https://orcid.org/0000-0002-4857-9125
Abstract
In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days vs. placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥ 100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C.
Overall, 18 219 patients with acute MI, multivessel coronary artery disease, and additional risk factors were randomized to either four weekly infusions of 6 g CSL112 or placebo. This exploratory post-hoc analysis evaluated cardiovascular outcomes by baseline LDL-C in patients prescribed guideline-directed statin therapy at the time of randomization (n = 15 731).
As baseline LDL-C increased, the risk of the primary endpoint at 90 days lowered in those treated with CSL112 compared with placebo. In patients with LDL-C ≥ 100 mg/dL at randomization, there was a significant risk reduction of cardiovascular death, MI, or stroke in the CSL112 vs. placebo group at 90, 180, and 365 days [hazard ratio .69 (.53–.90), .71 (.57–.88), and .78 (.65–.93)]. In contrast, there was no difference between treatment groups among those with LDL-C < 100 mg/dL at baseline.
In this population, treatment with CSL112 compared to placebo was associated with a significantly lower risk of recurrent cardiovascular events among patients with a baseline LDL-C ≥ 100 mg/dL. Further studies need to confirm that CSL112 efficacy is influenced by baseline LDL-C.
AEGIS-II trial exploratory post-hoc analysis by baseline low-density lipoprotein cholesterol (LDL-C) in patients prescribed guideline-directed statin therapy at the time of randomization. CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
See the editorial comment for this article ‘Can apoA-I infusion decrease cardiovascular events?’, by L. Tokgözoğlu et al., https://doi.org/10.1093/eurheartj/ehae774.
Introduction
Following acute myocardial infarction (AMI), there remains an elevated risk of recurrent ischemic events despite guideline-directed medical therapy that includes complete revascularization, low-density lipoprotein cholesterol (LDL-C) lowering therapy, and antiplatelet agents.1,2 Patients with AMI have impaired reverse cholesterol transport,3 a process where cholesterol is removed from the plaque via cholesterol efflux predominantly mediated by apolipoprotein A-I (apoA-I), which is the main protein on high-density lipoproteins (HDL).4 Furthermore, those patients with impaired or low cholesterol efflux post-AMI are at a higher risk of major adverse cardiovascular events (MACE), including all-cause death,5 both in the first 30 days post-AMI and over the ensuing 6 years.6
CSL112 is a human plasma-derived apoA-I formulated with phosphatidylcholine for intravenous infusion that increases apoA-I levels (2-fold increase from baseline) and cholesterol efflux capacity (4-fold increase from baseline) following AMI.7–10 In the ApoA-I Event Reducing in Ischemic Syndromes-II (AEGIS-II) trial, CSL112 administered weekly for 4 weeks starting within 5 days of an AMI in patients with multivessel coronary artery disease and other cardiovascular risk factors did not significantly reduce the risk of the primary efficacy endpoint of the time to first occurrence of cardiovascular death, myocardial infarction (MI), or stroke at 90 days compared to placebo.11 Nonetheless, given the well-established relationship between increased LDL-C and atherosclerotic plaque burden,12 as well as prior observations of greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥ 100 mg/dL on statin therapy,13,14 we hypothesized that a therapy that enhances cholesterol efflux, which is the first step in reverse cholesterol transport, may also be influenced by baseline LDL-C.
Methods
Study design
The details of the AEGIS-II trial design and primary results have been published previously.11,15 Briefly, AEGIS-II was an international, multicenter, randomized, double-blind, placebo-controlled trial that enrolled adult patients with type 1 (spontaneous plaque disruptions) AMI and multivessel coronary artery disease and with either pharmacologic treatment for diabetes or two or more risk factors. Risk factors included age of 65 years or more, prior history of MI, or peripheral artery disease. Key exclusion criteria included evidence of hepatobiliary disease, ongoing hemodynamic instability, left ventricular ejection fraction <30%, an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, scheduled coronary bypass graft surgery after randomization, or a body weight <50 kg. Recruitment took place between March 2018 and November 2022 at 886 sites in 49 countries. The study was approved by national regulatory agencies and institutional review boards or ethics committees at all participating sites, and all patients provided written informed consent (ClinicalTrials.gov, number NCT03473223).
Participants were randomly assigned (1:1) to receive either CSL112 6 g or a matching placebo intravenously administered over a 2-h period starting within 5 days of AMI. Patients received four consecutive weekly intravenous infusions of the study drug approximately 7 days apart and completed within 30 days of randomization. Assessments were conducted at screening at each infusion visit, and follow-up assessments were performed on Days 29, 60, and 90 and subsequently every 90 days until the final visit at 1 year.
Statistical analyses
Efficacy analyses were performed in patients in the intention-to-treat (ITT) population, regardless of treatment received. The primary efficacy endpoint of the AEGIS-II trial was the time to the first occurrence of the composite of cardiovascular death, MI, or stroke from the time of randomization through 90 days. Secondary endpoints included time to first occurrence of the composite at 180 and 365 days, as well as for each of the components of the composite endpoint at the various timepoints. The time to first occurrence of the composite of cardiovascular death and MI was an exploratory endpoint. All primary and secondary endpoints were adjudicated by a blinded clinical events committee using pre-specified criteria.
For this analysis, a cubic spline method was used to model the hazard ratio (HR) for CSL112 vs. placebo on the time to first occurrence of cardiovascular death, MI, or stroke at 90 days as a function of LDL-C as a continuous variable using all covariates that were used in the primary analysis plus spline (LDL-C) and interaction between spline (LDL-C) and treatment. A natural cubic spline with 4 knots placed at 20%, 40%, 60%, and 80% percentiles of the LDL-C was created, leading to five separate cubic curves in each of the five regions, while forcing the curves at the four knots to be continuous and smooth.
Treatment comparison for time-to-event endpoints by subgroup of baseline LDL-C (≥100 mg/dL vs. <100 mg/dL) was performed using Cox proportional hazard regression model adjusting for covariates, including fixed effects for treatment, geographic region, index MI type, index MI management, age, diabetes, peripheral arterial disease, and an interaction term for index AMI type and index AMI management was fitted to the model. The proportional hazard assumption for the treatment was assessed by plotting the Schoenfeld residuals as a function of follow-up duration and using the Kolmogorov-type supremum test. Endpoints analysed include the composite of cardiovascular death, MI and stroke, the individual components of this original primary endpoint, and the composite of cardiovascular death and MI. This subgroup analysis was limited to patients who had available baseline LDL-C levels and were prescribed statin therapy at the time of randomization (n = 15 731). Two-sided P-values are reported with a P < .05 indicating statistical significance.
The analyses presented here are post-hoc and, therefore, exploratory in nature and hypothesis generation; no adjustment is made for multiplicity. All statistical analyses were performed using SAS® version 9.4 (Cary, NC).
Role of the funding source
CSL Behring was involved in the study design, data collection, data analysis, data interpretation, and the preparation, review, and approval of the manuscript. The decision to submit the manuscript for publication was made by the academic leadership of the steering committee.
Results
A total of 18 219 participants were included in the ITT analysis of the main study, with 9112 randomized to CSL112 and 9107 to placebo. The majority of patients received all four infusions (89.8% of patients in the CSL112 group and 90.0% of patients in the placebo group). Ascertainment of the primary endpoint was complete for 99.4% of potential patient-years of follow-up, and ascertainment of vital status was complete for 99.5% of patients. Only one participant in each treatment group was lost to follow-up.
Baseline characteristics were well balanced between the two treatment arms overall11 and likewise, within those patients with an LDL-C ≥ 100 mg/dL at randomization and within those with an LDL-C < 100 mg/dL at baseline. In the overall population, before excluding those without baseline LDL-C level or lack of statin use, those with an LDL-C ≥ 100 mg/dL at baseline had a lower rate of statin (31.6% vs. 58.3%) and non-statin lipid-lowering medication (3.5% vs. 8.0%) use prior to the index MI; however, the majority of patients in both groups was prescribed statins at the time of randomization (91.4% for the LDL ≥ 100 mg/dL group vs. 93.4% for the LDL-C < 100 mg/dL group with 76.2% and 75.2% noted as high-intensity statin therapy in each group, respectively). After excluding patients without a baseline LDL-C level (n = 1248) and those not prescribed statin therapy (n = 1240), an analysis of the baseline characteristics by LDL-C subgroup showed that patients with baseline LDL-C ≥ 100 mg/dL tended to be younger, less often male, and were more often enrolled in Central or Eastern Europe than the patients with an LDL < 100 mg/dL (Table 1). With regard to cardiovascular risk factors, patients with LDL ≥ 100 mg/dL were more likely to be current smokers, but less likely to have hypertension, to have sustained a prior MI, or to have undergone prior coronary revascularization prior to the qualifying MI (Table 1). In patients with LDL ≥ 100 mg/dL, the index MI was more likely to have been a STEMI, and they were more likely to have undergone PCI for the index MI. High-intensity statin therapy was more commonly prescribed at randomization in subjects with LDL-C ≥ 100 mg/dL compared to those with LDL-C < 100 mg/dL (83.4% vs. 80.6%). Median HDL-C levels were similar between the groups. Compliance with LDL-C lowering therapy was excellent (approximately 99%) through the end of the study in both subgroups.
