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Corresponding author. Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol concentrations.
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Alirocumab reduced low-density lipoprotein cholesterol levels more than ezetimibe in statin-intolerant patients.
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Alirocumab led to fewer skeletal muscle adverse events compared with atorvastatin.
Background
Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies.
Methods
ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) received single-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe.
Results
Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38–0.99, P = .042).
Conclusions
Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Cholesterol Treatment Trialists (CTT) Collaboration Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
However, many patients may suffer statin-associated muscle symptoms and are unable to either take any dose or increase the dose sufficiently, even after trying an alternate statin, to achieve long-term reduction of LDL-C and cardiovascular risk.
Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
This is most likely an underestimate because patients with a history of, or at an increased risk of, intolerance were excluded from many of the trials in this meta-analysis. Observational data suggest a prevalence ranging from 7% to 29%.
Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
The Effect of Statins on Skeletal Muscle Function and Performance trial investigated the rate of statin intolerance in healthy statin-naïve patients. Overall, muscle complaints occurred in 9.4% of patients on atorvastatin 80 mg vs 4.6% on placebo (P = .05), indicating an approximate 5% rate of muscle events with high-dose statin.
Large, well-controlled randomized trials of cholesterol-lowering drugs in statin-intolerant patients are lacking, and there remains a need for an effective non-statin treatment for patients who are intolerant of these medications and remain at cardiovascular risk. Alirocumab is a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9. Alirocumab reduced LDL-C concentrations by 40% to 70% when given in combination with other lipid-lowering therapies or as monotherapy.
Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy.
Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.
Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized phase 3 trial.
Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial.
Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial.
Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study.
The ODYSSEY ALTERNATIVE study compared the reduction of LDL-C produced by alirocumab vs ezetimibe after 24 weeks of treatment in patients with primary hypercholesterolemia and well-documented statin intolerance. The study included a placebo run-in period before randomization, during which patients who developed muscle symptoms in the absence of statin exposure were excluded from continuing in the trial. Ezetimibe was selected as the active control as it is a recommended option for LDL-C lowering in statin-intolerant patients due to a favorable safety profile.
ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
The trial also sought to determine safety compared with atorvastatin in an at-risk population that had failed multiple attempts to use first-line evidence-based statin therapy. Thus, a blinded statin rechallenge arm was conducted in parallel with blinded alirocumab and ezetimibe arms. An optional open-label treatment period on alirocumab continued after 24 weeks of double-blind treatment.
Materials and methods
Study design
ODYSSEY ALTERNATIVE (NCT01709513) was a randomized, double-blind, double-dummy, active-controlled, parallel-group study conducted at 67 sites in 8 countries (Austria, Canada, France, Israel, Italy, Norway, the UK, and the USA), with enrollment from November 2012 to October 2013. The study rationale and methods have been published.
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
The study was conducted according to the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice. The institutional review board and ethics committee at each center approved the protocol; all participants gave written informed consent.
Study population
The population comprised patients (≥18 years) with primary hypercholesterolemia.
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
Patients at moderate or high cardiovascular risk (as defined in Supplemental Text 2) were eligible if they had a calculated serum LDL-C concentration ≥ 100 mg/dL (2.6 mmol/L) at screening; those at very high risk were eligible if they had a calculated serum LDL-C ≥70 mg/dL (1.8 mmol/L).
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
During screening, each patient completed a questionnaire that collected data on history of statin therapies and symptoms. Statin intolerance was defined as the inability to tolerate 2 or more statins because of unexplained skeletal muscle–related symptoms (eg, pain, aches, weakness, or cramping), other than those due to strain or trauma that began or increased during statin treatment and resolved with statin discontinuation (see Supplemental Text 2). One of the 2 statins had to have been discontinued while at or below the lowest-approved daily starting dose (ie, rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, pitavastatin 2 mg). A full list of the exclusion criteria is available.
