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PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab
Corresponding author. Endocrinologie métabolisme et prévention des maladies cardiovasculaires, Institut E3M et IHU cardiométabolique (ICAN), Bureau numéro 13, Hôpital Pitié-Salpêtrière, 83, Boulevard de l'Hôpital, 75013 Paris, France.
Analysis of alirocumab ODYSSEY trials by MI/ischemic stroke status (with/without).
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Alirocumab reduced LDL-C in patients with or without MI/ischemic stroke.
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Alirocumab reduced lipoprotein(a) regardless of MI/ischemic stroke status.
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Most patients with/without prior MI/ischemic stroke attained LDL-C goals.
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Alirocumab's safety profile was generally similar regardless of prior MI/ischemic stroke.
Background
Patients with prior cardiovascular events are at very high risk of recurrent events and may benefit from low-density lipoprotein cholesterol (LDL-C) lowering beyond that achieved with maximally tolerated statins.
Objective
To assess potential differences between the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor, alirocumab, in patients with vs without prior myocardial infarction (MI)/ischemic stroke.
Methods
Data (n = 4880) were pooled from nine ODYSSEY phase 3 trials of alirocumab 75/150 mg or 150 mg every 2 weeks, mostly on background statins ± other lipid-lowering therapies. Analyses were performed according to statin status, alirocumab dose, and control (placebo or ezetimibe).
Results
Baseline LDL-C, non–high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B levels were lower and lipoprotein(a) higher in patients with than without prior MI/ischemic stroke. LDL-C levels were reduced from baseline to week 24 in patients with (51.1%–62.9%) and without (43.6%–58.3%) prior MI/ischemic stroke, with no significant interaction between prior MI/ischemic stroke status and LDL-C–lowering efficacy of alirocumab vs controls. Alirocumab significantly reduced other lipid/lipoproteins (including lipoprotein[a]) similarly in patients with/without MI/ischemic stroke. Week 24 LDL-C goal attainment rates for subgroups with/without prior MI/ischemic stroke on background statins were 74.1%–84.8% and 63.7%–74.7%, respectively. The safety profile of alirocumab was generally similar regardless of prior MI/ischemic stroke status.
Conclusions
Alirocumab significantly reduced LDL-C and other atherogenic lipids/lipoproteins in patients with prior MI/ischemic stroke, and the majority of this very high cardiovascular risk population achieved LDL-C goals; efficacy and safety results were similar in patients without prior MI/ischemic stroke.
Patients who have had a myocardial infarction (MI) or ischemic stroke represent a population at very high risk of subsequent cardiovascular (CV) events.
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.
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR).
and increases with the number of previous CV events.
The high burden of recurrent CV events in these patients identifies them as a priority group for the development of strategies to reduce CV risk. Reduction of low-density lipoprotein cholesterol (LDL-C) is a primary target for CV risk reduction, and patients with prior CV events and elevated LDL-C levels despite high-intensity statin therapy may benefit from further LDL-C reduction.
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.
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR).
2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
Frequency of attainment of low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol goals in cardiovascular clinical practice (from the national cardiovascular data registry PINNACLE registry).
EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries.
Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial.
Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 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.
Patients with prior MI/ischemic stroke represent a very high-risk group that may benefit from additional lipid-lowering therapy with a PCSK9 inhibitor. However, such patients have not been specifically assessed in this setting and could potentially respond differently to alirocumab compared to those without a prior event because of interpopulation differences. For example, those with prior CV events may be on high-intensity statins (with other lipid-lowering therapies), be receiving various other medications (eg, antihypertensive/antidiabetic medications), and may have a differential demographic profile.
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR).
The large (n = 18,924) ODYSSEY OUTCOMES trial showed that, compared with placebo, alirocumab 75/150 mg every 2 weeks (Q2W) reduced major adverse CV events in patients with recent acute coronary syndrome
; however, the patient population in the current analysis differs and includes patients with a diagnosis of familial hypercholesterolemia (FH) and/or statin intolerance, placebo- or ezetimibe-treated controls, and different alirocumab-dosing regimens. This analysis of nine ODYSSEY phase 3 trials was performed to determine whether the LDL-C–lowering efficacy and safety of alirocumab are consistent between patients with and without prior MI and/or ischemic stroke.