Baseline characteristics of the patients on statin therapy at randomization
| Variable | LDL-C ≥ 100 mg/dL | LDL-C < 100 mg/dL | |||||
|---|---|---|---|---|---|---|---|
| Total (N = 5304) | CSL112 6 g (N = 2655) | Placebo (N = 2649) | Total (N = 10 427) | CSL112 6 g (N = 5198) | Placebo (N = 5229) | P-valuea | |
| Age, years, median (IQR) | 65 (57, 71) | 65 (57, 71) | 65 (57, 71) | 67 (61, 74) | 68 (61, 74) | 67 (60, 74) | |
| Age ≥65 years, n (%) | 2835 (53.5) | 1410 (53.1) | 1425 (53.8) | 6615 (63.4) | 3324 (63.9) | 3291 (62.9) | <.0001 |
| Male sex, n (%) | 3670 (69.2) | 1846 (69.5) | 1824 (68.9) | 7975 (76.5) | 4002 (77.0) | 3973 (76.0) | <.0001 |
| Race, n (%) | <.0001 | ||||||
| White | 4487 (84.6) | 2254 (84.9) | 2233 (84.3) | 8833 (84.7) | 4425 (85.1) | 4408 (84.3) | |
| Asian | 498 (9.4) | 239 (9.0) | 259 (9.8) | 882 (8.5) | 437 (8.4) | 445 (8.5) | |
| Black/African American | 122 (2.3) | 60 (2.3) | 62 (2.3) | 178 (1.7) | 90 (1.7) | 88 (1.7) | |
| Other/multiracial | 181 (3.4) | 95 (3.6) | 86 (3.2) | 481 (4.6) | 221 (4.3) | 260 (5.0) | |
| Missing | 16 (.3) | 7 (.3) | 9 (.3) | 53 (.5) | 25 (.5) | 28 (.5) | |
| Ethnicity, n (%) | <.0001 | ||||||
| Hispanic/Latino | 822 (15.5) | 432 (16.3) | 390 (14.7) | 1891 (18.1) | 911 (17.5) | 980 (18.7) | |
| Non-Hispanic/Latino | 4416 (83.3) | 2191 (82.5) | 2225 (84.0) | 8393 (80.5) | 4216 (81.1) | 4177 (79.9) | |
| Not reported | 64 (1.2) | 31 (1.2) | 33 (1.2) | 141 (1.4) | 71 (1.4) | 70 (1.3) | |
| Missing | 2 (.0) | 1 (.0) | 1 (.0) | 2 (.0) | 0 (.0) | 2 (.0) | |
| Geographic region, n (%) | <.0001 | ||||||
| Central and Eastern Europe | 2422 (45.7) | 1199 (45.2) | 1223 (46.2) | 3209 (30.8) | 1622 (31.2) | 1587 (30.3) | |
| Western Europe | 1123 (21.2) | 571 (21.5) | 552 (20.8) | 2957 (28.4) | 1464 (28.2) | 1493 (28.6) | |
| Latin America | 763 (14.4) | 407 (15.3) | 356 (13.4) | 1727 (16.6) | 840 (16.2) | 887 (17.0) | |
| Asia Pacific | 546 (10.3) | 263 (9.9) | 283 (10.7) | 1061 (10.2) | 543 (10.4) | 518 (9.9) | |
| North America | 450 (8.5) | 215 (8.1) | 235 (8.9) | 1473 (14.1) | 729 (14.0) | 744 (14.2) | |
| BMI (kg/m2), median (IQR) | 28.1 (25.5, 31.5) | 28.1 (25.5, 31.3) | 28.1 (25.4, 31.6) | 28.3 (25.4, 31.6) | 28.3 (25.4, 31.6) | 28.3 (25.5, 31.7) | |
| Current smoking, n (%) | 1596 (30.1) | 781 (29.4) | 815 (30.8) | 2471 (23.7) | 1230 (23.7) | 1241 (23.7) | <.0001 |
| Medical history, n (%) | |||||||
| Diabetes mellitus | 3506 (66.1) | 1769 (66.6) | 1737 (65.6) | 7170 (68.8) | 3595 (69.2) | 3575 (68.4) | .0007 |
| Peripheral artery disease | 649 (12.2) | 328 (12.4) | 321 (12.1) | 1342 (12.9) | 653 (12.6) | 689 (13.2) | .2579 |
| Prior MI | 1491 (28.1) | 754 (28.4) | 737 (27.8) | 4190 (40.2) | 2066 (39.7) | 2124 (40.6) | <.0001 |
| Prior PCI | 1361 (25.7) | 692 (26.1) | 669 (25.3) | 4529 (43.4) | 2244 (43.2) | 2285 (43.7) | <.0001 |
| Heart failure | 524 (9.9) | 258 (9.7) | 266 (10.0) | 1072 (10.3) | 515 (9.9) | 557 (10.7) | .4302 |
| Ischemic stroke | 245 (4.6) | 130 (4.9) | 115 (4.3) | 584 (5.6) | 282 (5.4) | 302 (5.8) | .0092 |
| Hypertension | 4014 (75.7) | 2017 (76.0) | 1997 (75.4) | 8450 (81.0) | 4219 (81.2) | 4231 (80.9) | <.0001 |
| Hypercholesterolemia | 2735 (51.6) | 1392 (52.4) | 1343 (50.7) | 7215 (69.2) | 3593 (69.1) | 3622 (69.3) | <.0001 |
| Index MI type, n (%) | <.0001 | ||||||
| STEMI | 3093 (58.3) | 1554 (58.5) | 1539 (58.1) | 4935 (47.3) | 2468 (47.5) | 2467 (47.2) | |
| NSTEMI | 2211 (41.7) | 1101 (41.5) | 1110 (41.9) | 5492 (52.7) | 2730 (52.5) | 2762 (52.8) | |
| Coronary angiography for the index MI, n (%) | 5197 (98.0) | 2600 (97.9) | 2597 (98.0) | 10 112 (97.0) | 5045 (97.1) | 5067 (96.9) | .0002 |
| PCI for the index MI, n (%) | 4826 (91.0) | 2416 (91.0) | 2410 (91.0) | 9027 (86.6) | 4519 (86.9) | 4508 (86.2) | <.0001 |
| Medications at randomization, n (%) | |||||||
| Aspirin | 5056 (95.3) | 2541 (95.7) | 2515 (94.9) | 9830 (94.3) | 4909 (94.4) | 4921 (94.1) | .0058 |
| P2Y12 inhibitor | 5061 (95.4) | 2540 (95.7) | 2521 (95.2) | 9848 (94.4) | 4921 (94.7) | 4927 (94.2) | .0096 |
| High-intensity statinb | 4423 (83.4) | 2228 (83.9) | 2195 (82.9) | 8402 (80.6) | 4184 (80.5) | 4218 (80.7) | <.0001 |
| Non-statin lipid-lowering drugs | 476 (9.0) | 239 (9.0) | 237 (8.9) | 1250 (12.0) | 623 (12.0) | 627 (12.0) | <.0001 |
| Medications prior to the index MI, n (%) | |||||||
| Statin | 1675 (31.6) | 848 (31.9) | 827 (31.2) | 6074 (58.3) | 3019 (58.1) | 3055 (58.4) | <.0001 |
| High-intensity statinb | 604 (11.4) | 309 (11.6) | 295 (11.1) | 2456 (23.6) | 1218 (23.4) | 1238 (23.7) | <.0001 |
| Non-statin lipid-lowering drugs | 188 (3.5) | 103 (3.9) | 85 (3.2) | 834 (8.0) | 404 (7.8) | 430 (8.2) | <.0001 |
| Lipid panel as baseline, median (IQR) | |||||||
| Total cholesterol (mg/dL) | 201.9 (184.8, 225.4) | 202.2 (185.2, 225.4) | 201.5 (184.1, 225.1) | 141.1 (122.2, 157.8) | 141.1 (122.6, 157.8) | 140.8 (122.2, 157.8) | <.0001 |
| LDL cholesterol (mg/dL) | 123.0 (110.6, 143.5) | 123.0 (111.0, 143.9) | 123.0 (110.2, 142.7) | 69.2 (53.4, 83.1) | 68.8 (53.0, 82.8) | 69.2 (54.1, 83.9) | <.0001 |
| HDL cholesterol (mg/dL) | 41.0 (34.8, 48.0) | 40.6 (34.8, 47.6) | 41.0 (34.8, 48.3) | 39.1 (32.9, 46.4) | 39.1 (32.9, 46.4) | 39.1 (33.3, 46.0) | <.0001 |
| Triglycerides (mg/dL) | 165.6 (128.4, 215.2) | 166.5 (130.2, 216.1) | 164.7 (126.7, 215.2) | 142.6 (109.8, 191.3) | 144.4 (109.8, 194.0) | 142.6 (109.8, 188.7) | <.0001 |
| Lipid panel at end of active treatment period, median (IQR) | |||||||
| Total cholesterol (mg/dL) | 145.0 (123.7, 172.5) | 151.2 (129.9, 178.7) | 140.0 (119.9, 165.5) | 124.9 (107.1, 146.6) | 129.9 (111.4, 151.6) | 120.7 (104.0, 141.1) | <.0001 |
| LDL cholesterol (mg/dL) | 70.4 (54.1, 90.9) | 73.1 (56.5, 93.2) | 68.1 (52.6, 88.2) | 52.2 (39.4, 66.9) | 53.8 (40.6, 68.1) | 51.0 (38.3, 66.1) | <.0001 |
| HDL cholesterol (mg/dL) | 42.2 (36.0, 50.3) | 44.5 (37.5, 53.8) | 39.8 (34.8, 47.2) | 41.0 (34.8, 49.9) | 43.3 (36.0, 53.4) | 39.8 (34.0, 47.2) | <.0001 |
| Triglycerides (mg/dL) | 139.9 (106.3, 187.8) | 144.4 (109.8, 192.2) | 136.4 (102.7, 183.3) | 132.9 (99.2, 182.5) | 136.4 (102.7, 188.7) | 128.4 (97.4, 175.4) | <.0001 |
| Renal function, n (%) | <.0001 | ||||||
| Normal (eGFR ≥90 mL/min/1.73 m2) | 1468 (27.7) | 748 (28.2) | 720 (27.2) | 2464 (23.6) | 1214 (23.4) | 1250 (23.9) | |
| Mild impairment (eGFR ≥60-<90 mL/min/1.73 m2) | 2670 (50.3) | 1358 (51.1) | 1312 (49.5) | 5329 (51.1) | 2684 (51.6) | 2645 (50.6) | |
| Moderate impairment (eGFR ≥30-<60 mL/min/1.73 m2) | 1130 (21.3) | 531 (20.0) | 599 (22.6) | 2560 (24.6) | 1256 (24.2) | 1304 (24.9) | |
| Severe impairment (eGFR <30 mL/min/1.73 m2) | 29 (.5) | 15 (.6) | 14 (.5) | 62 (.6) | 39 (.8) | 23 (.4) | |
| Missing | 7 (.1) | 3 (.1) | 4 (.2) | 12 (.1) | 5 (.1) | 7 (.1) | |
| Variable | LDL-C ≥ 100 mg/dL | LDL-C < 100 mg/dL | |||||
|---|---|---|---|---|---|---|---|
| Total (N = 5304) | CSL112 6 g (N = 2655) | Placebo (N = 2649) | Total (N = 10 427) | CSL112 6 g (N = 5198) | Placebo (N = 5229) | P-valuea | |
| Age, years, median (IQR) | 65 (57, 71) | 65 (57, 71) | 65 (57, 71) | 67 (61, 74) | 68 (61, 74) | 67 (60, 74) | |
| Age ≥65 years, n (%) | 2835 (53.5) | 1410 (53.1) | 1425 (53.8) | 6615 (63.4) | 3324 (63.9) | 3291 (62.9) | <.0001 |
| Male sex, n (%) | 3670 (69.2) | 1846 (69.5) | 1824 (68.9) | 7975 (76.5) | 4002 (77.0) | 3973 (76.0) | <.0001 |
| Race, n (%) | <.0001 | ||||||
| White | 4487 (84.6) | 2254 (84.9) | 2233 (84.3) | 8833 (84.7) | 4425 (85.1) | 4408 (84.3) | |
| Asian | 498 (9.4) | 239 (9.0) | 259 (9.8) | 882 (8.5) | 437 (8.4) | 445 (8.5) | |
| Black/African American | 122 (2.3) | 60 (2.3) | 62 (2.3) | 178 (1.7) | 90 (1.7) | 88 (1.7) | |
