Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

AIMS: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target. METHODS AND RESULTS: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and VLDL-C were 42 and 31 mg/dL, respectively (reference: <30 mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18 mg/dL at the highest dose. Over the same period, VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5 mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively. CONCLUSION: Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins.

In this randomized controlled trial of 286 participants with elevated triglycerides, treatment with vupanorsen, an ANGPTL3 inhibitor, lowered remnant cholesterol by up to 59% and VLDL cholesterol by up to 67% over placebo. The effect of the treatment was sustained throughout 24 weeks and consistent across key patient subgroups. ANGPTL3 inhibition may be a promising approach to treat patients with elevated triglycerides.

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF). OBJECTIVE: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes. METHODS: TRANSLATE-TIMI 70 was a randomized, placebo-controlled trial testing 7 dosing regimens of vupanorsen in 286 adults with hyperlipidemia. A total of 227 patients had HFF measured at baseline and 24 weeks and were included in this analysis. RESULTS: The median HFF at baseline was 8.5%. Vupanorsen led to dose-dependent relative increases in HFF of up to 76% at 24 weeks (p < 0.001), corresponding to an absolute increase of up to 7.0% at the highest dose (p < 0.001). Increases in HFF were numerically greater in patients who had elevated baseline HFF, body mass index, triglycerides, or diabetes. Vupanorsen also increased liver enzymes in a dose-dependent manner, and changes in HFF were moderately positively correlated with changes in aspartate transaminase (AST) (rho = 0.49, p < 0.001) and alanine transaminase (ALT) (rho = 0.50, p < 0.001). CONCLUSION: Vupanorsen, an inhibitor of ANGPTL3 protein synthesis, caused dose-dependent increases in HFF. Increases in HFF were only moderately correlated with elevations in AST and ALT, suggesting that liver enzymes are an imperfect indicator to detect increases in hepatic fat. These results highlight the need to monitor HFF in clinical trials of therapies targeting intracellular ANGPTL3 inhibition, especially those that are targeted to the liver.

Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).

Decision-Making During Percutaneous Coronary Intervention Guided by Optical Coherence Tomography: Insights From the LightLab Initiative.

BACKGROUND: Use of intracoronary imaging is associated with improved outcomes in patients undergoing percutaneous coronary intervention (PCI). Yet, the impact of intracoronary imaging on real-time physician decision-making during PCI is not fully known. METHODS: The LightLab Initiative is a multicenter, prospective, observational study designed to characterize the use of a standardized optical coherence tomography (OCT) workflow during PCI. Participating physicians performed pre-PCI and post-PCI OCT in accordance with this workflow and operator assessments of lesion characteristics and treatment plan were recorded for each lesion based on angiography alone and following OCT. Physicians were categorized as having low (n=15), intermediate (n=13), or high (n=14) OCT use in the year preceding participation. RESULTS: Among 925 patients with 1328 lesions undergoing PCI, the prescribed OCT workflow was followed in 773 (84%) of patients with 836 lesions. Operator lesion assessment and decision-making during PCI changed with OCT use in 86% (721/836) of lesions. Pre-PCI OCT use changed operator decision-making in 80% of lesions, including lesion assessment (45%), vessel preparation strategy (27%), stent diameter (37%), and stent length (36%). Post-PCI OCT changed stent optimization decision-making in 31% of lesions. These findings were consistent across strata of physician prior OCT experience. CONCLUSIONS: A standardized OCT workflow impacted PCI decision-making in 86% of lesions, with a predominant effect on pre-PCI lesion assessment and planning of treatment strategy. This finding was consistent regardless of operator experience level and provides insight into mechanisms by which intravascular imaging might improve PCI outcomes.

Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease.

BACKGROUND: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events and was safe and well tolerated over a median of 2.2 years of follow-up. However, large-scale, long-term data are lacking. METHODS: The parent FOURIER trial randomized 27 564 patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE [FOURIER Open-Label Extension]) in the United States and Europe; primary analyses were pooled across studies. The primary end point was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected. RESULTS: A total of 6635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in the parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 [95% CI, 0.75-0.96]; P=0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 [95% CI, 0.68-0.93]; P=0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 [95% CI, 0.60-0.99]; P=0.04). CONCLUSIONS: Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for >8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT02867813 and NCT03080935.

Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients With COVID-19: COVID-PACT.

BACKGROUND: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain. METHODS: COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit-level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit-level COVID-19 rates. RESULTS: At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08-3.55]; P=0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32-0.99]; P=0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose (P=0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; P=0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56-1.48]; P=0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy. CONCLUSIONS: In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04409834.

Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebo­controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.

Biomarker Prediction of Complex Coronary Revascularization Procedures in the FOURIER Trial.