Methods
This analysis included patient-level data from nine phase 3 ODYSSEY studies of 24–104 weeks’ duration (Fig. 1), including COMBO I,
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.
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 adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial.
Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial.
was not included in this analysis as it excluded patients with a history of CHD or CHD risk equivalents.
Figure 1Overview of studies included in this pooled analysis (randomized population). * Rosuvastatin 20–40 mg, atorvastatin 40–80 mg, or simvastatin 80 mg daily, or lower doses with an investigator-documented reason eg, intolerance; OPTIONS I used atorvastatin 20–40 mg and OPTIONS II used rosuvastatin 10–20 mg. † Other LLT not allowed in COMBO II.‡ Dose adjustment from 75 to 150 mg Q2W at week 12 if LDL-C was ≥70 mg/dL at week 8 (or, in OPTIONS I, OPTIONS II, and ALTERNATIVE studies, ≥70 mg/dL for patients with prior CHD or ≥100 mg/dL with CHD risk equivalents). Study names/sponsor study numbers are shown in boxes together with duration of double-blind treatment periods, clinicaltrials.gov registration numbers, and details of alirocumab dose, control and number of patients in the randomized populations. Note that statin control arms from OPTIONS I, OPTIONS II, and ALTERNATIVE studies were not included. CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; Q2W, every 2 weeks.
The studies included in this analysis enrolled patients with heterozygous FH (HeFH) and/or patients with non-FH who had established CHD or CV risk factors. At screening, LDL-C levels required for enrollment were ≥70 or ≥100 mg/dL, depending on risk, except for LONG TERM (LDL-C ≥70 mg/dL) and HIGH FH (LDL-C ≥160 mg/dL).
Patients were randomized to receive double-blind treatment with either alirocumab or control (ezetimibe in four studies and placebo in five) (Fig. 1). Two studies (LONG TERM and HIGH FH; n = 2448) evaluated alirocumab 150 mg Q2W vs placebo. In the other seven studies (n = 2432), patients received alirocumab 75 mg Q2W with dose increase to 150 mg Q2W at week 12 (notated as 75/150 mg Q2W in this report) if their prespecified LDL-C goals were not reached at week 8. In FH I and II and COMBO I and II, the alirocumab dose was increased if patients’ LDL-C levels were ≥70 mg/dL. In OPTIONS I and II and ALTERNATIVE, LDL-C goals were risk based; alirocumab dose was increased if LDL-C was ≥70 mg/dL for very high-risk patients with prior CV disease (or type 2 diabetes with organ damage in OPTIONS I and II) or ≥100 mg/dL for other patients.
Except for the ALTERNATIVE study, which was conducted in a statin-intolerant population and in which no background statin was used, patients received background statin ± other lipid-lowering therapy (other background lipid-lowering therapy was not used in COMBO II). In COMBO I and II, FH I and II, LONG TERM, and HIGH FH, patients were on maximally tolerated statin doses (atorvastatin 40–80 mg, rosuvastatin 20–40 mg, and simvastatin 80 mg daily or lower doses with an investigator-documented reason, eg, intolerance), whereas patients in OPTIONS I received atorvastatin 20 or 40 mg and patients in OPTIONS II received rosuvastatin 10 or 20 mg. Randomization in each individual study was stratified according to history of MI or ischemic stroke (yes/no).
Exclusion criteria in the trials included recent (within 3 months) MI, unstable angina leading to hospitalization, uncontrolled cardiac arrhythmia, coronary artery bypass graft surgery, percutaneous coronary intervention, carotid surgery or stenting, cerebrovascular accident, transient ischemic attack, endovascular procedure or surgical intervention for peripheral vascular disease, and history of New York Heart Association Class III or IV heart failure within the past 12 months.
Endpoints and analyses
The primary efficacy endpoint was the percentage change in LDL-C from baseline to week 24, analyzed in the intent-to-treat (ITT) population, which included all randomized patients with a baseline and at least one postbaseline LDL-C assessment, regardless of treatment adherence.