| Other/multiracial | 181 (3.4) | 95 (3.6) | 86 (3.2) | 481 (4.6) | 221 (4.3) | 260 (5.0) | |
| Missing | 16 (.3) | 7 (.3) | 9 (.3) | 53 (.5) | 25 (.5) | 28 (.5) | |
| Ethnicity, n (%) | <.0001 | ||||||
| Hispanic/Latino | 822 (15.5) | 432 (16.3) | 390 (14.7) | 1891 (18.1) | 911 (17.5) | 980 (18.7) | |
| Non-Hispanic/Latino | 4416 (83.3) | 2191 (82.5) | 2225 (84.0) | 8393 (80.5) | 4216 (81.1) | 4177 (79.9) | |
| Not reported | 64 (1.2) | 31 (1.2) | 33 (1.2) | 141 (1.4) | 71 (1.4) | 70 (1.3) | |
| Missing | 2 (.0) | 1 (.0) | 1 (.0) | 2 (.0) | 0 (.0) | 2 (.0) | |
| Geographic region, n (%) | <.0001 | ||||||
| Central and Eastern Europe | 2422 (45.7) | 1199 (45.2) | 1223 (46.2) | 3209 (30.8) | 1622 (31.2) | 1587 (30.3) | |
| Western Europe | 1123 (21.2) | 571 (21.5) | 552 (20.8) | 2957 (28.4) | 1464 (28.2) | 1493 (28.6) | |
| Latin America | 763 (14.4) | 407 (15.3) | 356 (13.4) | 1727 (16.6) | 840 (16.2) | 887 (17.0) | |
| Asia Pacific | 546 (10.3) | 263 (9.9) | 283 (10.7) | 1061 (10.2) | 543 (10.4) | 518 (9.9) | |
| North America | 450 (8.5) | 215 (8.1) | 235 (8.9) | 1473 (14.1) | 729 (14.0) | 744 (14.2) | |
| BMI (kg/m2), median (IQR) | 28.1 (25.5, 31.5) | 28.1 (25.5, 31.3) | 28.1 (25.4, 31.6) | 28.3 (25.4, 31.6) | 28.3 (25.4, 31.6) | 28.3 (25.5, 31.7) | |
| Current smoking, n (%) | 1596 (30.1) | 781 (29.4) | 815 (30.8) | 2471 (23.7) | 1230 (23.7) | 1241 (23.7) | <.0001 |
| Medical history, n (%) | |||||||
| Diabetes mellitus | 3506 (66.1) | 1769 (66.6) | 1737 (65.6) | 7170 (68.8) | 3595 (69.2) | 3575 (68.4) | .0007 |
| Peripheral artery disease | 649 (12.2) | 328 (12.4) | 321 (12.1) | 1342 (12.9) | 653 (12.6) | 689 (13.2) | .2579 |
| Prior MI | 1491 (28.1) | 754 (28.4) | 737 (27.8) | 4190 (40.2) | 2066 (39.7) | 2124 (40.6) | <.0001 |
| Prior PCI | 1361 (25.7) | 692 (26.1) | 669 (25.3) | 4529 (43.4) | 2244 (43.2) | 2285 (43.7) | <.0001 |
| Heart failure | 524 (9.9) | 258 (9.7) | 266 (10.0) | 1072 (10.3) | 515 (9.9) | 557 (10.7) | .4302 |
| Ischemic stroke | 245 (4.6) | 130 (4.9) | 115 (4.3) | 584 (5.6) | 282 (5.4) | 302 (5.8) | .0092 |
| Hypertension | 4014 (75.7) | 2017 (76.0) | 1997 (75.4) | 8450 (81.0) | 4219 (81.2) | 4231 (80.9) | <.0001 |
| Hypercholesterolemia | 2735 (51.6) | 1392 (52.4) | 1343 (50.7) | 7215 (69.2) | 3593 (69.1) | 3622 (69.3) | <.0001 |
| Index MI type, n (%) | <.0001 | ||||||
| STEMI | 3093 (58.3) | 1554 (58.5) | 1539 (58.1) | 4935 (47.3) | 2468 (47.5) | 2467 (47.2) | |
| NSTEMI | 2211 (41.7) | 1101 (41.5) | 1110 (41.9) | 5492 (52.7) | 2730 (52.5) | 2762 (52.8) | |
| Coronary angiography for the index MI, n (%) | 5197 (98.0) | 2600 (97.9) | 2597 (98.0) | 10 112 (97.0) | 5045 (97.1) | 5067 (96.9) | .0002 |
| PCI for the index MI, n (%) | 4826 (91.0) | 2416 (91.0) | 2410 (91.0) | 9027 (86.6) | 4519 (86.9) | 4508 (86.2) | <.0001 |
| Medications at randomization, n (%) | |||||||
| Aspirin | 5056 (95.3) | 2541 (95.7) | 2515 (94.9) | 9830 (94.3) | 4909 (94.4) | 4921 (94.1) | .0058 |
| P2Y12 inhibitor | 5061 (95.4) | 2540 (95.7) | 2521 (95.2) | 9848 (94.4) | 4921 (94.7) | 4927 (94.2) | .0096 |
| High-intensity statinb | 4423 (83.4) | 2228 (83.9) | 2195 (82.9) | 8402 (80.6) | 4184 (80.5) | 4218 (80.7) | <.0001 |
| Non-statin lipid-lowering drugs | 476 (9.0) | 239 (9.0) | 237 (8.9) | 1250 (12.0) | 623 (12.0) | 627 (12.0) | <.0001 |
| Medications prior to the index MI, n (%) | |||||||
| Statin | 1675 (31.6) | 848 (31.9) | 827 (31.2) | 6074 (58.3) | 3019 (58.1) | 3055 (58.4) | <.0001 |
| High-intensity statinb | 604 (11.4) | 309 (11.6) | 295 (11.1) | 2456 (23.6) | 1218 (23.4) | 1238 (23.7) | <.0001 |
| Non-statin lipid-lowering drugs | 188 (3.5) | 103 (3.9) | 85 (3.2) | 834 (8.0) | 404 (7.8) | 430 (8.2) | <.0001 |
| Lipid panel as baseline, median (IQR) | |||||||
| Total cholesterol (mg/dL) | 201.9 (184.8, 225.4) | 202.2 (185.2, 225.4) | 201.5 (184.1, 225.1) | 141.1 (122.2, 157.8) | 141.1 (122.6, 157.8) | 140.8 (122.2, 157.8) | <.0001 |
| LDL cholesterol (mg/dL) | 123.0 (110.6, 143.5) | 123.0 (111.0, 143.9) | 123.0 (110.2, 142.7) | 69.2 (53.4, 83.1) | 68.8 (53.0, 82.8) | 69.2 (54.1, 83.9) | <.0001 |
| HDL cholesterol (mg/dL) | 41.0 (34.8, 48.0) | 40.6 (34.8, 47.6) | 41.0 (34.8, 48.3) | 39.1 (32.9, 46.4) | 39.1 (32.9, 46.4) | 39.1 (33.3, 46.0) | <.0001 |
| Triglycerides (mg/dL) | 165.6 (128.4, 215.2) | 166.5 (130.2, 216.1) | 164.7 (126.7, 215.2) | 142.6 (109.8, 191.3) | 144.4 (109.8, 194.0) | 142.6 (109.8, 188.7) | <.0001 |
| Lipid panel at end of active treatment period, median (IQR) | |||||||
| Total cholesterol (mg/dL) | 145.0 (123.7, 172.5) | 151.2 (129.9, 178.7) | 140.0 (119.9, 165.5) | 124.9 (107.1, 146.6) | 129.9 (111.4, 151.6) | 120.7 (104.0, 141.1) | <.0001 |
| LDL cholesterol (mg/dL) | 70.4 (54.1, 90.9) | 73.1 (56.5, 93.2) | 68.1 (52.6, 88.2) | 52.2 (39.4, 66.9) | 53.8 (40.6, 68.1) | 51.0 (38.3, 66.1) | <.0001 |
| HDL cholesterol (mg/dL) | 42.2 (36.0, 50.3) | 44.5 (37.5, 53.8) | 39.8 (34.8, 47.2) | 41.0 (34.8, 49.9) | 43.3 (36.0, 53.4) | 39.8 (34.0, 47.2) | <.0001 |
| Triglycerides (mg/dL) | 139.9 (106.3, 187.8) | 144.4 (109.8, 192.2) | 136.4 (102.7, 183.3) | 132.9 (99.2, 182.5) | 136.4 (102.7, 188.7) | 128.4 (97.4, 175.4) | <.0001 |
| Renal function, n (%) | <.0001 | ||||||
| Normal (eGFR ≥90 mL/min/1.73 m2) | 1468 (27.7) | 748 (28.2) | 720 (27.2) | 2464 (23.6) | 1214 (23.4) | 1250 (23.9) | |
| Mild impairment (eGFR ≥60-<90 mL/min/1.73 m2) | 2670 (50.3) | 1358 (51.1) | 1312 (49.5) | 5329 (51.1) | 2684 (51.6) | 2645 (50.6) | |
| Moderate impairment (eGFR ≥30-<60 mL/min/1.73 m2) | 1130 (21.3) | 531 (20.0) | 599 (22.6) | 2560 (24.6) | 1256 (24.2) | 1304 (24.9) | |
| Severe impairment (eGFR <30 mL/min/1.73 m2) | 29 (.5) | 15 (.6) | 14 (.5) | 62 (.6) | 39 (.8) | 23 (.4) | |
| Missing | 7 (.1) | 3 (.1) | 4 (.2) | 12 (.1) | 5 (.1) | 7 (.1) | |
Note: To convert the values for HDL cholesterol and LDL cholesterol to millimoles per liter, multiply by .02586. To convert the values for triglycerides to millimoles per liter, multiply by .01129.
Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; IQR, interquartile range; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction.
aThe P-value is the Wilcoxon rank sum nonparametric for continuous χ2 tests for categorical in the comparison between total columns for LDL-C < 100 mg/dL compared with LDL-C ≥ 100 mg/dL.
bHigh-intensity statin therapy was derived based on reported use of atorvastatin ≥40 mg daily or rosuvastatin ≥20 mg daily.
Baseline characteristics of the patients on statin therapy at randomization
| Variable | LDL-C ≥ 100 mg/dL | LDL-C < 100 mg/dL | |||||
|---|---|---|---|---|---|---|---|
| Total (N = 5304) | CSL112 6 g (N = 2655) | Placebo (N = 2649) | Total (N = 10 427) | CSL112 6 g (N = 5198) | Placebo (N = 5229) | P-valuea | |
| Age, years, median (IQR) | 65 (57, 71) | 65 (57, 71) | 65 (57, 71) | 67 (61, 74) | 68 (61, 74) | 67 (60, 74) | |
| Age ≥65 years, n (%) | 2835 (53.5) | 1410 (53.1) | 1425 (53.8) | 6615 (63.4) | 3324 (63.9) | 3291 (62.9) | <.0001 |
| Male sex, n (%) | 3670 (69.2) | 1846 (69.5) | 1824 (68.9) | 7975 (76.5) | 4002 (77.0) | 3973 (76.0) | <.0001 |
| Race, n (%) | <.0001 | ||||||
| White | 4487 (84.6) | 2254 (84.9) | 2233 (84.3) | 8833 (84.7) | 4425 (85.1) | 4408 (84.3) | |
| Asian | 498 (9.4) | 239 (9.0) | 259 (9.8) | 882 (8.5) | 437 (8.4) | 445 (8.5) | |
| Black/African American | 122 (2.3) | 60 (2.3) | 62 (2.3) | 178 (1.7) | 90 (1.7) | 88 (1.7) | |
| Other/multiracial | 181 (3.4) | 95 (3.6) | 86 (3.2) | 481 (4.6) | 221 (4.3) | 260 (5.0) | |
| Missing | 16 (.3) | 7 (.3) | 9 (.3) | 53 (.5) | 25 (.5) | 28 (.5) | |
