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Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial*
Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-69.
*All of the information and data within this section is a summary of this publication.
The ODYSSEY ALTERNATIVE study evaluated the efficacy and safety of Praluent 75/150 mg compared to ezetimibe in patients at moderate to high cardiovascular (CV) risk**, statin intolerance† and had primary hypercholesterolaemia.
This 24 week, multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group, phase III study involved 314 adult patients (≥18 years) at moderate/high CV risk** (LDL-C level ≥2.6 mmol/L) or very high CV risk (LDL-C level ≥1.8 mmol/L) and statin intolerance (unable to tolerate ≥2 statins including one at the lowest approved starting dose) due to skeletal muscle-related symptoms†, and had primary hypercholesterolaemia.
Patients were randomised to subcutaneous Praluent 75 mg every 2 weeks (Q2W) plus oral placebo daily (n=126), subcutaneous placebo Q2W plus oral ezetimibe 10mg daily (n=125) or subcutaneous placebo Q2W plus oral atorvastatin 20mg daily (statin re-challenge arm, n=63) (Figure 1).
The study included a placebo run-in and statin re-challenge arm to confirm intolerance and Praluent dose was increased to 150 mg Q2W at Week 12 if Week 8 LDL-C was ≥1.8 mmol/L.
The primary efficacy endpoint was the percentage change in LDL-C from baseline to Week 24. Secondary endpoints included:
Efficacy comparisons versus atorvastatin were not assessed as this treatment arm was only included as an essential control to define the appropriate patient population.
Figure 1: ODYSSEY ALTERNATIVE: Study design - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691
*Praluent dose was 75 mg administered SC every two weeks, but at week 8, if LDL-C
level was ≥1.8 mmol/L in very high risk patients or ≥2.6 mmol/L in moderate/high risk CV
patients, a pre-specified dose up-titration to 150 mg every two weeks was performed at Week
12
† Statin intolerance defined as the inability to tolerate ≥2 statins
because of unexplained skeletal muscle-related symptoms associated with statin use
Baseline characteristics were well balanced between treatment groups with high rates of conorary heart disease (CHD) and CV risk factors (Table 1).
Table 1: ODYSSEY ALTERNATIVE: Baseline characteristics - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691
Praluent 75/150mg (n=126) |
Ezetimibe (n=125) |
Atorvastatin (n=63) |
|
---|---|---|---|
Demographics | |||
Age in years, mean ± SD | 64.1 ± 9.0 | 62.8 ± 10.1 | 63.4 ± 8.9 |
Male, % | 55.6 | 53.6 | 55.6 |
CV risk level | |||
Moderate*, % | 15.1 | 11.2 | 15.9 |
High#, % | 23.0 | 37.6 | 20.6 |
Very high‡, % | 57.9 | 49.6 | 55.6 |
LLT other than statin % | 37.3 | 44.0 | 54.0 |
Lipid parameters | |||
LDL-C, mmol/L ± SD | 4.9 ± 1.9 | 5.0 ± 1.98 | 4.8 ± 1.5 |
CV = cardiovascular; LLT = lipid-lowering therapy; SD = standard deviation
* 10-year fatal CV risk Systematic Coronary Risk Evaluation (SCORE)
≥1%–5%
# 10-year fatal CV risk SCORE ≥5%; moderate chronic kidney disease; diabetes
mellitus without target organ damage; or familial hypercholesterolaemia
‡ Documented history of CHD, ischemic stroke, peripheral artery disease,
transient ischemic attack, abdominal aortic aneurysm, or carotid artery occlusion >50%
without symptoms; carotid endarterectomy or carotid artery stent procedure; renal artery
stenosis or renal artery stent procedure; or diabetes mellitus with target organ damage
In statin intolerant adults, Praluent 75/150 mg 2QW led to significantly greater reductions in LDL-C compared to placebo (Figure 2) with sustained reductions from Week 4 to Week 24 (Figure 3). A significantly greater proportion of patients achieved a pre-specified LDL-C targets compared to placebo (Figure 4):
Figure 2: ODYSSEY ALTERNATIVE: Mean reduction in LDL-C from baseline to Week 24† - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691
*Praluent dose was 75 mg administered subcutaneously every two weeks, but if LDL-C
level was above the pre-specified target (≥1.8 mmol/L for patients at very high CV risk and
≥2.6 mmol/L for patients at moderate to high CV risk) at Week 8, a pre-specified dose
up-titration to 150 mg every two weeks was performed at Week 12
†This number refers to the number of patients receiving Praluent (ITT
analysis)
‡This number refers to the number of patients receiving ezetimibe (ITT
analysis)
Figure 3: ODYSSEY ALTERNATIVE: Mean LDL-C from baseline to Week 24. In a post-hoc ITT analysis, the mean (SD) change in LDL-C concentration in the atorvastatin arm was −31.9% (25.1%) at week 24 - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015;9:758-691
LDL-C concentrations vs study time points for on–treatment analysis. Values indicate achieved LDL-C concentration and least squares mean (SE) percent change from baseline.
Figure 4: ODYSSEY ALTERNATIVE: Proportion of patients achieving LDL-C** target at Week 24† - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691
†ITT analysis
*Praluent dose was 75 mg administered subcutaneously every two weeks, but if LDL-C
level was above the pre-specified target (≥1.8 mmol/L for patients at very high CV risk and
≥2.6 mmol/L for patients at moderate to high CV risk) at Week 8, a pre-specified dose
up-titration to 150 mg every two weeks was performed at Week 12
**Pre-specified LDL-C level target for moderate to high risk patients was <2.6
mmol/L and for very high risk patients was <1.8 mmol/L
Although the frequency of treatment-emergent and serious AEs were similar between treatment groups, treatment-emergent AEs (TEAEs) leading to discontinuations tended to be lower with the Praluent group (Table 2).
The incidence of skeletal muscular-related AEs was significantly lower in Praluent than in atorvastatin patients (32.5% versus 46.0%, respectively; HR=0.61; 95% CI: 0.38 –to 0.99; p=0.042) with a similar but non-significant trend for Praluent versus ezetimibe (HR=0.71; 95% CI: 0.47–1.06; p=0.096). Discontinuations due to skeletal muscular-related AEs were also lower in with Praluent versus atorvastatin (HR=0.67; 95% CI: 0.34–1.32; p=0.24) or ezetimibe (HR=0.78; 95%: CI 0.43–1.41; p=0.41), however these differences were not significant.
Table 2: ODYSSEY ALTERNATIVE: Treatment-emergent adverse events at Week 24 (safety population) - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691
Praluent (n=126) | Ezetimibe (n=124) | Atrovastatin (n=63) | |
---|---|---|---|
Any AE, n (%) | 104 (82.5) | 100 (80.6) | 54 (85.7) |
Serious AE, n (%) | 12 (9.5) | 10 (8.1) | 7 (11.1) |
AEs leading to discontinuation, n (%) | 23 (18.3) | 31 (25.0) | 16 (25.4) |
Musculoskeletal† AEs, n (%) | 41 (32.5) | 51 (41.1) | 29 (46.0) |
Musculoskeletal† AEs leading to discontinuation, n (%) | 20 (15.9) | 25 (20.2) | 14 (22.2) |
Injection site reactions, n (%) | 6 (4.8) | 6 (4.8) | 1 (1.6) |
Adjudicated CV adverse events‡, n (%) | 4 (3.2) | 1 (0.8) | 1 (1.6) |
Please refer to publication for full safety profile information
AE = adverse event; CV = cardiovascular
†Predefined category including myalgia, muscle spasms, muscular weakness,
musculoskeletal stiffness and muscle fatigue
‡ Including coronary heart disease death, nonfatal myocardial infarction,
fatal/nonfatal ischemic stroke, unstable angina requiring hospitalisation, congestive heart
failure requiring hospitalization, and ischemia-driven coronary revascularisation
**Moderate CV risk was defined as 10-year fatal cardiovascular risk SCORE between ≥1% and <5%. High CV risk was defined as 10-year fatal cardiovascular risk SCORE ≥5%; moderate chronic kidney disease; diabetes mellitus without organ damage; or familial hypercholesterolaemia. Very high CV risk was defined as documented history of CHD, ischaemic stroke, peripheral artery disease, transient ischaemic attack, abdominal aortic aneurysm, or carotid artery occlusion >50% without symptoms; carotid endarterectomy or carotid artery stent procedure; renal artery stenosis or renal stent procedure; or diabetes mellitus with target organ damage.
†Statin intolerance defined as the inability to tolerate ≥2 statins because of unexplained skeletal muscle-related symptoms associated with statin use
§Myalgia or myositis, muscle spasms, muscular weakness, musculoskeletal stiffness and muscle fatigue