

JO - Lancet

JF - Lancet

SN - 0140-6736

IS - 10204

ER -

ID: 59126942