| Ethnicity, n (%) | <.0001 | ||||||
| Hispanic/Latino | 822 (15.5) | 432 (16.3) | 390 (14.7) | 1891 (18.1) | 911 (17.5) | 980 (18.7) | |
| Non-Hispanic/Latino | 4416 (83.3) | 2191 (82.5) | 2225 (84.0) | 8393 (80.5) | 4216 (81.1) | 4177 (79.9) | |
| Not reported | 64 (1.2) | 31 (1.2) | 33 (1.2) | 141 (1.4) | 71 (1.4) | 70 (1.3) | |
| Missing | 2 (.0) | 1 (.0) | 1 (.0) | 2 (.0) | 0 (.0) | 2 (.0) | |
| Geographic region, n (%) | <.0001 | ||||||
| Central and Eastern Europe | 2422 (45.7) | 1199 (45.2) | 1223 (46.2) | 3209 (30.8) | 1622 (31.2) | 1587 (30.3) | |
| Western Europe | 1123 (21.2) | 571 (21.5) | 552 (20.8) | 2957 (28.4) | 1464 (28.2) | 1493 (28.6) | |
| Latin America | 763 (14.4) | 407 (15.3) | 356 (13.4) | 1727 (16.6) | 840 (16.2) | 887 (17.0) | |
| Asia Pacific | 546 (10.3) | 263 (9.9) | 283 (10.7) | 1061 (10.2) | 543 (10.4) | 518 (9.9) | |
| North America | 450 (8.5) | 215 (8.1) | 235 (8.9) | 1473 (14.1) | 729 (14.0) | 744 (14.2) | |
| BMI (kg/m2), median (IQR) | 28.1 (25.5, 31.5) | 28.1 (25.5, 31.3) | 28.1 (25.4, 31.6) | 28.3 (25.4, 31.6) | 28.3 (25.4, 31.6) | 28.3 (25.5, 31.7) | |
| Current smoking, n (%) | 1596 (30.1) | 781 (29.4) | 815 (30.8) | 2471 (23.7) | 1230 (23.7) | 1241 (23.7) | <.0001 |
| Medical history, n (%) | |||||||
| Diabetes mellitus | 3506 (66.1) | 1769 (66.6) | 1737 (65.6) | 7170 (68.8) | 3595 (69.2) | 3575 (68.4) | .0007 |
| Peripheral artery disease | 649 (12.2) | 328 (12.4) | 321 (12.1) | 1342 (12.9) | 653 (12.6) | 689 (13.2) | .2579 |
| Prior MI | 1491 (28.1) | 754 (28.4) | 737 (27.8) | 4190 (40.2) | 2066 (39.7) | 2124 (40.6) | <.0001 |
| Prior PCI | 1361 (25.7) | 692 (26.1) | 669 (25.3) | 4529 (43.4) | 2244 (43.2) | 2285 (43.7) | <.0001 |
| Heart failure | 524 (9.9) | 258 (9.7) | 266 (10.0) | 1072 (10.3) | 515 (9.9) | 557 (10.7) | .4302 |
| Ischemic stroke | 245 (4.6) | 130 (4.9) | 115 (4.3) | 584 (5.6) | 282 (5.4) | 302 (5.8) | .0092 |
| Hypertension | 4014 (75.7) | 2017 (76.0) | 1997 (75.4) | 8450 (81.0) | 4219 (81.2) | 4231 (80.9) | <.0001 |
| Hypercholesterolemia | 2735 (51.6) | 1392 (52.4) | 1343 (50.7) | 7215 (69.2) | 3593 (69.1) | 3622 (69.3) | <.0001 |
| Index MI type, n (%) | <.0001 | ||||||
| STEMI | 3093 (58.3) | 1554 (58.5) | 1539 (58.1) | 4935 (47.3) | 2468 (47.5) | 2467 (47.2) | |
| NSTEMI | 2211 (41.7) | 1101 (41.5) | 1110 (41.9) | 5492 (52.7) | 2730 (52.5) | 2762 (52.8) | |
| Coronary angiography for the index MI, n (%) | 5197 (98.0) | 2600 (97.9) | 2597 (98.0) | 10 112 (97.0) | 5045 (97.1) | 5067 (96.9) | .0002 |
| PCI for the index MI, n (%) | 4826 (91.0) | 2416 (91.0) | 2410 (91.0) | 9027 (86.6) | 4519 (86.9) | 4508 (86.2) | <.0001 |
| Medications at randomization, n (%) | |||||||
| Aspirin | 5056 (95.3) | 2541 (95.7) | 2515 (94.9) | 9830 (94.3) | 4909 (94.4) | 4921 (94.1) | .0058 |
| P2Y12 inhibitor | 5061 (95.4) | 2540 (95.7) | 2521 (95.2) | 9848 (94.4) | 4921 (94.7) | 4927 (94.2) | .0096 |
| High-intensity statinb | 4423 (83.4) | 2228 (83.9) | 2195 (82.9) | 8402 (80.6) | 4184 (80.5) | 4218 (80.7) | <.0001 |
| Non-statin lipid-lowering drugs | 476 (9.0) | 239 (9.0) | 237 (8.9) | 1250 (12.0) | 623 (12.0) | 627 (12.0) | <.0001 |
| Medications prior to the index MI, n (%) | |||||||
| Statin | 1675 (31.6) | 848 (31.9) | 827 (31.2) | 6074 (58.3) | 3019 (58.1) | 3055 (58.4) | <.0001 |
| High-intensity statinb | 604 (11.4) | 309 (11.6) | 295 (11.1) | 2456 (23.6) | 1218 (23.4) | 1238 (23.7) | <.0001 |
| Non-statin lipid-lowering drugs | 188 (3.5) | 103 (3.9) | 85 (3.2) | 834 (8.0) | 404 (7.8) | 430 (8.2) | <.0001 |
| Lipid panel as baseline, median (IQR) | |||||||
| Total cholesterol (mg/dL) | 201.9 (184.8, 225.4) | 202.2 (185.2, 225.4) | 201.5 (184.1, 225.1) | 141.1 (122.2, 157.8) | 141.1 (122.6, 157.8) | 140.8 (122.2, 157.8) | <.0001 |
| LDL cholesterol (mg/dL) | 123.0 (110.6, 143.5) | 123.0 (111.0, 143.9) | 123.0 (110.2, 142.7) | 69.2 (53.4, 83.1) | 68.8 (53.0, 82.8) | 69.2 (54.1, 83.9) | <.0001 |
| HDL cholesterol (mg/dL) | 41.0 (34.8, 48.0) | 40.6 (34.8, 47.6) | 41.0 (34.8, 48.3) | 39.1 (32.9, 46.4) | 39.1 (32.9, 46.4) | 39.1 (33.3, 46.0) | <.0001 |
| Triglycerides (mg/dL) | 165.6 (128.4, 215.2) | 166.5 (130.2, 216.1) | 164.7 (126.7, 215.2) | 142.6 (109.8, 191.3) | 144.4 (109.8, 194.0) | 142.6 (109.8, 188.7) | <.0001 |
| Lipid panel at end of active treatment period, median (IQR) | |||||||
| Total cholesterol (mg/dL) | 145.0 (123.7, 172.5) | 151.2 (129.9, 178.7) | 140.0 (119.9, 165.5) | 124.9 (107.1, 146.6) | 129.9 (111.4, 151.6) | 120.7 (104.0, 141.1) | <.0001 |
| LDL cholesterol (mg/dL) | 70.4 (54.1, 90.9) | 73.1 (56.5, 93.2) | 68.1 (52.6, 88.2) | 52.2 (39.4, 66.9) | 53.8 (40.6, 68.1) | 51.0 (38.3, 66.1) | <.0001 |
| HDL cholesterol (mg/dL) | 42.2 (36.0, 50.3) | 44.5 (37.5, 53.8) | 39.8 (34.8, 47.2) | 41.0 (34.8, 49.9) | 43.3 (36.0, 53.4) | 39.8 (34.0, 47.2) | <.0001 |
| Triglycerides (mg/dL) | 139.9 (106.3, 187.8) | 144.4 (109.8, 192.2) | 136.4 (102.7, 183.3) | 132.9 (99.2, 182.5) | 136.4 (102.7, 188.7) | 128.4 (97.4, 175.4) | <.0001 |
| Renal function, n (%) | <.0001 | ||||||
| Normal (eGFR ≥90 mL/min/1.73 m2) | 1468 (27.7) | 748 (28.2) | 720 (27.2) | 2464 (23.6) | 1214 (23.4) | 1250 (23.9) | |
| Mild impairment (eGFR ≥60-<90 mL/min/1.73 m2) | 2670 (50.3) | 1358 (51.1) | 1312 (49.5) | 5329 (51.1) | 2684 (51.6) | 2645 (50.6) | |
| Moderate impairment (eGFR ≥30-<60 mL/min/1.73 m2) | 1130 (21.3) | 531 (20.0) | 599 (22.6) | 2560 (24.6) | 1256 (24.2) | 1304 (24.9) | |
| Severe impairment (eGFR <30 mL/min/1.73 m2) | 29 (.5) | 15 (.6) | 14 (.5) | 62 (.6) | 39 (.8) | 23 (.4) | |
| Missing | 7 (.1) | 3 (.1) | 4 (.2) | 12 (.1) | 5 (.1) | 7 (.1) | |
| Variable | LDL-C ≥ 100 mg/dL | LDL-C < 100 mg/dL | |||||
|---|---|---|---|---|---|---|---|
| Total (N = 5304) | CSL112 6 g (N = 2655) | Placebo (N = 2649) | Total (N = 10 427) | CSL112 6 g (N = 5198) | Placebo (N = 5229) | P-valuea | |
| Age, years, median (IQR) | 65 (57, 71) | 65 (57, 71) | 65 (57, 71) | 67 (61, 74) | 68 (61, 74) | 67 (60, 74) | |
| Age ≥65 years, n (%) | 2835 (53.5) | 1410 (53.1) | 1425 (53.8) | 6615 (63.4) | 3324 (63.9) | 3291 (62.9) | <.0001 |
| Male sex, n (%) | 3670 (69.2) | 1846 (69.5) | 1824 (68.9) | 7975 (76.5) | 4002 (77.0) | 3973 (76.0) | <.0001 |
| Race, n (%) | <.0001 | ||||||
| White | 4487 (84.6) | 2254 (84.9) | 2233 (84.3) | 8833 (84.7) | 4425 (85.1) | 4408 (84.3) | |
| Asian | 498 (9.4) | 239 (9.0) | 259 (9.8) | 882 (8.5) | 437 (8.4) | 445 (8.5) | |
| Black/African American | 122 (2.3) | 60 (2.3) | 62 (2.3) | 178 (1.7) | 90 (1.7) | 88 (1.7) | |
| Other/multiracial | 181 (3.4) | 95 (3.6) | 86 (3.2) | 481 (4.6) | 221 (4.3) | 260 (5.0) | |
| Missing | 16 (.3) | 7 (.3) | 9 (.3) | 53 (.5) | 25 (.5) | 28 (.5) | |
| Ethnicity, n (%) | <.0001 | ||||||
| Hispanic/Latino | 822 (15.5) | 432 (16.3) | 390 (14.7) | 1891 (18.1) | 911 (17.5) | 980 (18.7) | |
| Non-Hispanic/Latino | 4416 (83.3) | 2191 (82.5) | 2225 (84.0) | 8393 (80.5) | 4216 (81.1) | 4177 (79.9) | |
| Not reported | 64 (1.2) | 31 (1.2) | 33 (1.2) | 141 (1.4) | 71 (1.4) | 70 (1.3) | |
| Missing | 2 (.0) | 1 (.0) | 1 (.0) | 2 (.0) | 0 (.0) | 2 (.0) | |
| Geographic region, n (%) | <.0001 | ||||||
| Central and Eastern Europe | 2422 (45.7) | 1199 (45.2) | 1223 (46.2) | 3209 (30.8) | 1622 (31.2) | 1587 (30.3) | |
| Western Europe | 1123 (21.2) | 571 (21.5) | 552 (20.8) | 2957 (28.4) | 1464 (28.2) | 1493 (28.6) | |
| Latin America | 763 (14.4) | 407 (15.3) | 356 (13.4) | 1727 (16.6) | 840 (16.2) | 887 (17.0) | |
| Asia Pacific | 546 (10.3) | 263 (9.9) | 283 (10.7) | 1061 (10.2) | 543 (10.4) | 518 (9.9) | |
| North America | 450 (8.5) | 215 (8.1) | 235 (8.9) | 1473 (14.1) | 729 (14.0) | 744 (14.2) | |
