Selected data taken from Evidence Review Group report for TA182 appraisal

Janette Greenhalgh; Adrian Bagust; Angela Boland; Kerry Dwan; Sophie Beale; Nigel Fleeman; Joanne McEntee; Yenal Dundar; Marty Richardson; Michael Fisher

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Greenhalgh J, Bagust A, Boland A, et al. Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis. Southampton (UK): NIHR Journals Library; 2015 Apr. (Health Technology Assessment, No. 19.29.)

Cover of Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis

Prasugrel (Efient^®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis.

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Appendix 4Selected data taken from Evidence Review Group report for TA182 appraisal

All data are for the overall population unless otherwise stated.

Summary of baseline characteristics of patients in TRITON-TIMI 38

Characteristic	Prasugrel (n = 6813)	Clopidogrel (n = 6795)
UA or NSTEMI (%)	74	74
STEMI (%)	26	26
Age (median) (years)	61	61
≥ 75 years (%)	13	13
Female (%)	25	27
White race (%)	92	93
Region of enrolment (%)
North America	32	32
Western Europe	26	26
Eastern Europe	24	25
Middle East, Africa, Asia-Pacific	14	14
South America	4	4
Medical history (%)
Hypertension	64	64
Hypercholesterolaemia	56	56
Diabetes mellitus	23	23
Tobacco use	38	38
Previous MI	18	18
Previous CABG	8	7
Creatinine clearance < 60 ml/minute	11	12
Index procedure (%)
PCI	99	99
CABG	1	1
Stent	94	95
Bare-metal stent only	48	47
≥ 1 drug-eluting stent	47	47
Multivessel PCI	14	14
Timing of study drug administration (%)^a
Before PCI	26	25
During PCI	73	74
After PCI	1	1

a: Administration of the study drug before PCI occurred before the first coronary guidewire was placed during the index PCI; administration during PCI occurred after the first coronary guidewire was placed or within 1 hour after the patient was taken from the cardiac catheterisation laboratory; and administration after PCI occurred more than 1 hour after the patient was taken from the cardiac catheterisation laboratory.
: Patients could have had more than one type of medical history, undergone more than one type of index procedure, or received more than one type of pharmacotherapy during index hospitalisation.

Primary end point analysis

These results are for the overall trial population (n = 13,608), which includes patients with a history of stroke or TIA. At the end of the trial period, there was a statistically significant reduction in the primary end point in the prasugrel arm compared with the clopidogrel arm. This result was largely attributable to differences in the occurrence of non-fatal MI. The ERG notes that there are no statistically significant differences in mortality (CV death or death from all causes) or non-fatal stroke between the groups.

TRITON-TIMI 38: efficacy results at 15 months (overall cohort)

End point	Clopidogrel (N = 6795)	Prasugrel (N = 6813)	HR (95% CI)	p-value^a
End point	n (%)	n (%)	HR (95% CI)	p-value^a
Primary
Death from CV causes, non-fatal MI or non-fatal stroke	781 (12.1)	643 (9.9)	0.81 (0.73 to 0.90)	< 0.001
Death from CV causes	150 (2.4)	133 (2.1)	0.89 (0.70 to 1.12)	0.31
Non-fatal MI	620 (9.5)	475 (7.3)	0.76 (0.67 to 0.85)	< 0.001
Non-fatal stroke	60 (1.0)	61 (1.0)	1.02 (0.71 to 1.45)	0.93
Secondary
Death from any cause	197 (3.2)	188 (3.0)	0.95 (0.78 to 1.16)	0.64
Death from CV causes, non-fatal MI or UTVR	798 (12.3)	652 (10.0)	0.81 (0.73 to 0.89)	< 0.001
Death from CV causes	150 (2.4)	133 (2.1)	0.89 (0.70 to 1.12)	0.31
Non-fatal MI	620 (9.5)	475 (7.3)	0.76 (0.67 to 0.85)	< 0.001
UTVR	233 (3.7)	156 (2.5)	0.66 (0.54 to 0.81)	< 0.001
Stent thrombosis^b	142 (2.4)	68 (1.1)	0.48 (0.36 to 0.64)	< 0.001
Death from CV causes, non-fatal MI, non-fatal stroke or rehospitalisation for ischaemia	938 (14.6)	797 (12.3)	0.84 (0.76 to 0.92)	< 0.001

a: Taken from published paper.³⁶
b: Stent thrombosis defined as definite or probable according to the Academic Research Consortium.
: p-values were calculated using the log-rank test. The analysis for the primary end point used the Gehan–Wilcoxon test for which the p-value was < 0.
: The percentages are Kaplan–Meier estimates of the rate of each end point at 15 months. As the Kaplan–Meier method takes into account censored data (i.e. sample losses before the final outcome occurs), each percentage does not correspond to the numerator divided by the denominator (because the denominator does not account for censored data).
: Patients could have had more than one type of end point.