Secondary efficacy endpoints included the proportion of patients achieving prespecified LDL-C treatment goals at week 24 and percentage change from baseline to week 24 in non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)].
LDL-C levels were calculated using the Friedewald equation
Safety was assessed in all randomized patients who received at least one full or partial dose of study treatment. Treatment-emergent adverse events (TEAEs) were events that occurred from the first dose of study treatment up to 70 days after the last dose.
Pooling strategy
Baseline data were pooled according to assignment to alirocumab or control treatment and MI/stroke status; a comparison of baseline data was conducted between overall pools of all patients (alirocumab and control) with MI/stroke vs those without MI/stroke. Efficacy data were analyzed in four pools according to alirocumab dose (75/150 or 150 mg Q2W), control (placebo/ezetimibe), and whether background statin was used, and data were compared between patients with or without MI/stroke. Safety data were analyzed in pools according to the control used in the trials (alirocumab vs placebo or ezetimibe) and are presented for patients with or without MI/stroke. In every analysis, data for the subgroup with/without prior MI/stroke are derived from recordings in the Interactive Voice Response System (IVRS) used for randomization, regardless of agreement with data derived from medical history.
Statistical analysis
A similar statistical approach was used as for the primary studies included in the analysis.
Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial.
Missing data were accounted for using a mixed-effect model with repeated measures approach, and least squares means, standard errors, and P-values were taken from the mixed-effect model with repeated measures analysis. Interaction P-values for the comparison of the difference between alirocumab and control in the percentage change for lipid/lipoprotein endpoints observed in subgroups with or without prior MI/ischemic stroke were derived according to the same mixed-effect model as for the primary analysis. The proportion of individuals achieving prespecified LDL-C goals was analyzed in the on-treatment population (pooled by alirocumab dosage and control treatment) by multiple imputation to account for missing data, followed by logistic regression. The on-treatment (modified ITT) population was defined as all randomized individuals who received at least one dose (or part) of the double-blind study treatment and had an evaluable primary efficacy endpoint during the treatment period. The treatment period was defined as the period ending on the date of the last injection plus 21 days or, in the case of ezetimibe or placebo for ezetimibe, the last capsule administration date plus 3 days, whichever came first.
Results
Patient characteristics
This analysis included 3136 and 1744 patients randomized to alirocumab or control (ezetimibe or placebo), respectively (Fig. 1). At baseline, 44.7% of patients had a history of MI/ischemic stroke, 1415 (45.1%) in the alirocumab, and 765 (43.9%) in the control groups (Table 1).
Table 1Baseline characteristics of patients by history of MI/ischemic stroke (randomized population)
Mean (SD), unless otherwise specified
With prior MI/ischemic stroke (n = 2180; 44.7%)
Without prior MI/ischemic stroke (n = 2700; 55.3%)
P-values for the overall cohort with prior MI/ischemic stroke vs overall cohort without prior MI/ischemic stroke were derived from the t-test for normally distributed continuous variables (comparing the mean difference of the two specified groups) or chi-square test for categorical variables.
Data for the subgroup with/without prior MI/stroke are derived from recordings in the IVRS used for randomization, which were not always in agreement with data from medical history—106 patients (3.6%) in the NO subgroup reported an MI or a stroke, by contrast, 53 (2.3%) in the YES subgroup did not report an MI or a stroke in their medical history.
∗ P-values for the overall cohort with prior MI/ischemic stroke vs overall cohort without prior MI/ischemic stroke were derived from the t-test for normally distributed continuous variables (comparing the mean difference of the two specified groups) or chi-square test for categorical variables.
† PCSK9 levels were analyzed only in COMBO II, FH I, and LONG TERM.
‡ Statin intensity: high, atorvastatin 40–80 mg, rosuvastatin 20–40 mg, or simvastatin 80 mg daily; moderate, atorvastatin 20 to <40 mg, rosuvastatin 10 to <20 mg, or simvastatin 40 to <80 mg daily; low, atorvastatin <20 mg, rosuvastatin <10 mg, or simvastatin <40 mg daily.