| BMI (kg/m2), median (IQR) | 28.1 (25.5, 31.5) | 28.1 (25.5, 31.3) | 28.1 (25.4, 31.6) | 28.3 (25.4, 31.6) | 28.3 (25.4, 31.6) | 28.3 (25.5, 31.7) | |
| Current smoking, n (%) | 1596 (30.1) | 781 (29.4) | 815 (30.8) | 2471 (23.7) | 1230 (23.7) | 1241 (23.7) | <.0001 |
| Medical history, n (%) | |||||||
| Diabetes mellitus | 3506 (66.1) | 1769 (66.6) | 1737 (65.6) | 7170 (68.8) | 3595 (69.2) | 3575 (68.4) | .0007 |
| Peripheral artery disease | 649 (12.2) | 328 (12.4) | 321 (12.1) | 1342 (12.9) | 653 (12.6) | 689 (13.2) | .2579 |
| Prior MI | 1491 (28.1) | 754 (28.4) | 737 (27.8) | 4190 (40.2) | 2066 (39.7) | 2124 (40.6) | <.0001 |
| Prior PCI | 1361 (25.7) | 692 (26.1) | 669 (25.3) | 4529 (43.4) | 2244 (43.2) | 2285 (43.7) | <.0001 |
| Heart failure | 524 (9.9) | 258 (9.7) | 266 (10.0) | 1072 (10.3) | 515 (9.9) | 557 (10.7) | .4302 |
| Ischemic stroke | 245 (4.6) | 130 (4.9) | 115 (4.3) | 584 (5.6) | 282 (5.4) | 302 (5.8) | .0092 |
| Hypertension | 4014 (75.7) | 2017 (76.0) | 1997 (75.4) | 8450 (81.0) | 4219 (81.2) | 4231 (80.9) | <.0001 |
| Hypercholesterolemia | 2735 (51.6) | 1392 (52.4) | 1343 (50.7) | 7215 (69.2) | 3593 (69.1) | 3622 (69.3) | <.0001 |
| Index MI type, n (%) | <.0001 | ||||||
| STEMI | 3093 (58.3) | 1554 (58.5) | 1539 (58.1) | 4935 (47.3) | 2468 (47.5) | 2467 (47.2) | |
| NSTEMI | 2211 (41.7) | 1101 (41.5) | 1110 (41.9) | 5492 (52.7) | 2730 (52.5) | 2762 (52.8) | |
| Coronary angiography for the index MI, n (%) | 5197 (98.0) | 2600 (97.9) | 2597 (98.0) | 10 112 (97.0) | 5045 (97.1) | 5067 (96.9) | .0002 |
| PCI for the index MI, n (%) | 4826 (91.0) | 2416 (91.0) | 2410 (91.0) | 9027 (86.6) | 4519 (86.9) | 4508 (86.2) | <.0001 |
| Medications at randomization, n (%) | |||||||
| Aspirin | 5056 (95.3) | 2541 (95.7) | 2515 (94.9) | 9830 (94.3) | 4909 (94.4) | 4921 (94.1) | .0058 |
| P2Y12 inhibitor | 5061 (95.4) | 2540 (95.7) | 2521 (95.2) | 9848 (94.4) | 4921 (94.7) | 4927 (94.2) | .0096 |
| High-intensity statinb | 4423 (83.4) | 2228 (83.9) | 2195 (82.9) | 8402 (80.6) | 4184 (80.5) | 4218 (80.7) | <.0001 |
| Non-statin lipid-lowering drugs | 476 (9.0) | 239 (9.0) | 237 (8.9) | 1250 (12.0) | 623 (12.0) | 627 (12.0) | <.0001 |
| Medications prior to the index MI, n (%) | |||||||
| Statin | 1675 (31.6) | 848 (31.9) | 827 (31.2) | 6074 (58.3) | 3019 (58.1) | 3055 (58.4) | <.0001 |
| High-intensity statinb | 604 (11.4) | 309 (11.6) | 295 (11.1) | 2456 (23.6) | 1218 (23.4) | 1238 (23.7) | <.0001 |
| Non-statin lipid-lowering drugs | 188 (3.5) | 103 (3.9) | 85 (3.2) | 834 (8.0) | 404 (7.8) | 430 (8.2) | <.0001 |
| Lipid panel as baseline, median (IQR) | |||||||
| Total cholesterol (mg/dL) | 201.9 (184.8, 225.4) | 202.2 (185.2, 225.4) | 201.5 (184.1, 225.1) | 141.1 (122.2, 157.8) | 141.1 (122.6, 157.8) | 140.8 (122.2, 157.8) | <.0001 |
| LDL cholesterol (mg/dL) | 123.0 (110.6, 143.5) | 123.0 (111.0, 143.9) | 123.0 (110.2, 142.7) | 69.2 (53.4, 83.1) | 68.8 (53.0, 82.8) | 69.2 (54.1, 83.9) | <.0001 |
| HDL cholesterol (mg/dL) | 41.0 (34.8, 48.0) | 40.6 (34.8, 47.6) | 41.0 (34.8, 48.3) | 39.1 (32.9, 46.4) | 39.1 (32.9, 46.4) | 39.1 (33.3, 46.0) | <.0001 |
| Triglycerides (mg/dL) | 165.6 (128.4, 215.2) | 166.5 (130.2, 216.1) | 164.7 (126.7, 215.2) | 142.6 (109.8, 191.3) | 144.4 (109.8, 194.0) | 142.6 (109.8, 188.7) | <.0001 |
| Lipid panel at end of active treatment period, median (IQR) | |||||||
| Total cholesterol (mg/dL) | 145.0 (123.7, 172.5) | 151.2 (129.9, 178.7) | 140.0 (119.9, 165.5) | 124.9 (107.1, 146.6) | 129.9 (111.4, 151.6) | 120.7 (104.0, 141.1) | <.0001 |
| LDL cholesterol (mg/dL) | 70.4 (54.1, 90.9) | 73.1 (56.5, 93.2) | 68.1 (52.6, 88.2) | 52.2 (39.4, 66.9) | 53.8 (40.6, 68.1) | 51.0 (38.3, 66.1) | <.0001 |
| HDL cholesterol (mg/dL) | 42.2 (36.0, 50.3) | 44.5 (37.5, 53.8) | 39.8 (34.8, 47.2) | 41.0 (34.8, 49.9) | 43.3 (36.0, 53.4) | 39.8 (34.0, 47.2) | <.0001 |
| Triglycerides (mg/dL) | 139.9 (106.3, 187.8) | 144.4 (109.8, 192.2) | 136.4 (102.7, 183.3) | 132.9 (99.2, 182.5) | 136.4 (102.7, 188.7) | 128.4 (97.4, 175.4) | <.0001 |
| Renal function, n (%) | <.0001 | ||||||
| Normal (eGFR ≥90 mL/min/1.73 m2) | 1468 (27.7) | 748 (28.2) | 720 (27.2) | 2464 (23.6) | 1214 (23.4) | 1250 (23.9) | |
| Mild impairment (eGFR ≥60-<90 mL/min/1.73 m2) | 2670 (50.3) | 1358 (51.1) | 1312 (49.5) | 5329 (51.1) | 2684 (51.6) | 2645 (50.6) | |
| Moderate impairment (eGFR ≥30-<60 mL/min/1.73 m2) | 1130 (21.3) | 531 (20.0) | 599 (22.6) | 2560 (24.6) | 1256 (24.2) | 1304 (24.9) | |
| Severe impairment (eGFR <30 mL/min/1.73 m2) | 29 (.5) | 15 (.6) | 14 (.5) | 62 (.6) | 39 (.8) | 23 (.4) | |
| Missing | 7 (.1) | 3 (.1) | 4 (.2) | 12 (.1) | 5 (.1) | 7 (.1) | |
Note: To convert the values for HDL cholesterol and LDL cholesterol to millimoles per liter, multiply by .02586. To convert the values for triglycerides to millimoles per liter, multiply by .01129.
Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; IQR, interquartile range; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction.
aThe P-value is the Wilcoxon rank sum nonparametric for continuous χ2 tests for categorical in the comparison between total columns for LDL-C < 100 mg/dL compared with LDL-C ≥ 100 mg/dL.
bHigh-intensity statin therapy was derived based on reported use of atorvastatin ≥40 mg daily or rosuvastatin ≥20 mg daily.
Major adverse cardiovascular events
As the LDL-C level at randomization increased, the treatment benefit of CSL112 on the risk of cardiovascular death, MI, or stroke through 90 days increased, as demonstrated by a decreasing HR (Figure 1) at LDL-C levels of approximately 85 mg/dL and higher. While prior studies on PCSK9 inhibitors suggest an LDL-C threshold of 100 mg/dL, the LDL-C threshold at which CSL112 becomes more effective requires further investigation and may be higher than 100 mg/dL.
HR of CVD, MI, and stroke to 90 days by LDL with baseline statin use (spline). Cubic spline analysis of the relationship between baseline LDL-C on the x-axis vs. the hazard ratio of the time to first occurrence of cardiovascular death, MI, or stroke at 90 days for CSL112 vs. placebo. The x-axis range is roughly from the 5th to 95th percentile of LDL-C since the HR estimates on the boundaries are not as reliable for splines. The dark line represents the point estimate of the HR, and the grey band represents the 95% confidence interval for the HR. A vertical line is drawn at LDL-C = 100 mg/dL and a horizontal line at HR = .8 for illustrative purposes. Abbreviations: CVD, cardiovascular disease; LDL, low-density lipoprotein; MI, myocardial infarction
Among patients with an LDL-C ≥ 100 mg/dL at randomization, there was a significant reduction in the risk of cardiovascular death, MI, or stroke at all timepoints in those treated with CSL112 compared to placebo (Table 2, Figure 2A) at 90 days [3.4% vs. 4.9%; HR .69; 95% confidence interval (CI) .53–.90; P = .007], 180 days (5.3% vs. 7.3%; HR .71; 95% CI, .57–.88; P = .002), and 365 days (7.8% vs. 9.9%; HR .78; 95% CI .65–.93; P = .006). In contrast, there was no difference between treatment groups among those patients with an LDL-C < 100 mg/dL at baseline (Table 2, Figure 2B). The proportional hazard assumption was not violated based on inspection of the Schoenfeld residuals and the Kolmogorov-type supremum test. The P-value for the treatment by LDL-C subgroup interaction at 90, 180, and 365 days were .04, .02, and .07. While the interaction P-value at 365 days did not achieve statistical significance at the .05 level, the interaction P-values were consistent with a likely difference in subgroups in this exploratory analysis.