Secondary end points

Statistically significant reductions in favour of prasugrel were found for three secondary clinical end points: (1) composite end point of CV death, non-fatal MI or UTVR; (2) composite end point of death from CV causes, non-fatal MI, non-fatal stroke or rehospitalisation for ischaemia; and (3) stent thrombosis.

Results of the secondary analyses in respect of the primary composite end point were presented at 3 days, 30 days, 90 days and day 4 to day 90. The CEs all show a statistically significant benefit of prasugrel over time.

TRITON-TIMI: primary efficacy outcomes at 3 days, 30 days, 90 days and day 4 to day 90 (overall cohort)

End point	Time	Clopidogrel (N = 6795) (%)	Prasugrel (N = 6813) (%)	HR for prasugrel (95% CI)	p-value
Death from CV causes, non-fatal MI, non-fatal stroke	3 days	5.6	4.7	0.82 (0.71 to 0.96)	< 0.01
	30 days	7.4	5.7	0.77 (0.67 to 0.88)	< 0.01
	90 days	8.4	6.8	0.80 (0.71 to 0.90)	< 0.001
	Day 4 to 90	6.9	5.6	0.80 (0.70 to 0.93)	< 0.003
Death from CV causes, non-fatal MI, UTVR	30 days	7.4	5.9	0.78 (0.69 to 0.89)	< 0.01
Death from CV causes, non-fatal MI, UTVR	90 days	8.7	6.9	0.79 (0.70 to 0.90)	< 0.01

: Patients could have had more than one type of end point.

Prespecified subgroup analyses

The subgroups included in the MS are as follows: UA/NSTEMI, STEMI, males, females, < 65 years, 65–74 years, ≥ 75 years, diabetes mellitus, type of stent, use of glycoprotein IIb/IIIa receptor antagonist, and renal function. The MS presents a forest plot showing the primary efficacy end point results within selected subgroups for the overall trial cohort. The forest plot shows a statistically significant benefit of prasugrel for all subgroups with the exception of females, patients aged ≥ 65 years and patients with creatinine clearance of < 60 ml/minute.

ST segment elevation myocardial infarction patient subgroup

The MS presents data relevant to the STEMI cohort. The relevant text can be found on page 53 of the MS. It is emphasised in the MS that the trial was not powered to compare the effects of prasugrel with clopidogrel in the STEMI population. A total of 3534 STEMI patients were randomised. The primary end point (CV death, non-fatal MI or non-fatal stroke) was statistically significantly reduced with prasugrel at 30 days (HR 0.68, p = 0.002) and 15 months (HR 0.79, 95% CI 0.65 to 0.97; p = 0.02). The secondary end point (CV death, MI or UTVR) was also statistically significantly reduced with prasugrel at 30 days (p = 0.02) and 15 months (p = 0.03). Stent thrombosis and the composite of CV death or non-fatal MI were reported to be statistically significantly reduced with prasugrel at 30 days and 15 months.

At 15 months, no statistically significant difference was reported between the prasugrel arm and the clopidogrel arm of the trial for non-CABG-related TIMI major bleeding (HR 1.11, 95% CI 0.70 to 1.77; p = 0.65). The MS concludes that for STEMI patients who are treated with PCI, prasugrel offers a greater reduction in ischaemic events without an excess risk in major bleeding.

Primary efficacy results for the unstable angina/non-ST segment elevation myocardial infarction, ST segment elevation myocardial infarction and all acute coronary syndrome groups in the TRITON-TIMI 38 trial

TRITON-TIMI 38: primary efficacy for unstable angina/non-ST segment elevation myocardial infarction, ST segment elevation myocardial infarction and all acute coronary syndrome groups (European Public Assessment Report)