§ Data for the subgroup with/without prior MI/stroke are derived from recordings in the IVRS used for randomization, which were not always in agreement with data from medical history—106 patients (3.6%) in the NO subgroup reported an MI or a stroke, by contrast, 53 (2.3%) in the YES subgroup did not report an MI or a stroke in their medical history.
Baseline patient characteristics were generally comparable between the alirocumab and control groups for patients with and without prior MI/ischemic stroke; however, there were several significant between-group differences when patients were pooled by prior MI/ischemic stroke status (with and without), regardless of randomization to alirocumab or control (Table 1). Patients with prior MI/ischemic stroke were older, more likely to be male and white, have hypertension, and be using high-intensity statin treatment, whereas patients without MI/ischemic stroke were more likely to have HeFH (36.9% vs 15.8%) or diabetes (34.7% vs 27.1%; P < .0001 for both).
In addition, in the pooled cohort of patients with prior MI/ischemic stroke (Table 1), mean total PCSK9 (P < .0006) and lipid/lipoprotein levels (LDL-C, non-HDL-C, HDL-C, apoB) were significantly lower than that of the overall pooled cohort of patients without prior MI/ischemic stroke (P < .0001 for all), while median Lp(a) was higher (P = .0058). As expected, the frequency of any CV history/risk factor, including acute or silent MI, unstable angina, coronary revascularization procedure, other clinically significant CHD, or congestive heart failure, was higher in the prior MI/ischemic stroke cohort than in the cohort without such a history (Table 1; P < .0001 for all).
Lipid parameter changes
Alirocumab significantly reduced LDL-C from baseline to week 24 in patients with or without prior MI/ischemic stroke vs control (placebo or ezetimibe) (P < .0001 for all; Fig. 2A). Mean LDL-C reduction at week 24 was generally comparable between patients with or without prior MI/ischemic stroke across the treatment pools (interaction P-values > .05 for all). Absolute LDL-C levels achieved at week 24 are shown in Figure 2B; regardless of prior MI/ischemic stroke status, alirocumab-treated patients achieved on-treatment LDL-C levels of 47.6–64.1 mg/dL in the three treatment pools on background statin therapy (vs 118.5–138.5 mg/dL with placebo and 80.7–84.7 mg/dL with ezetimibe) and in the single treatment pool not on background statin therapy, 96.7–107.0 mg/dL (vs 159.8–160.9 mg/dL with ezetimibe).
Figure 2Percentage change from baseline in LDL-C (A) and achieved LDL-C level (B) at week 24 in patients with or without prior MI/ischemic stroke (ITT analysis). *P < .0001 vs control. † Interaction P-value for percentage reduction in LDL-C (alirocumab minus control) for patients with vs without prior MI/ischemic stroke. Patients received maximally tolerated statins (rosuvastatin 20–40 mg, atorvastatin 40–80 mg, or simvastatin 80 mg daily), except for OPTIONS I (atorvastatin 20–40 mg) and OPTIONS II (rosuvastatin 10–20 mg), and ALTERNATIVE (no statins). ITT, intent-to-treat; LDL-C, low-density lipoprotein cholesterol; LS, least squares; MI, myocardial infarction; Q2W, every 2 weeks; SE, standard error.
In the seven studies that permitted alirocumab dose increase from 75 to 150 mg Q2W at week 12 for patients not achieving prespecified LDL-C goals at week 8, the proportion of patients with and without prior MI/ischemic stroke who received dose increase in the alirocumab 75/150 mg vs placebo on background statin therapy pool was 26% (60/231) and 39.2% (168/429), respectively. Corresponding proportions in the alirocumab 75/150 mg vs ezetimibe on background statin therapy pool were 17.2% (61/354) and 18.4% (51/277), and in the alirocumab 75/150 mg vs ezetimibe without background statin therapy pool, 52.2% (12/23) and 48.8% (42/86), respectively.