Cumulative incidence of the time to first occurrence of cardiovascular death, MI, or stroke. Cumulative incidence of the time to first occurrence of cardiovascular death, MI, or stroke through 90, 180, and 365 days among patients with (A) an LDL-C ≥ 100 mg/dL at baseline who were prescribed statin therapy and (B) an LDL-C < 100 mg/dL at baseline who were prescribed statin therapy. Abbreviations: LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction
Efficacy endpoints by LDL-C subgroup
| Endpoint | Timepoint | LDL ≥ 100 mg/dL | LDL < 100 mg/dL | ||||||
|---|---|---|---|---|---|---|---|---|---|
| CSL112 6 g (n = 2655) | Placebo (n = 2649) | HR (95% CI) | P-value | CSL112 6 g (n = 5198) | Placebo (n = 5229) | HR (95% CI) | P-value | ||
| Composite of MI, stroke, or death from CV causes | Through 90 days | 91 (3.4) | 129 (4.9) | .69 (.53–.90) | .007 | 276 (5.3) | 283 (5.4) | .98 (.83–1.15) | .783 |
| Through 180 days | 140 (5.3) | 194 (7.3) | .71 (.57–.88) | .002 | 380 (7.4) | 395 (7.6) | .97 (.84–1.11) | .643 | |
| Through 365 days | 206 (7.8) | 261 (9.9) | .78 (.65–.93) | .006 | 529 (10.3) | 556 (10.7) | .96 (.85–1.08) | .450 | |
| Composite of MI or death from CV causes | Through 90 days | 76 (2.9) | 116 (4.4) | .64 (.48–.86) | .003 | 255 (4.9) | 259 (5.0) | .99 (.83–1.17) | .879 |
| Through 180 days | 123 (4.7) | 175 (6.6) | .69 (.55–.87) | .002 | 346 (6.7) | 364 (7.0) | .96 (.82–1.11) | .540 | |
| Through 365 days | 181 (6.9) | 236 (8.9) | .75 (.62–.91) | .004 | 482 (9.4) | 515 (9.9) | .94 (.83–1.06) | .306 | |
| MI | Through 90 days | 61 (2.3) | 88 (3.4) | .68 (.49–.94) | .021 | 199 (3.9) | 210 (4.1) | .95 (.79–1.16) | .636 |
| Through 180 days | 100 (3.8) | 141 (5.4) | .70 (.54–.90) | .006 | 275 (5.4) | 301 (5.8) | .92 (.78–1.09) | .327 | |
| Through 365 days | 148 (5.6) | 186 (7.1) | .78 (.63–.97) | .027 | 380 (7.5) | 423 (8.2) | .90 (.79–1.04) | .150 | |
| Death from CV causes | Through 90 days | 20 (.8) | 39 (1.5) | .50 (.29–.86) | .012 | 67 (1.3) | 74 (1.4) | .90 (.64–1.25) | .511 |
| Through 180 days | 34 (1.3) | 53 (2.0) | .63 (.41–.97) | .037 | 90 (1.7) | 95 (1.8) | .94 (.70–1.25) | .660 | |
| Through 365 days | 53 (2.0) | 71 (2.7) | .73 (.51–1.04) | .080 | 137 (2.7) | 142 (2.7) | .95 (.75–1.21) | .697 | |
| Stroke | Through 90 days | 17 (.6) | 16 (.6) | 1.05 (.53–2.07) | .897 | 29 (.6) | 27 (.5) | 1.07 (.63–1.80) | .809 |
| Through 180 days | 21 (.8) | 23 (.9) | .90 (.50–1.63) | .729 | 45 (.9) | 39 (.8) | 1.15 (.75–1.77) | .513 | |
| Through 365 days | 31 (1.2) | 33 (1.3) | .93 (.57–1.51) | .757 | 64 (1.3) | 62 (1.2) | 1.04 (.73–1.48) | .824 | |
| Endpoint | Timepoint | LDL ≥ 100 mg/dL | LDL < 100 mg/dL | ||||||
|---|---|---|---|---|---|---|---|---|---|
| CSL112 6 g (n = 2655) | Placebo (n = 2649) | HR (95% CI) | P-value | CSL112 6 g (n = 5198) | Placebo (n = 5229) | HR (95% CI) | P-value | ||
| Composite of MI, stroke, or death from CV causes | Through 90 days | 91 (3.4) | 129 (4.9) | .69 (.53–.90) | .007 | 276 (5.3) | 283 (5.4) | .98 (.83–1.15) | .783 |
| Through 180 days | 140 (5.3) | 194 (7.3) | .71 (.57–.88) | .002 | 380 (7.4) | 395 (7.6) | .97 (.84–1.11) | .643 | |
| Through 365 days | 206 (7.8) | 261 (9.9) | .78 (.65–.93) | .006 | 529 (10.3) | 556 (10.7) | .96 (.85–1.08) | .450 | |
| Composite of MI or death from CV causes | Through 90 days | 76 (2.9) | 116 (4.4) | .64 (.48–.86) | .003 | 255 (4.9) | 259 (5.0) | .99 (.83–1.17) | .879 |
| Through 180 days | 123 (4.7) | 175 (6.6) | .69 (.55–.87) | .002 | 346 (6.7) | 364 (7.0) | .96 (.82–1.11) | .540 | |
| Through 365 days | 181 (6.9) | 236 (8.9) | .75 (.62–.91) | .004 | 482 (9.4) | 515 (9.9) | .94 (.83–1.06) | .306 | |
| MI | Through 90 days | 61 (2.3) | 88 (3.4) | .68 (.49–.94) | .021 | 199 (3.9) | 210 (4.1) | .95 (.79–1.16) | .636 |
| Through 180 days | 100 (3.8) | 141 (5.4) | .70 (.54–.90) | .006 | 275 (5.4) | 301 (5.8) | .92 (.78–1.09) | .327 | |
| Through 365 days | 148 (5.6) | 186 (7.1) | .78 (.63–.97) | .027 | 380 (7.5) | 423 (8.2) | .90 (.79–1.04) | .150 | |
| Death from CV causes | Through 90 days | 20 (.8) | 39 (1.5) | .50 (.29–.86) | .012 | 67 (1.3) | 74 (1.4) | .90 (.64–1.25) | .511 |
| Through 180 days | 34 (1.3) | 53 (2.0) | .63 (.41–.97) | .037 | 90 (1.7) | 95 (1.8) | .94 (.70–1.25) | .660 | |
| Through 365 days | 53 (2.0) | 71 (2.7) | .73 (.51–1.04) | .080 | 137 (2.7) | 142 (2.7) | .95 (.75–1.21) | .697 | |
| Stroke | Through 90 days | 17 (.6) | 16 (.6) | 1.05 (.53–2.07) | .897 | 29 (.6) | 27 (.5) | 1.07 (.63–1.80) | .809 |
| Through 180 days | 21 (.8) | 23 (.9) | .90 (.50–1.63) | .729 | 45 (.9) | 39 (.8) | 1.15 (.75–1.77) | .513 | |
| Through 365 days | 31 (1.2) | 33 (1.3) | .93 (.57–1.51) | .757 | 64 (1.3) | 62 (1.2) | 1.04 (.73–1.48) | .824 | |
Abbreviations: CI, confidence interval; CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction.
Efficacy endpoints by LDL-C subgroup
| Endpoint | Timepoint | LDL ≥ 100 mg/dL | LDL < 100 mg/dL | ||||||
|---|---|---|---|---|---|---|---|---|---|
| CSL112 6 g (n = 2655) | Placebo (n = 2649) | HR (95% CI) | P-value | CSL112 6 g (n = 5198) | Placebo (n = 5229) | HR (95% CI) | P-value | ||
| Composite of MI, stroke, or death from CV causes | Through 90 days | 91 (3.4) | 129 (4.9) | .69 (.53–.90) | .007 | 276 (5.3) | 283 (5.4) | .98 (.83–1.15) | .783 |
| Through 180 days | 140 (5.3) | 194 (7.3) | .71 (.57–.88) | .002 | 380 (7.4) | 395 (7.6) | .97 (.84–1.11) | .643 | |
| Through 365 days | 206 (7.8) | 261 (9.9) | .78 (.65–.93) | .006 | 529 (10.3) | 556 (10.7) | .96 (.85–1.08) | .450 | |
| Composite of MI or death from CV causes | Through 90 days | 76 (2.9) | 116 (4.4) | .64 (.48–.86) | .003 | 255 (4.9) | 259 (5.0) | .99 (.83–1.17) | .879 |
| Through 180 days | 123 (4.7) | 175 (6.6) | .69 (.55–.87) | .002 | 346 (6.7) | 364 (7.0) | .96 (.82–1.11) | .540 | |
| Through 365 days | 181 (6.9) | 236 (8.9) | .75 (.62–.91) | .004 | 482 (9.4) | 515 (9.9) | .94 (.83–1.06) | .306 | |
| MI | Through 90 days | 61 (2.3) | 88 (3.4) | .68 (.49–.94) | .021 | 199 (3.9) | 210 (4.1) | .95 (.79–1.16) | .636 |
| Through 180 days | 100 (3.8) | 141 (5.4) | .70 (.54–.90) | .006 | 275 (5.4) | 301 (5.8) | .92 (.78–1.09) | .327 | |
| Through 365 days | 148 (5.6) | 186 (7.1) | .78 (.63–.97) | .027 | 380 (7.5) | 423 (8.2) | .90 (.79–1.04) | .150 | |
| Death from CV causes | Through 90 days | 20 (.8) | 39 (1.5) | .50 (.29–.86) | .012 | 67 (1.3) | 74 (1.4) | .90 (.64–1.25) | .511 |
| Through 180 days | 34 (1.3) | 53 (2.0) | .63 (.41–.97) | .037 | 90 (1.7) | 95 (1.8) | .94 (.70–1.25) | .660 | |
| Through 365 days | 53 (2.0) | 71 (2.7) | .73 (.51–1.04) | .080 | 137 (2.7) | 142 (2.7) | .95 (.75–1.21) | .697 | |
| Stroke | Through 90 days | 17 (.6) | 16 (.6) | 1.05 (.53–2.07) | .897 | 29 (.6) | 27 (.5) | 1.07 (.63–1.80) | .809 |
| Through 180 days | 21 (.8) | 23 (.9) | .90 (.50–1.63) | .729 | 45 (.9) | 39 (.8) | 1.15 (.75–1.77) | .513 | |
| Through 365 days | 31 (1.2) | 33 (1.3) | .93 (.57–1.51) | .757 | 64 (1.3) | 62 (1.2) | 1.04 (.73–1.48) | .824 | |
| Endpoint | Timepoint | LDL ≥ 100 mg/dL | LDL < 100 mg/dL | ||||||
|---|---|---|---|---|---|---|---|---|---|
| CSL112 6 g (n = 2655) | Placebo (n = 2649) | HR (95% CI) | P-value | CSL112 6 g (n = 5198) | Placebo (n = 5229) | HR (95% CI) | P-value | ||
| Composite of MI, stroke, or death from CV causes | Through 90 days | 91 (3.4) | 129 (4.9) | .69 (.53–.90) | .007 | 276 (5.3) | 283 (5.4) | .98 (.83–1.15) | .783 |
| Through 180 days | 140 (5.3) | 194 (7.3) | .71 (.57–.88) | .002 | 380 (7.4) | 395 (7.6) | .97 (.84–1.11) | .643 | |
| Through 365 days | 206 (7.8) | 261 (9.9) | .78 (.65–.93) | .006 | 529 (10.3) | 556 (10.7) | .96 (.85–1.08) | .450 | |
| Composite of MI or death from CV causes | Through 90 days | 76 (2.9) | 116 (4.4) | .64 (.48–.86) | .003 | 255 (4.9) | 259 (5.0) | .99 (.83–1.17) | .879 |
| Through 180 days | 123 (4.7) | 175 (6.6) | .69 (.55–.87) | .002 | 346 (6.7) | 364 (7.0) | .96 (.82–1.11) | .540 | |
| Through 365 days | 181 (6.9) | 236 (8.9) | .75 (.62–.91) | .004 | 482 (9.4) | 515 (9.9) | .94 (.83–1.06) | .306 | |
| MI | Through 90 days | 61 (2.3) | 88 (3.4) | .68 (.49–.94) | .021 | 199 (3.9) | 210 (4.1) | .95 (.79–1.16) | .636 |
| Through 180 days | 100 (3.8) | 141 (5.4) | .70 (.54–.90) | .006 | 275 (5.4) | 301 (5.8) | .92 (.78–1.09) | .327 | |
| Through 365 days | 148 (5.6) | 186 (7.1) | .78 (.63–.97) | .027 | 380 (7.5) | 423 (8.2) | .90 (.79–1.04) | .150 | |
| Death from CV causes | Through 90 days | 20 (.8) | 39 (1.5) | .50 (.29–.86) | .012 | 67 (1.3) | 74 (1.4) | .90 (.64–1.25) | .511 |
| Through 180 days | 34 (1.3) | 53 (2.0) | .63 (.41–.97) | .037 | 90 (1.7) | 95 (1.8) | .94 (.70–1.25) | .660 | |
| Through 365 days | 53 (2.0) | 71 (2.7) | .73 (.51–1.04) | .080 | 137 (2.7) | 142 (2.7) | .95 (.75–1.21) | .697 | |
| Stroke | Through 90 days | 17 (.6) | 16 (.6) | 1.05 (.53–2.07) | .897 | 29 (.6) | 27 (.5) | 1.07 (.63–1.80) | .809 |
| Through 180 days | 21 (.8) | 23 (.9) | .90 (.50–1.63) | .729 | 45 (.9) | 39 (.8) | 1.15 (.75–1.77) | .513 | |
| Through 365 days | 31 (1.2) | 33 (1.3) | .93 (.57–1.51) | .757 | 64 (1.3) | 62 (1.2) | 1.04 (.73–1.48) | .824 | |
Abbreviations: CI, confidence interval; CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction.
Likewise, for the composite endpoint of time to first occurrence of cardiovascular death or MI (Table 2, Figure 3A), there was a significantly lower risk in those treated with CSL112 compared to placebo among patients with LDL-C ≥ 100 mg/dL at randomization at all timepoints. There was no difference in event rates among patients with an LDL < 100 mg/dL at baseline (Table 2, Figure 3B). The P-values for the treatment by LDL-C subgroup interaction at 90, 180, and 365 days were .02, .02, and .07, respectively.
Cumulative incidence of the time to first occurrence of cardiovascular death or MI. Cumulative incidence of the time to first occurrence of cardiovascular death or MI through 90, 180, and 365 days among patients with (A) an LDL-C ≥ 100 mg/dL at baseline who were prescribed statin therapy and (B) an LDL-C < 100 mg/dL at baseline who were prescribed statin therapy. Abbreviations: LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction
With regard to the individual components of the original primary endpoint, the risk of recurrent MI was significantly reduced in the CSL112 treatment group compared to placebo at all time points (Table 2, Figure 4A), and the risk of cardiovascular death was significantly lower at 90 and 180 days, although the difference did not meet nominal statistical significance at 365 days (Table 2, Figure 5A). There was no difference between the treatment groups in the risk of these endpoints among patients with an LDL < 100 mg/dL at baseline (Table 2, Figures 4B and 5B). There was no difference in the risk of stroke in either subgroup (Table 2).