Primary efficacy end point and components at study end

Event	Prasugrel, n (%)^a	Clopidogrel, n (%)^a	HR (95% CI)^b	p-value^c
UA/NSTEMI	N = 5044	N = 5030
CV death, non-fatal MI or non-fatal stroke	469 (9.30)	565 (11.23)	0.820 (0.726 to 0.927)	0.002
CV death	90 (1.78)	92 (1.83)	0.979 (0.732 to 1.309)	0.885
Non-fatal MI	357 (7.08)	464 (9.22)	0.761 (0.663 to 0.873)	< 0.001
Non-fatal stroke	40 (0.79)	41 (0.82)	0.979 (0.633 to 1.513)	0.922
All cause death	130 (2.58)	121 (2.41)	1.076 (0.840 to 1.378)	0.563
All MI	366 (7.26)	476 (9.46)	0.760 (0.663 to 0.871)	< 0.001
All stroke	49 (0.97)	46 (0.91)	1.068 (0.714 to 1.597)	0.748
STEMI	N = 1769	N = 1765
CV death, non-fatal MI or non-fatal stroke	174 (9.84)	216 (12.24)	0.793 (0.649 to 0.968)	0.019
CV death	43 (2.43)	58 (3.29)	0.738 (0.497 to 1.094)	0.129
Non-fatal MI	118 (6.67)	156 (8.84)	0.746 (0.588 to 0.948)	0.016
Non-fatal stroke	21 (1.19)	19 (1.08)	1.097 (0.590 to 2.040)	0.770
All cause death	58 (3.28)	76 (4.31)	0.759 (0.539 to 1.068)	0.113
All MI	119 (6.73)	157 (8.90)	0.748 (0.589 to 0.949)	0.016
All stroke	26 (1.47)	25 (1.42)	1.032 (0.596 to 1.787)	0.911
All ACS	N = 6813	N = 6795
CV death, non-fatal MI or non-fatal stroke	643 (9.44)	781 (11.49)	0.812 (0.732 to 0.902)	< 0.001
CV death	133 (1.95)	150 (2.21)	0.886 (0.701 to 1.118)	0.307
Non-fatal MI	475 (6.97)	620 (9.12)	0.757 (0.672 to 0.853)	< 0.001
Non-fatal stroke	61 (0.90)	60 (0.88)	1.016 (0.712 to 1.451)	0.930
All cause death	188 (2.76)	197 (2.90)	0.953 (0.781 to 1.164)	0.639
All MI	485 (7.12)	633 (9.32)	0.757 (0.673 to 0.852)	< 0.001
All stroke	75 (1.10)	71 (1.04)	1.055 (0.763 to 1.460)	0.745

a: Percentage of randomly assigned subjects reaching the primary end point.
b: HR and a 95% CI used as an estimate of overall RR, prasugrel compared with clopidogrel, over the course of the study.
c: Two-sided p-values are based on Gehan–Wilcoxon test comparing event free survival distributions of prasugrel and clopidogrel for the composite primary end point. The individual components of the end points were tested using log-rank test. Clinical presentation, UA/NSTEMI compared with STEMI, was used as a stratification factor in analysis involving all ACS subjects.

Patients with diabetes mellitus

TRITON-TIMI 38: clinical events by diabetic status

End point	Clopidogrel (%)	Prasugrel (%)	HR (95% CI)	p-value	p-value for the subgroup analyses that compare diabetes with no diabetes
Patients without diabetes mellitus	N = 5225	N = 5237
Primary efficacy end point of death from CV causes, non-fatal MI or non-fatal stroke	10.6	9.2	0.86 (0.76 to 0.98)	0.02
Death from CV causes or MI	10.0	8.5	0.85 (0.75 to 0.97)	0.01
Fatal or non-fatal MI	8.7	7.2	0.82 (0.72 to 0.95)	0.006
Death from CV causes	1.9	1.7	0.91 (0.68 to 1.23)	0.53
Stent thrombosis	2.0	0.9	0.45 (0.31 to 0.65)	< 0.001
Death from CV causes, non-fatal MI, non-fatal stroke or major bleeding event	12.3	11.5	0.92 (0.82 to 1.03)	0.16
Patients with diabetes mellitus	N = 1570	N = 1576
Primary efficacy end point of death from CV causes, non-fatal MI or non-fatal stroke	17.0	12.2	0.70 (0.58 to 0.85)	< 0.001	0.09
Death from CV causes or MI	15.4	10.8	0.68 (0.56 to 0.84)	< 0.001	0.08
Fatal or non-fatal MI	13.2	8.2	0.60 (0.48 to 0.76)	< 0.001	0.02
Death from CV causes	4.2	3.4	0.85 (0.58 to 1.24)	0.40	0.78
Stent thrombosis	3.6	2.0	0.52 (0.33 to 0.84)	0.007	0.63
Death from CV causes, non-fatal MI, non-fatal stroke or major bleeding event	19.2	14.6	0.74 (0.62 to 0.89)	0.001	0.05

: Event rates are reported using Kaplan–Meier estimates at 450 days. Comparisons are expressed as HRs and 95% CIs including the entire duration of follow-up. Testing for an interaction between the efficacy of prasugrel compared with clopidogrel and diabetic status was performed by constructing a Cox proportional-hazards model using terms for both the main effect and the interaction.
: Reproduced from MS.