At week 12 (before any potential dose increase from 75 mg Q2W), patients with and without a history of MI/ischemic stroke treated with alirocumab 75 mg Q2W demonstrated significantly greater reductions from baseline in LDL-C levels ([46.6%–53.1%] and [43.3%–46.5%], respectively) vs placebo or ezetimibe (P < .001), with no significant between-group difference (P-interaction > .05 for all, Supplementary Fig. 1). Reductions from baseline in LDL-C levels at week 12 for patients treated with alirocumab 150 mg Q2W differed significantly between patients with and without prior MI/ischemic stroke (64.9% vs 60.7%; P-interaction = .0067); however, the between-group difference was no longer significant at week 24 (62.9% vs 58.3%; P-interaction = .1485, Fig. 2A). Overall, similar LDL-C reductions were observed with alirocumab vs control from week 4 onward, regardless of history of MI/ischemic stroke, and were maintained through the treatment period (Supplementary Fig. 2).
In studies in which patients received background statin therapy, significantly more alirocumab-treated patients with (74.1%–84.8%) and without (63.7%–74.7%) prior MI/ischemic stroke achieved their LDL-C target levels at week 24 (Fig. 3) vs those allocated to placebo (4.5%–9.0% and 2.3%–6.7%, respectively) or ezetimibe (51.4% and 45.7%, respectively; P < .0001 for all). In the ALTERNATIVE study with no background statin therapy, 50.0% (vs 0.3% with control; P < .001) and 36.6% (vs 2.5% with control; P < .0001) of alirocumab-treated patients with and without prior MI/ischemic stroke achieved their LDL-C goal. Of note, patients with and without prior MI/stroke in ALTERNATIVE had relatively high mean baseline LDL-C levels, 174.0 mg/dL and 199.5 mg/dL, respectively.
Figure 3Proportion of patients (%) with or without prior MI/ischemic stroke achieving LDL-C <70 mg/dL at week 24 (mITT analysis). *P < .0001 vs control. †P < .001 vs control. LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; mITT, modified intent-to-treat; Q2W, every 2 weeks.
Reductions from baseline to week 24 in secondary lipid/lipoprotein endpoints (non-HDL-C, apoB, and Lp[a]) were generally consistent between patients with and without a history of MI/ischemic stroke across each dose pool, regardless of background statin therapy (Fig. 4). In further analysis of patients with baseline Lp(a) > 30 mg/dL, similar to that seen in the overall population, reductions in Lp(a) from baseline to week 24 were consistent between patients with and without a history of MI/ischemic stroke across each dose pool on background statin therapy (Supplementary Fig. 3). The alirocumab 75/150 mg Q2W vs ezetimibe (no background statin) is not shown because there were limited patients with prior MI/ischemic stroke in this subgroup, only 7 in the control arm. There was a significant difference between patients with and without prior MI/ischemic stroke for reductions from baseline to week 24 in apoB in the alirocumab 150 mg Q2W dose pool (54.5% vs 50.1%; P-interaction = .0321, Fig. 4B), which may be related to the significantly higher baseline apoB levels in patients without than in those with prior MI/ischemic stroke.
Figure 4Percentage change from baseline to week 24 in (A) non–HDL-C, (B) apoB, and (C) Lp(a) levels in patients with or without prior MI/ischemic stroke (ITT analysis). † Interaction P-value for percentage reduction in lipid/lipoprotein (alirocumab minus control) for patients with vs without prior MI/ischemic stroke. apoB, apolipoprotein B; ITT, intent-to-treat; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); LS, least squares; MI, myocardial infarction; non–HDL-C, non–high-density lipoprotein cholesterol; Q2W, every 2 weeks; SE, standard error.
Alirocumab was generally well tolerated compared with controls, regardless of previous history of MI/ischemic stroke. The proportion of alirocumab-treated patients with at least one TEAE was similar compared with controls for patients with (79.7% vs 81.5%) and without (79.9% vs 81.1%) prior MI/ischemic stroke in the placebo-controlled pools, and the ezetimibe-controlled pools, (78.3% vs 79.1%) and (74.6% vs 69.2%), respectively (Table 2). In addition, the overall rates of treatment-emergent serious adverse events, discontinuations, and deaths because of TEAEs were similar between the alirocumab and control (placebo/ezetimibe) groups for patients with and without prior MI/ischemic stroke (Table 2). Although the rate of treatment-emergent serious adverse events differed between alirocumab-treated patients with prior MI/ischemic stroke and those without in the placebo- (20.7% vs 13.5%) and ezetimibe-controlled pool (22.2% vs 13.8%), this was also seen for patients with vs without prior MI/ischemic stroke that received placebo (21.0% vs 14.2%) or ezetimibe (21.7% vs 9.7%). Among TEAEs reported in ≥5% of patients, the frequency of mild and transient injection-site reactions tended to be higher in the alirocumab than the control groups.
Table 2Safety analysis in patients with or without MI/ischemic stroke (safety population)
Accidental overdose was an event suspected by the investigator or spontaneously notified by the patient (not based on systematic injection/capsule counts) and defined as at least twice the intended dose within the intended therapeutic interval.
∗ Accidental overdose was an event suspected by the investigator or spontaneously notified by the patient (not based on systematic injection/capsule counts) and defined as at least twice the intended dose within the intended therapeutic interval.
In this pooled analysis of 4880 high-risk patients with or without prior MI/ischemic stroke, compared with placebo or ezetimibe, alirocumab treatment resulted in significantly greater incremental reductions in LDL-C levels in patients on background statin therapy and was generally well tolerated, regardless of prior MI/stroke status. LDL-C reductions with alirocumab were sustained (for 24–104 weeks, depending on the study) and the majority of alirocumab-treated patients on statin background therapy achieved their LDL-C target levels, regardless of MI/ischemic stroke status. These data suggest that PCSK9 inhibition may benefit patients who have had an MI and/or an ischemic stroke and are at very high risk of recurrent CV events.
In support of this, in a previous post hoc analysis of the LONG TERM study in high-risk patients (n = 2341), compared with placebo, the risk of major adverse CV events (death from CHD, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) over 80 weeks of follow-up was 48% lower with alirocumab (nominal P = .02).
Efficacy and safety of alirocumab in individuals with type 2 diabetes mellitus with or without mixed dyslipidaemia: Analysis of the ODYSSEY LONG TERM trial.
alirocumab significantly reduced LDL-C and other atherogenic lipids/lipoproteins and was generally well tolerated. In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in subjects with elevated risk cardiovascular outcomes trial,
the PCSK9 inhibitor, evolocumab, significantly reduced major vascular events in patients with stable ASCVD, whereas in patients within 2 years of their most recent MI or with multiple prior MIs, there were marked reductions in risk with LDL-C lowering.
In the current analysis, baseline LDL-C levels were lower in patients with prior MI/ischemic stroke, which may reflect the lower proportion of patients with HeFH in this group vs those without such a history and/or more frequent treatment with high-intensity statin therapy (58.4% vs 53.0%, respectively). These variations are most likely because of the differences in inclusion criteria between the different studies.
Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized 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.
Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies.
The levels of C-reactive protein were low regardless of treatment allocation and MI/ischemic stroke status, which likely reflects the individual study inclusion criteria of patients on stable statin therapy.
Despite these differences in baseline patient characteristics, there was no appreciable effect on alirocumab efficacy or safety, regardless of MI/ischemic stroke history. Of note, despite the lower baseline LDL-C and other lipid/lipoprotein levels (non-HDL-C, HDL-C, and apoB) in the cohort with prior MI/ischemic stroke, similar mean percentage reductions were seen with alirocumab, regardless of prior MI/ischemic stroke status, supporting that high-risk individuals with lipid/lipoprotein levels even modestly above goals may gain substantial benefits.
Although alirocumab dose increase from 75 to 150 mg Q2W was similar for patients with and without prior MI/ischemic stroke in two of the three treatment pools in which dose increase was permitted, in the alirocumab 75/150 mg on background statin therapy vs placebo treatment pool, the frequency of dose increase was lower in those without than with prior MI/ischemic stroke (26% vs 39.2%). Patients without prior MI/stroke in this treatment pool were more likely to have HeFH, have higher baseline LDL-C, and be receiving lower statin doses, primarily because patient data in this treatment pool were accessed from the trials FH I/FH II
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.
Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol and nonhigh-density lipoprotein cholesterol for cardiovascular risk reduction in randomized trials.
Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American heart association/American stroke association.
In this analysis, at baseline, median Lp(a) was significantly higher but apoB levels were lower in the overall pooled cohort of patients with than without prior MI/ischemic stroke; nevertheless, alirocumab significantly reduced non-HDL-C, apoB, and Lp(a) levels from baseline to week 24, regardless of MI/ischemic stroke status and background statin therapy.
In this pooled analysis of high-risk patients with or without prior MI/ischemic stroke, alirocumab was generally well tolerated with a favorable safety profile. As previously shown in pooled safety data from 14 randomized alirocumab trials (n = 5234),
there tended to be a higher frequency of injection-site reactions with alirocumab than controls. Importantly, an analysis of patient data (n = 4197) pooled from six ODYSSEY phase 3 trials, which were also included in this analysis, showed that mean overall treatment adherence over at least 1 year was high with alirocumab 75 or 150 mg Q2W and comparable with control (98.0% vs 97.8%).
Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years.
One of the limitations of this post hoc analysis is that although the efficacy of alirocumab in terms of LDL-C reductions in patients according to MI/ischemic stroke history was assessed, it was not prospectively designed to demonstrate a direct effect on CV outcomes. The effect of alirocumab 75/150 mg Q2W on CV events has been evaluated in the ODYSSEY OUTCOMES study, in which alirocumab reduced MACE, MI, and ischemic stroke, was associated with a lower rate of all-cause death and was generally well tolerated compared with placebo in 18,924 patients with recent acute coronary syndrome on background statin.
In summary, atherogenic lipid reductions and safety findings associated with at least 1 year of alirocumab treatment were similar in patients with vs without prior MI/ischemic stroke at baseline. These findings support the use of alirocumab as an atherogenic lipid/lipoprotein-lowering therapeutic option in addition to maximally tolerated statin ± other LLTs in high-risk patients such as those with a history of MI/ischemic stroke.
Acknowledgment
The authors thank the patients, their families, and all investigators involved in this analysis. The following people from the study sponsors provided editorial comments on the manuscript: Michael Howard, MBA, L. Veronica Lee, MD, and Corinne Hanotin, MD (Sanofi), and Robert Pordy, MD, Carol Hudson, MS, and Eva-Lynne Greene, MS (Regeneron Pharmaceuticals, Inc). Additional statistical analysis was provided by Desmond Thompson, PhD, consultant to medical affairs at Regeneron Pharmaceuticals, Inc Medical writing support, under the direction of the authors, was provided by Nila Bhana, MSc, and Susanne Ulm, PhD, of Prime (Knutsford, UK), supported by Sanofi and Regeneron Pharmaceuticals, Inc, according to Good Publication Practice guidelines (https://www.ismpp.org/gpp3).
Funding: This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. The sponsors were involved in the study design, collection, analysis, and interpretation of data, as well as data checking of information provided in the article. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication
Authors' contributions: E. Bruckert, D.J. Kereiakes, and M.J. Koren contributed to data acquisition, analysis or interpretation of data, revising the manuscript critically for important intellectual content and gave approval of the version to be submitted. M. Louie, A. Letierce, K. Miller, and C.P. Cannon contributed to the analysis and interpretation of data, revising the manuscript critically for important intellectual content and gave approval of the version to be submitted.
Financial disclosures
E. Bruckert has received honoraria from Aegerion, Genfit, MSD, Sanofi, Regeneron Pharmaceuticals, Inc, AstraZeneca, Unilever, Akcea, and Servier.
D.J. Kereiakes reports no disclosures.
M.J. Koren has received research grants and consultant/advisory board fees from Regeneron Pharmaceuticals, Inc, and Sanofi.
M.J. Louie is an employee and stockholder of Regeneron Pharmaceuticals, Inc.
A. Letierce is an employee of and shareholder in Sanofi.
K. Miller is an employee and stockholder of Regeneron Pharmaceuticals, Inc.
C.P. Cannon has received research grants from Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, and Merck; and consultant fees from Alnylam, Amarin, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Janssen, Kowa, Merck, Pfizer, Regeneron Pharmaceuticals, Inc, and Sanofi.
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