Cumulative incidence of the time to first occurrence of MI. Cumulative incidence of the time to first occurrence of MI through 90, 180, and 365 days among patients with (A) an LDL-C ≥ 100 mg/dL at baseline who were prescribed statin therapy and (B) an LDL-C < 100 mg/dL at baseline who were prescribed statin therapy. Abbreviations: LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction
Cumulative incidence of the time to cardiovascular death. Cumulative incidence of the time to cardiovascular death through 90, 180, and 365 days among patients with (A) an LDL-C ≥ 100 mg/dL at baseline who were prescribed statin therapy and (B) an LDL-C < 100 mg/dL at baseline who were prescribed statin therapy. Abbreviations: LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction
Safety outcomes
Overall, there were similar rates of adverse events with CSL112 compared to placebo within those with an LDL-C ≥ 100 mg/dL at baseline and within those with LDL < 100 mg/dL (see Supplementary data online, Table S1). The safety findings in this subgroup analysis were consistent with those seen in the overall AEGIS-II population.11
Discussion
Among patients with AMI, multivessel coronary artery disease, and additional cardiovascular risk factors, higher baseline LDL-C was correlated with a lower risk of recurrent cardiovascular events with CSL112 compared to placebo. When evaluated by the cut point associated with greater risk reductions seen with PCSK9 inhibitors,13,14 those with baseline LDL-C level ≥ 100 mg/dL and prescribed guideline-recommended LDL-C lowering therapy with statins, four weekly infusions of CSL112, reduced the risk of cardiovascular death, MI, or stroke through 90 days. The treatment effect persisted through 180 and 365 days with an absolute risk reduction of up to 2.1% at 1 year. The risk of cardiovascular death was lower in the CSL112 treatment group at 90 and 180 days, and the risk of recurrent MI was reduced at 90, 180, and 365 days. In contrast, there was no treatment effect for any of the endpoints at any of the timepoints among those patients with an LDL-C < 100 mg/dL at baseline (Structured Graphical Abstract) .
Therefore, it appears that a treatment effect of apoA-I infusion therapy that increases cholesterol efflux capacity may be present in patients who are hyperlipidaemic at baseline, which supports the hypothesis that the LDL-C ≥ 100 mg/dL group had greater burden of cholesterol within plaque macrophages that was recalcitrant to statin therapy and/or had not been exposed to statin therapy for a sufficient time to reduce plaque cholesterol burden.
Notably, the treatment effect of CSL112 in the subgroup of patients with a baseline LDL-C ≥ 100 mg/dL was on a background of statin therapy, the majority of which was high-intensity statin therapy, and that LDL-C levels decreased as expected during the month-long treatment period from a median of 123 to 70 mg/dL. This could suggest a complementary or synergistic mechanism between LDL-C lowering and enhancement of cholesterol efflux, as both LDL-C lowering and enhancement of cholesterol efflux have been shown to have atheroprotective effects. Interestingly, in a nested case–control study of the Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial that measured cholesterol efflux capacity, the efflux capacity while treated with high-intensity statin therapy (rosuvastatin) was inversely associated with incident cardiovascular events, whereas this relationship was not apparent based on baseline cholesterol efflux capacity.16
Conversely, in the subgroup of patients with baseline LDL-C < 100 mg/dL (median 69 mg/dL), there was no apparent effect of CSL112. The impact of statins on plaque characteristics by various invasive and non-invasive imaging modalities has been well studied, and the totality of evidence suggests that statins induce plaque regression in a dose-dependent manner and proportionally to reductions in LDL-C,17 with a proposed threshold for regression occurring at LDL-C levels < 70 mg/dL. In addition, statins have been demonstrated to increase fibrous and calcified plaque volume and to decrease non-calcified, fibrofatty, and necrotic core volumes.17 Although all patients enrolled had evidence of multivessel coronary artery disease at baseline, one could hypothesize that if a patient had LDL-C levels at the time of AMI that were adequate to favourably alter plaque characteristics, then a therapy targeting cholesterol efflux from plaque may not be as effective.
The observations described within this subgroup analysis are consistent with the proposed biologic effect of an apoA-I infusion therapy that rapidly and robustly enhances cholesterol efflux capacity, thereby leading to remodelling of atherosclerotic plaque to a more stable phenotype by decreasing the lipid content within plaque macrophages and increasing the collagen content.18,19 Modulating residual risk via this mechanism in conjunction with LDL-C lowering for the subgroup of patients with higher LDL-C levels at the time of presentation with MI remains a viable concept, albeit one that would require additional prospective data.
This study had several limitations. This is a post-hoc subgroup analysis from the main AEGIS-II study, so this examination is exploratory; however, the results may be valid if analysed considering the following: (i) a priori, one would anticipate a greater treatment effect among patients with hyperlipidaemia and a higher plaque burden; (ii) the interaction P-value was significant; (iii) the results did not go in the opposite direction (show harm) in those with an LDL-C < 100 mg/dL, but rather, were neutral; (iv) animal and human data demonstrate favourable remodelling of atherosclerotic plaque following infusion of apoA-I18–20; and (v) impaired cholesterol efflux capacity has been associated with poorer outcomes post-MI,6 and CSL112 has previously been shown to improve cholesterol efflux in the post-MI setting.21 Other limitations of this analysis include the lack of LDL-C measurement beyond the end of the treatment period (30 days), and that the duration of statin treatment prior to presentation with AMI is not known. Finally, it is unknown whether an alternate dosing regimen of CSL112 (i.e. a higher dose, more than four infusions, or a different dosing frequency) could have impacted the findings.
In conclusion, in patients with AMI, multivessel coronary artery disease, and additional cardiovascular risk factors treated with background LDL-C lowering therapy, treatment with CSL112 was associated with a significantly lower risk of recurrent cardiovascular events compared to placebo among patients with a baseline LDL-C ≥ 100 mg/dL. There was no difference between the treatment groups among patients with an LDL-C < 100 mg/dL at baseline. Further prospective data would be needed to confirm that the efficacy of CSL112 is influenced by baseline LDL-C.
Notes
AEGIS-II Committees and Investigators:
Executive Committee
The Executive Committee members and their affiliation are as follows:
(Chairman) C. Michael Gibson, MS, MD, PERFUSE Study Group/Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; John H. Alexander, MD, MHS, Duke Clinical Research Institute/Duke University Medical Center, Durham, NC, USA; Philip A. Aylward, BM, BCh, PhD, South Australian Health and Medical Research Institute/SAHMRI, Adelaide, AUS; Deepak L. Bhatt, MD, MPH, Icahn School of Medicine at Mount Sinai Health System, New York, NY, USA; Christoph Bode, MD, University of Freiburg, Freiburg, Germany; Shaun G. Goodman, MD, MSc, Canadian Heart Research Centre, Toronto, Ontario, Canada; Robert A. Harrington, MD, Weill Cornell Medicine, New York, NY, USA, John J. P. Kastelein, MD, PhD, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands; Kenneth W. Mahaffey, MD, Stanford University Medical Center, Stanford, CA, USA; A. Michael Lincoff, MD, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH, USA; Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Stephen J. Nicholls, MBBS, PhD, Victorian Heart Hospital, Monash Heart and Intensive Care, Clayton, AUS; Stuart J. Pocock, PhD, London School of Hygiene and Tropical Medicine, London, UK; Paul M Ridker, MD, Brigham and Women's Hospital, Boston, MA, USA; P. Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, Cardiology Department, Université Paris, Diderot, Paris, France; Michal Tendera, MD, Medical University of Silesia, Katowice, Poland; Danielle Duffy, MD, CSL Behring, King of Prussia, PA, USA; and Pierluigi Tricoci, MD, PhD, MHS, CSL Behring, King of Prussia, PA, USA.
Publication Committee
The Publication Committee is a subgroup of the Executive Committee. The Publication Committee members and their affiliation are as follows:
(Chairman) C. Michael Gibson, MS, MD, PERFUSE Study Group/Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; John H. Alexander, MD, MHS, Duke Clinical Research Institute/Duke University Medical Center, Durham, NC, USA; John J. P. Kastelein, MD, PhD, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands; A. Michael Lincoff, MD, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH, USA; Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Stuart J. Pocock, PhD, London School of Hygiene and Tropical Medicine, London, UK; P. Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, Cardiology Department, Université Paris, Diderot, Paris, France; and Danielle Duffy, MD, Cardiovascular & Metabolism Clinical Research, CSL Behring, King of Prussia, PA, USA.
Steering Committee
The Steering Committee is composed of the academic leadership of the clinical study, the country leaders, and members of the sponsoring company. The Steering Committee reported to the Executive Committee of the trial. The Steering Committee members and their affiliation are as follows:
(Chairman) C. Michael Gibson, MS, MD, PERFUSE Study Group/Beth Israel Deaconess Medical Center, Harvard Medical School USA; (Argentina) Cecilia Bahit, MD, INECO Neurociencias Rosario, Argentina; (Australia) Gemma Figtree, MB BS, DPHIL (OXON), FRACP, FCSANZ, FAHA, Royal North Shore Hospital, Australia; (Austria) Kurt Huber, MD, FESC, FACC, FAHA, Wilhelminen Hospital, Austria; (Belgium) Pascal Vranckx, MD, Department of Cardiology and Critical Care Medicine, Heart Centre Hasselt, Belgium; (Brazil) Renato D. Lopes, MD, PhD, Duke University Medical Center, USA and Brazilian Clinical Research Institute, Brazil; (Brazil) Jose Carlos Nicolau, MD, PhD, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil; (Bulgaria) Nina Gotcheva, MD, PhD, Department of Cardiology, MHAT ‘National Cardiology Hospital’ EAD, Bulgaria; (Canada) Kevin Bainey, MD, MSc, Division of Cardiology, Mazankowski Alberta Heart Institute (MAHI) at University of Alberta, Canada; (Chile) Juan Carlos Prieto, MD, Cardiovascular Department, Clinic Hospital, University of Chile, Chile; (Colombia) Miguel Urina Triana, MD, MSc, PhD, FACC, Universidad Simón Bolívar, Colombia; (Czech Republic) Miroslav Solar, MD, I. Interní akutní kardioangiologická kliniky Fakultní nemocnice, Czech Republic; (Denmark, retired) Svend Eggert Jensen, MD, PhD, FESC, Aalborg University Hospital, Department of Cardiology, Denmark; (Denmark, current) Morten Bøttcher, MD PhD, Aarhus University, Godstrup Hospital, Denmark; (Estonia) Margus Viigimaa, MD, PhD, FESC, Tallinn University of Technology, North Estonia Medical Centre, Estonia; (Finland) Mika Laine, MD, Helsinki University Central Hospital, Finland; (France) Gilles Montalescot, MD, PhD, ACTION Study Group, Pitié-Salpêtrière Hospital, France; (Georgia) Tamaz Shaburishvili, MD, Tbilisi Heart and Vascular Clinic, Tbilisi, Georgia; (Germany) Daniel Duerschmied, MD, Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany; (Greece) Dimitris Tousoulis, MD, Athens University Medical School, Greece; (Hong Kong) Michael Lee, MD, Queen Elizabeth Hospital, Hong Kong; (Hungary) Bela Merkely, MD, PhD, Heart and Vascular Center of Semmelweis University, Hungary; (Israel) Basil Lewis, MD, Lady Davis Carmel Medical Center, Israel; (Italy) Giuseppe Ambrosio, MD, PhD, Università di Perugia, Ospedale S. Maria della Misericordia, Italy; (Japan) Satoshi Yasuda, MD, National Cerebral and Cardiovascular Center, Japan; (Latvia) Andrejs Erglis, MD, Latvian Centre of Cardiology, Pauls Stradins Clinical University Hospital, Latvia; (Lithuania) Rimvydas Slapikas, MD, PhD, Hospital of Lithuanian University of Health Sciences Kaunas Clinics, Lithuania; (Malaysia) Alan Fong, MD, Clinical Research Centre, Sarawak General Hospital Jalan Hospital, Malaysia; (Mexico) Jose Luis Leiva Pons, MD, Autonomous University of San Luis Potosi, San Luis Potosi (Mexico); (The Netherlands) Jan H. Cornel, MD, Medisch Centrum Alkmaar, The Netherlands; (New Zealand) Harvey White, MD, Green Lane Cardiovascular Research Unit, Te Toka Tumai Auckland, Te Whatu Ora—Health New Zealand; (Norway) Vibeke Juliebø, MD, Akershus University Hospital, Norway; (Peru) Manuel Horna, MD, FACC, FASE, FESC, Clínica Delgado Auna Peru; (Poland) Jaroslaw Trebacz, MD, Krakowski Szpital Specjalistyczny im. Jana Pawła II, Poland; (Portugal) João Morais, MD, Hospital Santo André, Portugal; (Romania) Dragos Vinereanu, MD, University of Medicine and Pharmacy Carol Davila, University and Emergency Hospital, Romania; (Russia) Sergey Zenin, MD, Regional Cardiology Dispensary, Russia; (Serbia) Nebojsa Tasic, MD, Dedinje Cardiovascular Institute, Serbia; (Singapore) Jack Tan, MD, National Heart Center Singapore, Singapore; (Slovakia) Jan Murin, MD, PhD, Comenius University, Slovakia; (South Africa) Lesley Burgess, MD, Tread Research, South Africa; (South Korea) Hyun Jae Kang, MD, Seoul National University Hospital, South Korea; (Spain) Angel Cequier Fillat, MD, Servicio de Cardiología. Hospital Universitario de Bellvitge, Spain; (Sweden) Emil Hagström, MD, Uppsala Clinical Research Center, Uppsala University, Sweden; (Switzerland) Stephan Windecker, MD, Bern University Hospital, Bern, Switzerland; European Cardiovascular Research Institute (ECRI), Switzerland; (Taiwan) Jiunn-Lee Lin, MD, National Taiwan University Hospital, Taiwan; (Thailand) Piyamitr Sritara, MD, PhD, Ramathibodi Hospital, Thailand; (Turkey) Umit Guray, MD, Ankara Numune Education and Research Hospital, Turkey; (United Kingdom) Vijay Kunadian, MD, Newcastle University, United Kingdom; (Ukraine) Alexandr Parkhomenko, MD, National Scientific Center, Ukraine; (United States) Marc Bonaca, MD, MPH, University of Colorado School of Medicine, Anschutz Medical Campus, USA; and (United States) Thomas J. Povsic, MD, Duke Clinical Research Institute, Duke Health, USA.
We would like to thank Dr. Anthony Gershlick, the country leader of the United Kingdom, and Dr. Amadeu Betriu, the country leader of Spain for their enormous contribution to the study before their untimely deaths. We miss them as friends and colleagues.
Supplementary data
Supplementary data are available at European Heart Journal online.
Declarations
Disclosure of Interest
Dr. Gibson receives research funding from CSL Behring, Janssen Pharmaceuticals, Johnson and Johnson Corporation, and SCAD Alliance. He receives consulting fees from Angel/Avertix Medical Corporation, AstraZeneca, Bayer Corporation, Beren Therapeutics, Boehringer Ingelheim, Boston Clinical Research Institute, Boston Scientific, Bristol-Myers Squibb, Cardiovascular Research Foundation, CeleCor Therapeutics, CSL Behring, DCRI, Esperion, EXCITE International ($0 Received), Fortress Biotech, Gilead Sciences, Inc., Janssen, Pharmaceuticals, Johnson & Johnson Corporation, MashUp MD, MD Magazine, Microport, MJHealth, Novartis, NovoNordisk, Pfizer, PHRI, PLxPharma, SCAI, Solstic Health/New Amsterdam Pharma, Somahlution/Marizyme, Vectura, Web MD, and Women as One. He has equity in nference, Dyad Medical, Absolutys, Fortress Biotech, and royalties as contributor to UpToDate. Dr. Duffy is an employee of CSL Behring. Dr. Bahit receives modest honorarium from MSD, Pfizer, Bristol-Myers Squibb, CSL Behring, Janssen, Boehringer Ingelheim, and Anthos Therapeutics. Dr. Chi has received research grant support paid to the Beth Israel Deaconess Medical Center, Harvard Medical School from Bayer, Janssen Scientific Affairs, and CSL Behring. Dr. White reports grant support paid to the institution for the ODYSSEY OUTCOMES trial from Sanofi and Regeneron Pharmaceuticals, for the STRENGTH Trial from Omthera Pharmaceuticals, for the HEART-FID Study from American Regent, for the Dal GenE study from DalCor Pharma Uk Inc., for the AEGIS II Study from CSL Behring, for the Clear Outcomes Study from Esperion Therapeutics, for the SOLIST-WHF and SCORED studies from Sanofi Aventis Australia Pty Ltd., for the Librexia AF and ACS studies from Janssen, and for ISCHEMIA and the MINT studies from the National Institutes of Health. He also received personal fees as a steering committee member from DalCor Pharma UK, CSL Behring, Sanofi Australia Pty Ltd., Janessen, and Esperion Therapeutics. He was on the advisory boards for CSL Behring and VEVRE. Dr. Korjian has received research grant support paid to the Beth Israel Deaconess Medical Center, Harvard Medical School from CSL Behring. Dr. Alexander has research grants from Artivion/CryoLife, Bayer, Bristol-Myers Squibb, CSL Behring, Ferring, the US FDA, Humacyte, and the US NIH and has received advisory board/consulting payments from AbbVie, o Artivion/CryoLife, AtriCure, Bayer, Bristol-Myers Squibb, Eli Lilly, Ferring, GlaxoSmithKline, Janssen, Novostia, Pfizer, Portola, Theravance, and Veralox. Dr. Lincoff has received honoraria from Novo Nordisk, Eli Lilly, Akebia, Ardelyx, Becton Dickson, Endologix, Fibrogen, GlaxoSmithkline, Medtronic, Neovasc, Provention Bio, ReCor, Brainstorm Cell, Alnylam, and Intarcia for consulting activities and research funding to his institution from AbbVie, Esperion, Astra Zeneca, CSL Behring, Novartis, and Eli Lilly. Dr. Heise is an employee of CSL Behring. Pr. Kingwell is an employee and shareholder of CSL Ltd. Dr. Nicolau is recipient of a scholarship from National Council of Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq) #303448/2021-0, research grants from Amgen, Astrazeneca, Bayer, CSL Behring, Daiichi Sankyo, Dalcor, Esperion, Ionis, Janssen, Novartis, Novo Nordisk, Sanofi, and Vifor, and consulting fees from Libbs. Dr. Lopes has received Research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis, funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk, and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novo Nordisk. Dr. Cornel reports membership in advisory boards with Amgen and AstraZeneca. Dr. Lewis has received consulting fees from Janssen R&D and Idorsia. Prof. Parkhomenko has received research grants from CSL-Behring, Amgen, Novo-Nordisk, and Boehringer Ingelheim and consulting or speaking fees from Novo Nordisk, AstraZeneca, Pfizer, Sanofi, and Boehringer Ingelheim. Dr. Vinereanu has received research grants from CSL Behring, Bayer, Novartis, Amgen, and Boehringer Ingelheim and consultancy fees from Bayer, Novartis, Amgen, and Boehringer Ingelheim. Dr. Goodman has received research grant support (e.g. steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (e.g. advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE Ltd., Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma and salary support/honoraria from the Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, Jewish General Hospital, New York University Clinical Coordinating Centre, PERFUSE Research Institute, Peter Munk Cardiac Centre Clinical Trials and Translation Unit, and TIMI Study Group (Brigham Health). Dr. Bode receives research support from CSL Behring. Dr. Steg receives research grants from Amarin and Sanofi, does clinical trials (steering committee, CEC, DSMB) for Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, CSL-Behring, Idorsia, Janssen, Novartis, Novo-Nordisk, Pfizer, and Sanofi, receives consulting or speaking fees from Amarin, Amgen, BMS, and Novo-Nordisk, and is a Senior Associate Editor at Circulation. Dr. Libby is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. Dr. Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc. Dr. Libby's laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk, and Genentech. Dr. Libby is on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. Dr. Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Dr. Libby receives funding support from the National Heart, Lung, and Blood Institute (1R01HL134892 and 1R01HL163099-01), the RRM Charitable Fund, and the Simard Fund. Dr. Sacks has received support from CSL Behring. Dr. Bainey receives research support from CSL Behring. Dr. Ridker has received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, NovoNordisk, and the NHLBI, and during the past 5 years has served as a consultant to Novartis, Flame, Agepha, Ardelyx, Arrowhead, AstraZeneca, CSL Behring, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer Ingelheim, RTI, Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics. Dr. Ridker has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). Dr. Mahaffey receives research funding from the American Heart Association, Apple, Inc., Bayer, California Institute of Regenerative Medicine, CLS Behring, Eidos, Ferring, Gilead, Google (Verily), Idorsia, Johnson and Johnson, Luitpold, Novartis, PAC-12, Predordior, and Sanifit and consulting fees from Applied Therapuetics, Bayer, BMS, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson and Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, and Theravance, and has equity in Human, Medeloop, Precordior, and Regencor. Dr. Aylward receives research support from CSL and Janssen Advisory board and honoraria and speaker fees from Novartis, Boehringer Ingelheim, Amgen, and Astra Zeneca. Dr. Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx, and Sanofi-Regeneron and is also a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi- Regeneron, Vaxxinity, CSL Sequiris, and Novo Nordisk. Dr. Pocock consults with CSL Behring as a member of executive and publications committees. Dr. Mehran reports institutional research payments from Abbott, Abiomed, Affluent Medical, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, AtriCure Inc., Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CeloNova, CERC, Chiesi, Cleerly Health Inc., Concept Medical, Cytosorbents, Daiichi Sankyo, Duke, Element Science, Essential Medical, Faraday, Idorsia Pharmaceuticals, Janssen, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Population Health Research Institute, Protembis, RecCor Medical Inc., RenalPro, RM Global, Sanofi, Shockwave, Vivasure, and Zoll and personal fees from Affluent Medical, Boehringer Ingelheim, Cardiovascular Research Foundation (CRF), Cordis, Daiichi Sankyo Brasil, E.R. Squibb & Sons, Esperion Science/Innovative Biopharma, Europa Group/Boston Scientific, Gaffney Events, Educational Trust, Henry Ford Health Cardiology, Ionis Pharmaceuticals, Lilly and Company, MedCon International, Novartis, NovoNordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Vectura, VoxMedia, WebMD, IQVIA, Radcliffe, and TARSUS Cardiology and no fees from AMA (Scientific Advisory Board) and SCAI (Women in Innovations Committee Member) and fees from the Faculty CRF Honorarium from JAMA Cardiology (Associate Editor), ACC (BOT Member, SC Member CTR Program), and has <1% equity in Applied Therapeutics, Elixir Medical, Stel, CntrolRad (spouse). Dr. Harrington declares the following research relationships: Baim Institute (DSMB), CSL (RCT Executive Committee), Janssen (RCT Chair), NHLBI (RCT Executive Committee; DSMB Chair), PCORI (RCT Co-Chair), and DCRI; consulting relationships: Atropos Health, Bitterroot Bio, BMS, BridgeBio, Element Science, Edwards Lifesciences, Foresite Labs, ad Medscape/WebMD; and Board of Directors: American Heart Association, College of the Holy Cross, Cytokinetics.
Data Availability
Data collected for this study will not be made available to others.
Funding
This study was sponsored by CSL Behring, LLC.
Ethical Approval
The study was approved by national regulatory agencies and institutional review boards or ethics committees at all participating sites, and all patients provided written informed consent (ClinicalTrials.gov, number NCT03473223).
Pre-registered Clinical Trial Number
ClinicalTrials.gov, number NCT03473223.