TRITON-TIMI 38: bleeding rates by diabetes mellitus status

End point	Patients with diabetes mellitus (n = 3146) %	Patients without diabetes mellitus (n = 10,462) %	HR (95% CI)	p-value
Major non-CABG-related bleeding event	2.6	2.0	1.28 (0.97 to 1.68)	0.08
Major non-CABG-related or minor bleeding event	4.8	4.2	1.15 (0.95 to 1.41)	0.15

: Reproduced from MS.

TRITON-TIMI 38: bleeding rates for prasugrel compared with clopidogrel by diabetes mellitus status

End point	Clopidogrel %	Prasugrel %	HR (95% CI)	p-value	p-value for the subgroup analyses that compare diabetes with no diabetes
Patients without diabetes mellitus	N = 5225	N = 5237
Major non-CABG-related bleeding event	1.6	2.4	1.43 (1.07 to 1.91)	0.02
Major non-CABG-related or minor bleeding event	3.6	4.9	1.32 (1.08 to 1.61)	0.006
Patients with diabetes mellitus	N = 1570	N = 1576
Major non-CABG-related bleeding event	2.6	2.5	1.06 (0.66 to 1.69)	0.81	0.29
Major non-CABG-related or minor bleeding event	4.3	5.3	1.30 (0.92 to 1.82)	0.13	0.93

: Reproduced from MS.

Patients with stents

In this group, 6461 patients received bare-metal stents, 5743 patients received drug-eluting stents and 640 patients received both types of stent. In the ‘stented’ group as a whole, the occurrence of the primary end point was reduced in the prasugrel arm compared with the clopidogrel arm (9.7% compared with 11.9%, HR 0.81; p = 0.0001). Similar results were reported for drug-eluting stents and bare-metal stents.

Efficacy and bleeding and net clinical benefit in selected subpopulations

TRITON-TIMI 38: efficacy, bleeding and net clinical benefit in selected populations

End point	Clopidogrel n/N (%)	Prasugrel n/N (%)	HR for prasugrel (95% CI)	p-value
History of stroke or TIA
Death from CV causes, non-fatal MI, non-fatal stroke (primary efficacy end point)	35/256 (14.4)	47/262 (19.1)	1.37 (0.89 to 2.13)	0.15
Non-CABG-related TIMI major bleeding	6/252 (2.9)	14/257 (5.0)	2.46 (0.94 to 6.42)	0.06
Death from any cause, non-fatal MI, non-fatal stroke, or non-CABG-related non-fatal TIMI major bleeding	39/256 (16.0)	57/262 (23.0)	1.54 (1.02 to 2.32)	0.04
Aged ≥ 75 years, body weight < 60 kg, or history of stroke or TIA
Death from CV causes, non-fatal MI, non-fatal stroke (primary efficacy end point)	199/1347 (16.0)	198/1320 (16.1)	1.02 (0.84 to 1.24)	0.83
Non-CABG-related TIMI major bleeding	38/1328 (3.3)	52/1305 (4.3)	1.42 (0.93 to 2.15)	0.10
Death from any cause, non-fatal MI, non-fatal stroke, non-CABG-related non-fatal TIMI major bleeding	239/1347 (19.0)	249/1320 (20.2)	1.07 (0.90 to 1.28)	0.43

: The percentages are Kaplan–Meier estimates of the rate of each end point at 15 months. As the Kaplan–Meier method takes into account censored data (i.e. sample losses before the final outcome occurs), each percentage does not correspond to the numerator divided by the denominator (because the denominator does not account for censored data).
: Reproduced from MS.

TRITON-TIMI 38 recurrent events analysis

This analysis compared the number of subsequent events (after the first event within the primary end point) that occurred within each arm of the trial. More subsequent events were recorded in the clopidogrel arm than in the prasugrel arm (115 compared with 58; p < 0.001).

Copyright © Queen’s Printer and Controller of HMSO 2015. This work was produced by Greenhalgh et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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Greenhalgh J, Bagust A, Boland A, et al. Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis. Southampton (UK): NIHR Journals Library; 2015 Apr. (Health Technology Assessment, No. 19.29.) Appendix 4, Selected data taken from Evidence Review Group report for TA182 appraisal.
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Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis.