Odyssey Outcomes: Addition of PCSK9i to background Statin therapy further reduces MACE.

Elderly patients sub-analysis overview

Study outcomes

Primary outcome: composite of death from CHD, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization

Key secondary outcome: all-cause death

All outcomes were adjudicated by physicians who were unaware of the trial-group assignments

*Pre-specified analysis: Age <65 years (n=13,840), age≥65 years (n=5,084). The Cox regression model with age as a continuous variable, randomized treatment and the interaction was used to estimate the event rate at 3 years and HRs comparing alirocumab versus placebo at specific ages to test the interaction between age and treatment with alirocumab

Baseline characteristics by age group

Characteristic	<65 years (n=13,840)	≥65 years (n=5084)	P-value
Age (years), mean ± SD	54.2 ± 6.3	70.5 ± 4.7
Women, n (%)	2948 (21.3)	1814 (35.7)	<0.0001
Medical history before index ACS, n (%)
Hypertension	8390 (60.6)	3859 (75.9)	<0.0001
Diabetes mellitus	3787 (27.4)	1657 (32.6)	<0.0001
Myocardial infarction	2499 (18.1)	1134 (22.3)	<0.0001
Percutaneous coronary intervention	2212 (16.0)	1029 (20.2)	<0.0001
Coronary artery bypass graft	582 (4.2)	465 (9.1)	<0.0001
Stroke	337 (2.4)	274 (5.4)	<0.0001
Peripheral artery disease	428 (3.1)	331 (6.5)	<0.0001
Congestive heart failure	1800 (13.0)	1014 (19.9)	<0.0001
Index, ACS, n (%)	n=13,818	n=5075	<0.0001
STEMI	5039 (36.4)	1497 (29.4)
Non-STEMI	6422 (46.4)	2753 (54.2)
Unstable angina	2357 (17.0)	825 (16.2)
PCI or CABG for index ACS, n (%)	10,201 (73.7)	3475 (68.4)	<0.0001

SD, Standard deviation

Characteristic	<65 years (n=13,840)	≥65 years (n=5084)	P-value
The from index ACS to randomization (months), mean ± SD	3.6 ± 2.8	3.8 ± 2.8	0.0003
Body mass index (kg/m²), mean ± SD	28.8 ± 4.9	27.8 ± 4.6	<0.0001
Renal function
eGFR (mL/min), mean ± SD	83.1 ± 18.5	70.2 ± 18.2	<0.0001
eGFR <60 mL/min, n (%)	1,163 (8.4)	1,377 (27.1)	<0.0001
Lipid-lowering drugs at randomization, n (%)			<0.0001
High-intensity atorvastatin/rosuvastatin	12,565 (90.8)	4,246 (83.5)
Low- or moderate-intensity atorvastatin/rosuvastatin	1,027 (7.4)	580 (11.4)
No statin	222 (1.6)	238 (4.7)
Ezetibime	408 (2.9)	142 (2.8)	0.57

Abbreviation

eGFR, estimated glomerular filtration rate

Treatment effect by age group: Primary composite outcome

Relative Risk Reduction Hazard Ratio (Alirocumab vs Placebo)

≥65 years: 0.78, 95% CI 0.68-0.91

<65 years: 0.89, 95% CI 0.80-1.00

Interaction p-value: 0.19

Absolute Risk Reduction At 3 years (Placebo - Alirocumab)

≥65 years: 3.88%, 95% Cl 1.74-6.02

<65 years: 0.91%, 95% Cl -0.13 to 1.95

Interaction p-value: 0.015

Treatment effect by age group: All cause death

Relative Risk Reduction Hazard Ratio (Alirocumab vs Placebo)

≥65 years: 0.77, 95% CI 0.62-0.95

<65 years: 0.94, 95% CI 0.77-1.15

Interaction p-value: 0.46

Absolute Risk Reduction At 3 years (Placebo - Alirocumab)

≥65 years: 2.08%, 95% Cl 0.48-3.67

<65 years: 0.11%, 95% Cl -0.50 to 1.72

Interaction p-value: 0.024

Safety: Adverse events by age group

Adverse Event	Randomized Treatment		Relative Risk (95%CI) Alirocumab vs Placebo
	Alirocumab, N (%)	Placebo, N (%)
Any adverse event
≥65 years	1,974 (79.0)	2,042 (79.3)	1.00 (0.97 -1.02)
<65 years	5,191 (74.7)	5,240 (76.3)	0.98 (0.96 -1.00)
Serious adverse event
≥65 years	703 (28.1)	781 (30.3)	0.93 (0.85 -1.01)
<65 years	1,499 (21.6)	1,569 (22.8)	0.94 (0.89 -1.00)
Adverse event leading to discontinuation of treatment
≥65 years	121 (4.8)	128 (5.0)	0.97 (0.76 -1.24)
<65 years	222 (3.2)	196 (2.9)	1.12 (0.93 -1.35)
Neurocognitive disorder
≥65 years	52 (2.1)	65 (2.5)	0.82 (0.57 -1.18)
<65 years	91 (1.3)	102 (1.5)	0.88 (0.67 -1.17)
New-onset diabetes in patients w/o diabetes at baseline
≥65 years	156 (9.2)	167 (9.7)	0.95 (0.77 -1.17)
<65 years	492 (9.7)	509 (10.2)	0.95 (0.84 -1.07)
Hemorrhagic stroke - adjudicated
≥65 years	1 (0.0)	6 (0.2)	0.17 (0.02 -1.42)
<65 years	8 (0.1)	10 (0.1)	0.79 (0.31 -2.00)
Alanine aminotransferase> 3 x upper limit of normal
≥65 years	64 (2.6)	70 (2.8)	0.94 (0.67 -1.31)
<65 years	148 (2.1)	158 (2.3)	0.92 (0.74 -1.15)
Aspartate
≥65 years	52 (2.1)	48 (1.9)	1.11 (0.75 -1.64)
<65 years	108 (1.6)	118 (1.7)	0.90 (0.70 -1.17)

Elderly Patients’ sub-analysis conclusions¹

Alirocumab demonstrated an effective RRR for primary MACE outcome, and was associated with an effective reduction of all-cause death across age categories
There was a highly significant interaction of treatment effect and age on the absolute reduction of all-cause death, and although adverse events generally were more frequent in older patients, there was no increase occurrence in any of the safety endpoints

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