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
The study comprised 5 periods: 1-week screening; 2-week washout of ezetimibe, statins (for patients taking a less than lowest-approved daily starting dose or regimen), and red yeast rice; 4-week single-blind placebo run-in to exclude patients with non-statin–related muscle symptoms; 24-week double-blind treatment; and 8-week off-treatment follow-up.
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
See Supplemental Text 2 for details on diet and use of non-statin medications. As an alternative to the 8-week follow-up, patients who successfully completed the double-blind treatment period or discontinued due to a muscle-related adverse event (AE) were offered up to 196 weeks of alirocumab in an open-label treatment period, starting at their planned week 24 visit.
Patients who completed the placebo run-in without experiencing a skeletal muscle–related AE were randomized to alirocumab, ezetimibe, or atorvastatin (2:2:1, respectively, permuted block design), with stratification for history of myocardial infarction or ischemic stroke, to receive subcutaneous (SC) alirocumab 75 mg twice weekly (Q2W) and oral placebo for ezetimibe or atorvastatin daily, or SC placebo Q2W for alirocumab and either oral ezetimibe 10 mg daily or atorvastatin 20 mg daily (statin rechallenge arm). Oral and SC medications were blinded.
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
At week 12 of the 24-week double-blind treatment period, the alirocumab dose was increased to 150 mg Q2W (also in a 1-mL volume) if the patient's week 8 LDL-C concentration remained elevated (≥70 mg/dL [1.8 mmol/L] in very high cardiovascular risk patients or ≥100 mg/dL [2.6 mmol/L] in moderate or high cardiovascular risk patients).
After 24 weeks, all eligible patients could enter the open-label treatment phase of the study and continue alirocumab 75 mg SC Q2W for approximately 3 years (see Supplemental Text 2).
Efficacy outcome measures
The primary efficacy end point was the percent change in calculated LDL-C concentration from baseline to week 24 by intent-to-treat (ITT) approach. Key secondary efficacy end points were changed from baseline to 24 weeks using on-treatment (modified ITT) LDL-C values, and percent change from baseline to 12 and 24 weeks in LDL-C, apolipoprotein B, non–high-density lipoprotein cholesterol (non–HDL-C), total cholesterol, lipoprotein(a), HDL-C, apolipoprotein A1, and fasting triglyceride concentrations. All efficacy end points were assessed for alirocumab vs ezetimibe arms (see Supplemental Text 2). Efficacy comparisons vs atorvastatin were not assessed as this treatment arm was only included as an essential control to define the appropriate patient population.
Safety outcome measures
Safety end points included AEs, irrespective of their possible relationship to the study drug, defined as those that developed, worsened, or became serious during each of the 3 phases of the study: pretreatment, double blind, and open label. All AEs were assessed by both patient self-reports and AE query. Skeletal muscle AEs included a predefined category of AEs (comprising myalgia or myositis, muscle spasms, muscular weakness, musculoskeletal stiffness, and muscle fatigue) that were identified, on the basis of expert opinion, to be closely related to statin intolerance (see Supplemental Text 2).
Statistical analysis
A sample of 42 patients in both the alirocumab and ezetimibe treatment groups would provide 95% power to detect a 20% difference between alirocumab and ezetimibe in least squares (LS) mean percent change from baseline to week 24 in LDL-C, using a 2-sided t-test and assuming a common standard deviation (SD) of 25%.
Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy.
The overall study sample size for safety parameters during the double-blind treatment period was planned to be 250 patients, allocating 100 patients to both the alirocumab and ezetimibe arms and 50 patients to the statin arm. With specific attention to study treatment withdrawal due to AEs, 100 patients in both the alirocumab and ezetimibe arms would give a 96% probability of recording at least 1 withdrawal event assuming that the event occurs in approximately 3.3% of the population for each arm, based on product information.
The ITT analysis used for evaluation of the primary end point included all calculated LDL-C values, irrespective of treatment adherence, up to week 24. Missing data were accounted for using a mixed-effect model with repeated measures approach.
