Despite high cardiovascular risk, many patients with acute coronary syndrome (ACS) do not receive timely intensification of lipid-lowering therapy (LLT). To predict the impact of LLT intensification on cardiovascular events and attainment of low-density lipoprotein cholesterol (LDL-C) goals in this population. A Monte Carlo simulation was conducted using data from 54,154 patients withACSto estimate 5-year rates of a composite endpoint of myocardial infarction, ischemic stroke, or cardiovascular death. Three immediate LLT strategies were modeled: (1) high-intensity statin (HIS) +ezetimibe (EZE), (2) HIS +alirocumab (ALI), and (3) HIS +EZE +ALI (triple LLT). Two delayed strategies were also assessed: (1) HIS +EZE at baseline with ALI added at 6 months if LDL-C goals were unmet, and (2) HIS alone at baseline with sequential addition of EZE at 6 months and ALI at 12 months if goals were unmet. LDL-C goals included <55mg/dL and <40mg/dL, each with and without ≥50% reduction. Subgroups included patients with prior ischemic stroke or without revascularization during ACS hospitalization. Triple LLT reduced the predicted 5-year event rate from 22.2% (95% CI: 21.8-22.6) with HIS alone to 14.3% (95% CI: 14.0-14.6), yielding an absolute risk reduction of 8.0% (95% CI: 7.6-8.3) and a relative reduction of 35.8% (95% CI: 34.4-37.2). Predicted benefit was greater in patients with prior ischemic stroke or no revascularization, with LDL-C goals achieved in nearly all patients. Triple LLT initiated at ACS hospitalization may markedly reduce cardiovascular events through earlier and more complete achievement of LDL-C targets.

Background: Lipoprotein(a) [Lp(a)] and other atherogenic lipoproteins each contain one molecule of apolipoprotein B (apoB) per particle. Recent studies have suggested that on a per particle basis, Lp(a) is more strongly associated with major adverse cardiovascular events (MACE) than low density lipoprotein. Hypothesis: In statin-treated patients with recent acute coronary syndrome (ACS), we tested the hypothesis that, on a per particle basis, Lp(a) and its change on treatment with alirocumab (ALI) are more strongly associated with MACE than other [non-Lp(a)] apoB-containing particles. Methods: Molar apolipoprotein(a) [corresponding to Lp(a)] and apo B were measured by mass spectrometry at baseline and month 4 (M4) in a subgroup of 11,957 patients who provided consent for use of stored samples in the ODYSSEY OUTCOMES trial. Non-Lp(a) apoB in nmol/L was calculated as total apo B – Lp(a). Lp(a) and non-Lp(a) apo B at baseline in the placebo group, and absolute changes in their levels on ALI, were related to risk of MACE using proportional hazards models. The latter analysis was adjusted for baseline Lp(a) and non-Lp(a) apo B and stratified by baseline Lp(a) (&lt;125 nmol/L and ≥125 nmol/L). Results: Baseline levels of Lp(a) and non-Lp(a) apoB are shown in the Table. In the placebo group, both baseline Lp(a) and non-Lp(a) apo B independently predicted MACE. At M4 in the ALI group, median Lp(a) change from baseline was -40.9 and -7.0 in those with baseline levels ≥ or &lt;125 nmol/L, respectively. Corresponding median changes in non-Lp(a) apoB were -739 and -776 nmol/L (all P&lt;0.001). In the ALI group with baseline Lp(a)&gt;125 nmol/L, the decrease from baseline in Lp(a), but not the decrease in non-Lp(a) apo B, was significantly related to risk of MACE. Among those with baseline Lp(a)≤125 nmol/L, the decrease from baseline in non-Lp(a) apo B, but not in Lp(a), with ALI was significantly related to risk of MACE. Conclusions: On a per particle basis, baseline Lp(a) and non-Lp(a) apo B both predicted MACE. Among those with high baseline Lp(a), reduction in MACE with ALI was predominantly associated with reduction of Lp(a); among those with lower baseline Lp(a) reduction in MACE with ALI was predominantly associated with reduction in non-Lp(a) apo-B. Lp(a) may be an important target of treatment with ALI in those with elevated levels after ACS.

Two of a kind: mass and molar immunoassay-based lipoprotein (a) concentrations are similarly prognostic for MACE risk and predictive of alirocumab benefit in ODYSSEY OUTCOMES

Background: Baseline (BL) lipoprotein(a) (Lp(a)) concentration is similarly related to cardiovascular (CV) risk when measured in either mass or molar units by immunoassay (IA). Because of Lp(a) isoform variation in mass, differences may exist between Lp(a) measurement methods in terms of relating change to risk reduction. We determined whether the reduction in major adverse cardiovascular events (MACE) by PCSK9 inhibitor alirocumab (ALI) had a similar relationship to the reduction in Lp(a) concentration as measured by 3 different methods. Methods: Lp(a) was measured by IA-mass (Siemens), IA-molar (Roche), and mass spectrometry (MS)-molar assays at BL and month 4 (M4) in a subgroup of patients in the ODYSSEY OUTCOMES trial which compared PCSK9 inhibitor ALI with placebo in patients with recent acute coronary syndrome. Changes in Lp(a) from BL to M4 were related to subsequent risk of MACE (coronary heart disease (CHD) death, nonfatal myocardial infarction (NFMI), fatal + nonfatal ischemic stroke, or unstable angina hospitalization) in the ALI group. Proportional hazards models were adjusted for BL Lp(a), BL LDL-C and its change from BL to M4, and other patient characteristics. Hazard ratios (HR) were calculated for the median change of each Lp(a) assay. All analyses were by intention-to-treat. Results: Among 5500 patients randomized to ALI with available data from all 3 Lp(a) assays, 443 experienced a subsequent MACE. Changes in Lp(a) IA-mass and MS-molar concentration were significantly related to reduced MACE risk, while change in IA-molar concentration was marginally significant; associations were more evident with CHD death + NFMI ( Figure ). MACE HRs for median change were similar across tests. Conclusion: With caveats of a modest number of MACE for analysis, moderately elevated Lp(a) levels, and intra-patient variability in serial values, 3 Lp(a) assay methods appeared similarly predictive of ALI MACE reduction.

Background: Cohort studies and clinical trials have shown a greater prevalence of diabetes among subjects with lower levels of lipoprotein(a) [Lp(a)]. Some healthy cohort studies have shown a greater incidence of new onset diabetes (NOD) among those with lower Lp(a). It is unknown whether the risk of NOD associates with Lp(a) levels in patients (pts) with established cardiovascular disease or whether pharmacologic reduction of Lp(a) with PCSK9 inhibitors modulates this risk. Objective: Using data from the ODYSSEY OUTCOMES trial that compared the PCSK9 inhibitor alirocumab (ALI) with placebo (PBO) in pts with recent acute coronary syndrome, we examined whether NOD was related to baseline Lp(a) level and whether any such relationship was modified by ALI treatment. Methods and Results: Lp(a) was measured with a mass assay in 13,480 trial pts without diabetes at baseline; median (IQR) baseline Lp(a) was 21.9 mg/dL (6.9-61.1); median follow-up was 2.7 years. Intensive statin therapy was utilized in 89%. In the PBO group, NOD was greatest in Quartile 1 and least in Quartile 4 of baseline Lp(a) ( Figure , 4.6 vs 3.1 cases per 100 pt-years, P trend 0.0003). ALI lowered Lp(a) by a median of 23% from baseline. Absolute median reduction in Lp(a) with ALI ranged from nil in baseline Lp(a) Quartile 1 to 15 mg/dL in Quartile 4. Treatment HR (ALI/PBO) for NOD was neutral overall (0.95, 95% CI 0.85-1.05) but varied across baseline Lp(a) quartiles from 0.79 (0.64-0.96) in Quartile 1 to 1.09 (0.87-1.38) in Quartile 4 ( Figure , P trend =0.025). Conclusion: In pts with recent acute coronary syndrome, there is greater NOD among those with lower baseline Lp(a) levels. ALI has an overall neutral effect on NOD: In pts with low baseline Lp(a), ALI has minimal effect on Lp(a) levels and tends to reduce NOD. In pts with high baseline Lp(a), ALI reduces Lp(a) levels with a non-significant excess of NOD. The findings may have implications for emerging therapies that reduce Lp(a) more substantially than PCSK9 inhibitors.

Introduction: It is controversial whether triglyceride (TG) levels are independently associated with post-acute coronary syndrome (ACS) major adverse cardiovascular events (MACE) in patients treated with statins. PCSK9 inhibitors such as alirocumab (ALI) produce substantial reductions in LDL-C, modest reductions in lipoprotein(a) and TG-rich lipoproteins, and reduce MACE. Objective: Using data from the ODYSSEY OUTCOMES trial that compared ALI with placebo in 18,924 patients with recent ACS on optimized statin treatment, we performed a prespecified analysis to determine if MACE (death from coronary heart disease, myocardial infarction, ischemic stroke, or unstable angina) was associated with baseline TG levels in patients treated with placebo, and if MACE reduction with ALI was influenced by baseline TG or the change in TG under treatment. Methods and Results: Proportional hazards models relating continuous baseline TG or the change in TG from baseline to Month 4 with MACE were adjusted for baseline variables: age, region, LDL-C, lipoprotein(a), diabetes, hypertension, BMI, heart failure, peripheral artery disease and cerebrovascular disease. At baseline, median TG level was 130 mg/dL. Median absolute change from baseline to month 4 in the ALI group was -17 (-49, 12) mg/dL. Within the placebo group, baseline TG was associated with MACE (HR per 10 mg/dL increment 1.007, 95% CI 1.001–1.014, p=0.03), although spline analysis suggested non-linearity ( Figure ; spline effect p=0.01) with higher risk above approximately 190 mg/dL. MACE reduction by ALI (HR 0.85, 95% CI 0.78–0.93) did not depend on baseline TG (interaction p=0.99). In the ALI group, change in TG from baseline to Month 4 did not predict MACE after Month 4 (p=0.47). Conclusions: Among patients with recent ACS on optimized statin treatment, baseline TG levels are an independent predictor of MACE. The beneficial effect of ALI on MACE did not depend on either baseline or on treatment TG levels .

P1226Very low achieved low-density lipoprotein cholesterol level with alirocumab treatment after acute coronary syndrome: ODYSSEY OUTCOMES

4115Effect of alirocumab on recurrent cardiovascular events after acute coronary syndrome, according to the intensity of background statin treatment

FRI0528 HIGH INTENSIVE THERAPEUTIC LOWERING OF SYSTEMIC CHOLESTEROL DOES NOT AMELIORATE OA DEVELOPMENT IN KNEE JOINTS OF HUMANIZED DYSLIPIDEMIC MICE

Alirocumab too costly to be cost effective after MI

REDUCTION OF TYPE 1 AND TYPE 2 MYOCARDIAL INFARCTIONS IN PATIENTS TREATED WITH ALIROCUMAB: INSIGHTS FROM THE ODYSSEY TRIAL

POST-ACUTE CORONARY SYNDROME PATIENTS WITH POLYVASCULAR DISEASE DERIVE LARGE ABSOLUTE BENEFIT FROM ALIROCUMAB: ODYSSEY OUTCOMES

ICER publishes final evidence update on alirocumab

Treatment with alirocumab in one patient with sitosterolemia

Alirocumab and Cardiovascular Outcomes in Patients with Acute Coronary Syndrome (ACS) and Diabetes—Prespecified Analyses of ODYSSEY OUTCOMES

Open-label ODYSSEY APPRISE study: Interim data from the first 843 participants

ON-TREATMENT LDL-C LEVELS WHEN ALIROCUMAB DOSE IS DECREASED FROM 150 TO 75 MG EVERY 2 WEEKS IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: RESULTS FROM ODYSSEY

BackgroundEfficacy-safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO), have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in 69 patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated LDLC therapy, we assessed efficacy and safety of ALI and EVO.MethodsPost-commercially, we started 29 patients on ALI 75 mg, 18 on ALI 150 mg, and 22 on EVO 140 mg every 2 weeks added to a maximally tolerated LDLC-lowering regimen. Since LDLC lowering did not differ between ALI 150 and EVO 140 mg, ALI 150-EVO 140 data were pooled (ALI-EVO). Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed.ResultsOf the 69 patients, 25 had HeFH, 25 CVD, and 19 had both. At entry, 23 (33%) took statins and 46 (67%) were statin-intolerant. Mean ± SD and median follow-up were 49 ± 13 and 49 weeks on ALI 75 mg, and 37 ± 12 and 33 weeks on ALI-EVO. In the ALI-EVO group (n = 40), median LDLC fell from 165 mg/dl at entry to 70 mg/dl (median − 59%, p < .0001). AHA 10-year calculated CVD risk fell from 10.2 to 5.5% (median − 28%, p < .0001), and by the NIH calculator from 14.2 to 3.6% (median − 78%, p < .0001). In the ALI 75 mg group (n = 29), entry LDLC fell from 115 to 68 mg/dl (median − 39%, p < .0001). AHA 10-year calculated CVD risk fell from 11.5 to 7.3% (median − 20%, p = .004), and NIH 10-year risk from 12.9 to 5.1% (median 67%, p < .0001). Absolute and percent change in LDLC was independent of statin use. There were flu-like symptoms in 14% of patients. Adverse events did not differ (p > 0.05) between ALI 75 mg and ALI-EVO.ConclusionIn patients with HeFH and/or CVD, LDLC decreased from 115 to 68 mg/dl (39%) on ALI 75 mg with mean follow-up of 49 weeks, and from 165 to 70 mg/dl (59%) on ALI-EVO over 37 weeks, p < .0001 for both. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering.

CONTRASTING US PATIENTS WITH A FILL VERSUS A PRESCRIPTION FOR ALIROCUMAB: EARLY EVIDENCE FROM ADMINISTRATIVE CLAIMS, EMR AND LAB DATA

ALIROCUMAB EFFICACY AND SAFETY IN PATIENTS WITH HYPERCHOLESTEROLEMIA AND WITH OR WITHOUT CLINICAL ATHEROSCLEROTIC CARDIOVASCULAR DISEASE: POOLED ANALYSIS OF 10 ODYSSEY RANDOMIZED TRIALS