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
The first secondary end point was an on-treatment (modified ITT) analysis. Further secondary end points, in order of hierarchical testing, included percent change in LDL-C from baseline to week 12 (ITT and on-treatment), the percent change in other lipid parameters, and the proportion of patients reaching their cardiovascular-risk-based LDL-C goal at week 24 in both the ITT and on-treatment analyses (see also Supplemental Table 1). The modified ITT population included all randomized and treated patients with a baseline LDL-C measurement and at least 1 measurement after 4 to 24 weeks of treatment, as long as the patient was on study treatment. For this analysis, all available measurements from weeks 4 to 24 within the on-treatment time window were used in the mixed-effect model with repeated measures model. Binary efficacy end points were analyzed using the multiple imputation approach followed by logistic regression; continuous efficacy end points anticipated to have a non-normal distribution (ie, triglycerides and lipoprotein[a]) were analyzed using the same multiple imputation approach followed by robust regression. The analysis was performed using SAS version 9.2 software.
Results
Patients and intervention
Of the 519 patients screened, 361 met the eligibility criteria (and entered the placebo run-in), and 314 (87.0%) completed the placebo run-in and were randomized to 1 of the 3 treatment arms: 126 to alirocumab, 125 to ezetimibe, and 63 to atorvastatin (Fig. 1). Of the 47 patients who failed to complete the placebo run-in, 25 had skeletal muscle–related symptoms as defined by exclusion criteria, and 23 of 47 (48.9%) had at least 1 skeletal muscle–related AE according to a predefined category of AEs, of which the most common was myalgia (9 of 47; 19.1%) and muscle spasms (7 of 47; 14.9%) (Supplemental Table 2). Others excluded from entering the double-blind treatment period did so for reasons such as withdrawal of consent and unstable dose of concomitant medicine.
Patient baseline characteristics and lipid parameters were evenly distributed across the study arms (Table 1). Overall mean (SD) age was 63.4 (9.5) years, 54.8% were men, 93.9% were white, and mean (SD) baseline LDL-C was 191.3 (69.3) mg/dL (range 81.0–577.0 mg/dL; 5.0 [1.8] mmol/L, range 2.1–14.9 mmol/L). Rates of coronary heart disease and cardiovascular risk factors were high. All patients with known data had reported the development of muscle symptoms since starting the most recent statin therapy before entering the study (Supplemental Table 3). In most cases, symptoms were new, bilateral, and constant.
During the double-blind treatment period, 141 (45.0%) patients received lipid-modifying therapy with bile acid sequestrants, nicotinic acid, fenofibrate, or omega-3 fatty acids (Table 1). In this population of patients with very high baseline LDL-C, half of the patients (n = 54, 49.5%) in the alirocumab arm required a dose increase from 75 to 150 mg Q2W per protocol.
Ninety-six (76.2%) patients in the alirocumab arm, 82 (65.6%) in the ezetimibe arm, and 42 (66.7%) in the atorvastatin arm remained on treatment throughout the double-blind treatment period (Fig. 1). The primary reason for treatment discontinuation was the occurrence of an AE. A total of 281 patients (89.5% of those randomized) who completed the double-blind period entered the ongoing open-label treatment period with alirocumab, 117 of 126 (92.9%) from the alirocumab arm, 105 of 124 (84.7%) from the ezetimibe arm, and 59 of 63 (93.7%) from the atorvastatin arm.
Efficacy
For the primary ITT efficacy analysis, LS mean (standard error [SE]) change in LDL-C concentrations from baseline to week 24 were −45.0% (2.2%) for alirocumab and −14.6% (2.2%) for ezetimibe, with a difference between groups of −30.4% (3.1%; P < .0001). For the on-treatment analysis, the LS mean (SE) change from baseline was −52.2% (2.0%) for alirocumab and −17.1% (2.0%) for ezetimibe (LS mean difference of −35.1% [2.8%], P < .0001). A substantial reduction in LDL-C concentration occurred over the first 4 weeks, which was greater in the alirocumab arm (Fig. 2) and persisted throughout the 24-week treatment period. The on-treatment values demonstrate a durable treatment effect. The distribution of baseline and achieved LDL-C values for alirocumab and ezetimibe at 24 weeks is shown in Figure 3. At week 24, 52 (41.9%) patients on alirocumab and 5 (4.4%) of those on ezetimibe (P < .0001; ITT analysis) reached an LDL-C goal of <70 mg/dL (1.8 mmol/L) in very high cardiovascular risk patients or <100 mg/dL (<2.6 mmol/L) in moderate-to-high-risk patients. Corresponding results in the on-treatment population were 51.2% and 5.6% (P < .0001). The greater effect of alirocumab relative to ezetimibe on LDL-C-lowering from baseline to week 24 was consistent across most of the prespecified subgroups in the ITT population (Supplemental Fig. 1). In addition, reductions in apolipoprotein B, non–HDL-C, total cholesterol and lipoprotein(a) concentrations were greater for alirocumab vs ezetimibe (all P < .0001; Table 2). There were no statistically significant differences between the 2 groups in changes in triglyceride, HDL-C, and apolipoprotein A1 concentrations.
Figure 2LDL-C concentrations vs study time points (on-treatment analysis using raw data). Values at week 12 and week 24 data points indicate achieved LDL-C concentration and LS mean (SE) percent change from baseline. 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. ITT, intent-to-treat; LDL-C, low-density lipoprotein cholesterol; LS, least squares; Pts, patients; SD, standard deviation; SE, standard error.
Figure 3Distribution by 10-mg/dL increments of LDL-C concentration at baseline and week 24 in patients on alirocumab (left panel) or ezetimibe (right panel; modified ITT population using raw data). Comparison between week 24 and baseline is descriptive and exploratory, as 24-week data were not available for all patients. ITT, intent-to-treat; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; SE, standard error.
Hierarchical testing terminated at the end point of HDL-C (baseline–week 24, ITT), and this statistical comparison and all subsequent ones were not considered statistically significant.
7.7 (1.7)
6.8 (1.7)
0.9 (2.4)
−3.8 to 5.6
.70
Fasting triglycerides (baseline–wk 24, ITT)
−9.3 (2.7)
−3.6 (2.8)
−5.7 (3.9)
−13.3 to 1.9
.14
Apolipoprotein A1 (baseline–wk 24, ITT)
4.8 (1.2)
2.9 (1.2)
1.9 (1.7)
−1.5 to 5.3
.28
CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; ITT, intent-to-treat; LDL-C, low-density lipoprotein cholesterol; LS, least squares; SD, standard deviation; SE, standard error.
∗ Alirocumab 75 mg subcutaneous every 2 weeks (Q2W) with a dose increase to 150 mg Q2W at week 12 depending on week 8 LDL-C values.
† 10 mg/d oral ezetimibe.
‡ Hierarchical testing terminated at the end point of HDL-C (baseline–week 24, ITT), and this statistical comparison and all subsequent ones were not considered statistically significant.
Overall rates of treatment-emergent and serious AEs were generally similar between treatment arms, and there were no deaths in the study (Table 3). Discontinuations due to treatment-emergent AEs trended lower in the alirocumab treatment arm. Myalgia was the most common AE in all groups. Muscle spasms occurred in 4.0% of alirocumab patients vs 7.3% of ezetimibe patients and 11.1% of atorvastatin patients. One case of myositis occurred in the atorvastatin arm. The rate of skeletal muscle–related AEs was significantly lower with alirocumab vs atorvastatin (hazard ratio [HR] 0.61, 95% confidence interval (CI) 0.38 to 0.99, P = .042; Fig. 4). A similar trend was observed for alirocumab vs ezetimibe (HR 0.71, 95% CI 0.47–1.06, P = .096), but it did not reach statistical significance. The difference in the rate of skeletal muscle–related AEs was seen soon after study drug initiation (Fig. 4). The rate of study treatment discontinuation due to skeletal muscle–related AEs was nonsignificantly different for alirocumab vs atorvastatin (HR 0.67, 95% CI 0.34–1.32, P = .24) or ezetimibe (HR 0.78, 95% CI 0.43–1.41, P = .41).
Treatment-emergent AEs are AEs that developed, worsened, or became serious during the AE period (defined as the time from the first dose of double-blind study treatment to the last injection plus 70 days [10 weeks], as residual effect of alirocumab was expected until 10 weeks after last injection).
and laboratory parameters (safety population) at 24 weeks
Alirocumab 75 mg subcutaneous every 2 weeks (Q2W) with a dose increase to 150 mg Q2W at week 12 depending on week 8 low-density lipoprotein cholesterol values.
AE resulting in death, is life threatening, requiring hospitalization, resulting in significant disability or incapacity, resulting in a congenital anomaly or birth defection, or is an important medical event.
∗ Treatment-emergent AEs are AEs that developed, worsened, or became serious during the AE period (defined as the time from the first dose of double-blind study treatment to the last injection plus 70 days [10 weeks], as residual effect of alirocumab was expected until 10 weeks after last injection).
† Alirocumab 75 mg subcutaneous every 2 weeks (Q2W) with a dose increase to 150 mg Q2W at week 12 depending on week 8 low-density lipoprotein cholesterol values.
‖ AE resulting in death, is life threatening, requiring hospitalization, resulting in significant disability or incapacity, resulting in a congenital anomaly or birth defection, or is an important medical event.
¶ Predefined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, and muscle fatigue.
Treatment-emergent AEs that occurred in ≥2% of any treatment group are detailed in Supplemental Table 4. Briefly, those occurring in ≥5% of patients were myalgia (24.6%), nasopharyngitis (6.3%), upper respiratory tract infection (5.6%), and arthralgia (5.6%) in the alirocumab arm; myalgia (23.4%), nasopharyngitis (8.1%), arthralgia (7.3%), muscle spasms (7.3%), and back pain (5.6%) in the ezetimibe arm; and myalgia (27.0%), muscle spasms (11.1%), arthralgia (7.9%), fatigue (7.9%), back pain (7.9%), headache (6.3%), muscular weakness (6.3%), paresthesia (6.3%), and vomiting (6.3%) in the atorvastatin arm. One nonfatal myocardial infarction occurred in the alirocumab arm.
None of the patients experienced 2 consecutive LDL-C measurements of <25 mg/dL (<0.6 mmol/L). Fourteen of the 16 patients with myalgia in the atorvastatin arm discontinued treatment, of which 13 entered the open-label treatment period (including the patient on atorvastatin who developed myositis) and were further monitored.
Open-label treatment period
The mean (SD) duration of exposure to alirocumab during the open-label treatment period at the time of this analysis was 41.2 (11.3) weeks (range 2.0–78.1 weeks). Nearly four-fifths (79.0%) of the patients reported experiencing an AE: 4.6% reported an event leading to treatment discontinuation; and 24.2% reported a skeletal muscle–related AE, of which 2.1% discontinued medication as a consequence (Supplemental Table 5). One (0.4%) patient died.
Discussion
In patients at moderate-to-high cardiovascular risk who had reported intolerance to 2 or more statins in the past, self-administered alirocumab reduced LDL-C by 45.0% vs baseline, compared with a reduction of 14.6% for ezetimibe, at 24 weeks of treatment, with a difference between groups of 30.4%. Even greater reductions of LDL-C were observed with alirocumab in the on-treatment analysis owing to the number of patients who discontinued study drug but remained in the study for both treatment arms. Substantially more patients on alirocumab (41.9%) vs ezetimibe (4.4%) reached an LDL-C <70 mg/dL or <100 mg/dL (depending on cardiovascular risk level). Although mean baseline LDL-C concentration was very high (191.3 mg/dL), as anticipated in this population, half of the patients on alirocumab achieved the prespecified LDL-C concentrations without an increase in dose. Alirocumab was associated with a significantly lower rate of musculoskeletal AEs vs atorvastatin.
Statins are currently the most effective treatment for hypercholesterolemia, reducing LDL-C by 30% to 50%
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
The present study recruited patients with a documented history of intolerance to at least 2 statins (including 1 at the lowest recommended daily starting dose). The presence of intolerance was carefully scrutinized through the novel trial design, which incorporated a placebo run-in phase to exclude patients who experienced symptoms in the absence of statin therapy, and a statin rechallenge arm to document the rate of reproducible statin intolerance.
Over the 4-week placebo run-in, 6.4% of the screened patients failed to qualify for the double-blind treatment, suggesting that some patients may experience muscle symptoms because of negative expectations surrounding the potential for statin treatment or for reasons unrelated to statin therapy. During the 24-week double-blind treatment period, 46.0% of patients reported skeletal muscle AEs when rechallenged with atorvastatin 20 mg, a dose judged sufficient to elicit statin-related muscle symptoms, while not preventing patients from consenting to participate in the study,
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
Long-term persistence with statin treatment in a not-for-profit health maintenance organization: a population-based retrospective cohort study in Israel.
This rate of discontinuations is consistent with the Cleveland Clinic experience, which reported a rate of 27.5%, in which 72.5% of patients with statin intolerance were able to tolerate a subsequent trial of statin therapy.
As such, we have documented in a prospective randomized blinded study that many patients with a history of statin intolerance actually “can” tolerate a statin.
In the present study, alirocumab-treated patients experienced a lower rate of muscle-related AEs vs atorvastatin and showed a trend toward a lower rate vs ezetimibe. The notable rate of skeletal muscle–related AEs in all treatment groups in this study may be related to the novel definition used, namely myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, and muscle fatigue. Although across-trial comparisons have recognized limitations, it is useful to contrast the rates of myalgia (a common Medical Dictionary for Regulatory Activities term) in this population with those from similar studies. The rate of myalgia in alirocumab-treated patients was higher in the present study than in the ODYSSEY MONO study
Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized phase 3 trial.
(24.6% vs 3.8%, respectively), with most cases occurring within the first 14 weeks of this 24-week trial; but the rate was also higher with ezetimibe (23.4% vs 3.9%, respectively), a drug that is usually well tolerated.
Similarly, the rates of myalgia were higher than in the Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects (GAUSS-2) trial in which patients were randomized to evolocumab or ezetimibe (8% with evolocumab and 18% with ezetimibe).
Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.
However, the study designs and definitions for statin intolerance differed, and the duration of treatment was significantly shorter in GAUSS-2 (12 vs 24 weeks). Furthermore, the absence of a statin rechallenge arm in GAUSS-2 may have avoided behaviors associated with negative expectations surrounding possible statin treatment.
During the open-label treatment period of this study (mean of 41 weeks), when patients knew that they were not receiving statin therapy, rates of skeletal muscle–related AEs were substantially lower than those during the double-blind period (24.2% vs 32.5%, respectively). Similarly, discontinuations due to skeletal muscle–related AEs were also lower (2.1% vs 15.9%, respectively). Rates of muscle symptoms and muscle-related discontinuations in the open-label treatment period are reasonably consistent with the overall ODYSSEY program (15.1% and 0.4%, respectively). These findings raise the possibility that this statin-intolerant population may have been anticipating the possibility of side effects if rechallenged with a statin during the double-blind period, expressing behavior learned in response to prior statin exposure when reporting muscle symptoms, whether treatment-related or not.
In contrast, the rates of muscle-related AEs in the atorvastatin arm reinforce the challenges clinicians face when diagnosing statin intolerance. One would anticipate that a sizable proportion of statin-intolerant patients would report a recurrence of symptoms when rechallenged with atorvastatin 20 mg. It may be, however, that randomized patients had prior muscle symptoms with a statin other than atorvastatin or at a higher dose; also, the study duration or the dose chosen may have been insufficient for symptoms to manifest in some patients. Furthermore, symptoms in patients who declined to participate may have been more severe than in those who agreed. Our study would suggest that a careful rechallenge of patients with a possible history of statin intolerance would be warranted, and in those who truly do have statin intolerance (either from clear prior documentation or prospective rechallenge), alirocumab would be a powerful means of lowering their LDL-C.
The mean LDL-C concentration at baseline was ≥190 mg/dL, a recognized risk threshold for drug treatment regardless of cardiovascular risk level. As such, these statin-intolerant patients are unlikely, if taking a less than optimal statin dose or less-effective non-statin therapies, to achieve the lipid reductions recommended, or anticipated, in guidelines.
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
In the present study, alirocumab was significantly more effective than ezetimibe at reducing LDL-C, total cholesterol, non–HDL-C, apolipoprotein B, and lipoprotein(a). Favorable changes in triglycerides (decrease of 9.3%) and HDL-C (increase of 7.7%) were also seen with alirocumab; they did not, however, differ in comparison to ezetimibe and were within the boundaries expected.
The reduction in LDL-C of 31.9% with atorvastatin (although exploratory only) was as expected, given the dropout rate and ITT approach, which included off-treatment data.
Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial.
The study design, which included placebo run-in and statin rechallenge to confirm statin intolerance, may have resulted in hypervigilance by study participants regarding potential statin re-exposure. The definition of statin intolerance differs from those used in other reports, and these results cannot be generalized to all individuals with statin-associated muscle symptoms, particularly those who refuse to be rechallenged with a statin and who may have had even more severe symptoms than the participants. It should also be noted that the study population was predominantly white—an aspect that would benefit from being addressed in future studies. Finally, the study duration was short, and the rate of treatment discontinuation may increase over the longer term.
Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial.
and will be assessed in a pooled analysis from the overall ODYSSEY program.
Conclusions
Alirocumab demonstrated significantly greater LDL-C-lowering vs ezetimibe after 24 weeks of treatment in a population with a history of statin intolerance at moderate to very high cardiovascular risk and with elevated LDL-C concentrations at baseline. In this population, alirocumab was well tolerated, with significantly lower rates of musculoskeletal AEs compared with atorvastatin and a trend toward lower rates compared with ezetimibe. There was also a trend toward lower rates of muscular events leading to treatment discontinuation when compared with atorvastatin or ezetimibe. More patients achieved LDL-C goals with alirocumab vs ezetimibe. Accordingly, alirocumab may provide a suitable clinical option in the future management of patients who are intolerant of statins.
Acknowledgment
The authors thank the study patients and investigators, and the following persons from the sponsors for their contributions to data collection and analysis, assistance with statistical analysis, or critical review of the article: (1) Regeneron: William J. Sasiela, PhD, Lisa Collins, BSc, Jaman Maroni, MD, Michael Louie, MD, MPH, and Carol Hudson, BPharm; (2) Sanofi: Jay Edelberg, MD, PhD, L. Veronica Lee, MD, Holly C. Schachner, MD, Guillaume Lecorps, MSc, and Michael Howard, MBA.
Writing support was provided by Sophie K. Rushton-Smith, PhD, funded by Sanofi and Regeneron Pharmaceuticals, Inc.
The design and conduct of the study, analysis of the study data, and opinions, conclusions, and interpretation of the data are the responsibility of the authors. The authors were responsible for all editorial decisions and received no honoraria related to the development/presentation of this publication.
Authors' contributions: C.P.C., T.A.J., S.L.K., M.T.B-D., R.P., and D.A.G. were involved in the study design. P.M.M., P.D.T., J.R.G., J.B., F.J.Z., E.B., and S.L.K. were involved in data acquisition.
All authors were involved in data analysis and interpretation and in revising the article.
All authors approved the final article for submission.
Financial disclosures
This study is funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Dr Moriarty has received research support from Amgen, Kowa, Lilly, Novartis, Sanofi, Regeneron, Genzyme, Pfizer, Catabasis, Esperion, B. Braun, and Kaneka; has received honoraria from Amarin and Kowa; and has received payments as a consultant for Regeneron, Duke Clinical Research Institute, Lilly, Catabasis, B Braun, Kaneka, and Genzyme. Dr Thompson is an employee of Hartford Hospital, Hartford, CT; has received research grants from National Institutes of Health, Genomas Pharmaceuticals, Roche, Sanofi, Regeneron, Esperion, Amarin, and Pfizer; honoraria from Merck, AstraZeneca, Kowa, and Amarin; has been an expert witness on cases on cardiac complications of exercise and cases of statin myopathy; has an ownership interest in Abbvie, Abbott Labs, General Electric, and J&J; and has been a consultant/advisory board member for Amgen, AstraZeneca, Regeneron, Merck, Genoma, Runners World, Sanofi, Esperion, and Amarin. Dr Cannon has received personal fees from Sanofi and Regeneron Pharmaceuticals, Inc during the conduct of the study; has received grants from Accumetrics, Arisaph, AstraZeneca, and Boehringer-Ingelheim, has received personal fees from CSL Behring, Essentialis, Janssen, Lipimedix, BMS, and Pfizer, and has received grants and personal fees from GlaxoSmithKline, Merck, and Takeda, outside the submitted work. Dr Guyton has received research support from Regeneron/Sanofi, Genzyme/Sanofi, GlaxoSmithKline, Amarin Pharma, and Amgen; has received speaker honoraria from Merck; holds stock in Eli Lilly; and has received consulting fees from Regeneron/Sanofi, Novella, and Merck. Dr Bergeron has received research support as a clinical investigator from Amarin, Amgen, Catabesis, Isis, Merck, Novartis, Pfizer, Regeneron, and Sanofi; has been a consultant/advisory board member for Aegerion (Canada), Amgen (Canada), Sanofi (Canada), and Valeant (Canada); and has given educational lectures to GPs for Merck and Valeant. Dr Zieve has received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genkyotex, Novartis, Novo-Nordisk, Pfizer, Regeneron, and Sanofi; and has stock ownership in Johnson and Johnson. Dr Bruckert has received research grants from Amgen, Danone, and Aegerion; has received honoraria from Genfit and AstraZeneca; and has been a consultant/advisory board member for Aegerion, Amgen, MSD, Unilever, Danone, and Sanofi-Regeneron. Dr Jacobson is a consultant/advisory board member for Amarin, Amgen, AstraZeneca, Merck, Regeneron, and Sanofi. Dr Kopecky has received personal fees from Applied Clinical Intelligence, Prime Therapeutics, Esperion Therapeutics, Merck, Inc, and Fusion Conferences; has received nonfinancial support from Genzyme, Regeneron, and Amgen, and has received other support from the American Society for Preventive Cardiology, Mayo Clinic Support Services Texas Non Profit Health Organization, and the Familial Hypercholesterolemia Foundation outside the submitted work. Dr Baccara-Dinet is an employee of Sanofi. Drs Du and Pordy are employees of Regeneron Pharmaceuticals, Inc. Dr Gipe is an employee of Regeneron Pharmaceuticals, Inc; and has stock ownership in Regeneron Pharmaceuticals, Inc.
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy.
Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.
Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized phase 3 trial.
Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial.
Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial.
Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study.
ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
Long-term persistence with statin treatment in a not-for-profit health maintenance organization: a population-based retrospective cohort study in Israel.
Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.
We applaud the decision of Moriarty et al1 to include a statin control arm in their study comparing alirocumab vs ezetimibe in patients with well-documented statin intolerance, the first time this has been done on a large scale. This enabled them to show clearly that most nominally statin-intolerant patients can in fact tolerate a statin, a finding consistent with a much smaller study.2
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