BACKGROUND: Biomarkers are known to predict major adverse cardiovascular events. However, the association of biomarkers with complex coronary revascularization procedures or high-risk coronary anatomy at the time of revascularization is not understood. OBJECTIVES: We examined the associations between baseline biomarkers and major coronary events (MCE) and complex revascularization procedures. METHODS: FOURIER was a randomized trial of the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab vs placebo in 27,564 patients with stable atherosclerosis. We analyzed adjusted associations among the biomarkers, MCE (coronary death, myocardial infarction, or revascularization), and complex revascularization (coronary artery bypass graft or complex percutaneous coronary intervention) using a multimarker score with 1 point assigned for each elevated biomarker (high-sensitivity C-reactive protein ≥2 mg/L; N-terminal pro-B-type natriuretic peptide ≥450 pg/mL; high-sensitivity troponin I ≥6 ng/L; growth-differentiation factor-15 ≥1,800 pg/mL). RESULTS: When patients were grouped by the number of elevated biomarkers (0 biomarkers, n = 6,444; 1-2 biomarkers, n = 12,439; ≥3 biomarkers, n = 2,761), there was a significant graded association between biomarker score and the risk of MCE (intermediate score: HRadj: 1.57 [95% CI: 1.38-1.78]; high score: HRadj: 2.90 [95% CI: 2.47-3.40]), and for complex revascularization (intermediate: HRadj: 1.33 [95% CI: 1.06-1.67]; high score: HRadj: 2.07 [95% CI: 1.52-2.83]) and its components (Ptrend <0.05 for each). The number of elevated biomarkers also correlated with the presence of left main disease, multivessel disease, or chronic total occlusion at the time of revascularization (P < 0.05 for each). CONCLUSIONS: A biomarker-based strategy identifies stable patients at risk for coronary events, including coronary artery bypass graft surgery and complex percutaneous coronary intervention, and predicts high-risk coronary anatomy at the time of revascularization. These findings provide insight into the relationships between cardiovascular biomarkers, coronary anatomical complexity, and incident clinical events. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633).

Re-adjudication of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) with study-level meta-analysis of hospitalization for heart failure from cardiovascular outcomes trials with dipeptidyl peptidase-4 (DPP-4) inhibitors.

BACKGROUND: Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the cardiovascular (CV) safety of sitagliptin versus placebo on CV outcomes in patients with type 2 diabetes and CV disease and found sitagliptin noninferior to placebo. Subsequently, based on feedback from FDA, the Sponsor of the trial, Merck & Co., Inc., engaged a separate academic research organization, the TIMI Study Group, to re-adjudicate a prespecified set of originally adjudicated events. METHODS: TIMI adjudicated in a blinded fashion all potential hospitalization for heart failure (HHF) events, all potential MACE+ events previously adjudicated as not an endpoint event, and a random subset (~10%) of MACE+ events previously adjudicated as an endpoint event. An updated study-level meta-analysis of four randomized, placebo-controlled, CV outcomes trials with dipeptidyl peptidase 4 (DPP-4) inhibitors was then performed. RESULTS: After re-adjudication of potential HHF events in the intent-to-treat population, there were 224 patients with a confirmed event in the sitagliptin arm (1.05/100 person-years) and 239 patients in the placebo arm (1.13/100 person-years), corresponding to a hazard ratio (HR) of 0.94 (95% confidence interval [95% CI]: 0.78-1.13, p = .49). Concordance between the outcome of the original adjudication and the re-adjudication for HHF events was 82.7%. The meta-analysis of CV outcomes trials with DPP-4 inhibitors with placebo and involving 43 522 patients yielded an HR of 1.07 (95% CI: 0.83-1.39), with moderate heterogeneity (p = .45, I2 = 62.07%). CONCLUSION: The results of this independent re-adjudication process and analyses of CV outcomes from TECOS were consistent with the original adjudication results and overall study findings. An updated study-level meta-analysis showed no overall significant risk for HHF with DPP-4 inhibitors, but with statistical heterogeneity.

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

BACKGROUND: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. METHODS: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3. RESULTS: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P<0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship' and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). CONCLUSIONS: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.

Effect of Evolocumab in Patients With Prior Percutaneous Coronary Intervention.

BACKGROUND: Patients with prior percutaneous coronary intervention (PCI) are at high residual risk for multiple types of coronary events within and beyond the stented lesion. This risk might be mitigated by more intensive LDL-C (low-density lipoprotein cholesterol)-lowering beyond just with statin therapy. METHODS: FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27 564 patients with stable atherosclerotic disease on statin to the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab or placebo with a median follow-up of 2.2 years. The end points of interest were major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization), and major coronary events (a composite of coronary heart death, myocardial infarction, or coronary revascularization). We compared the risk of MACE and the magnitude of relative and absolute risk reductions with evolocumab in patients with and without prior PCI. RESULTS: Seventeen thousand seventy-three patients had prior PCI. In the placebo arm, those with prior PCI had higher rates of MACE (13.2% versus 8.3%; hazard ratio [HR]adj 1.61 [95% CI, 1.42-1.84]; P<0.0001) and major coronary events (11.5% versus 6.0%; HRadj, 1.72 [95% CI, 1.49-1.99]; P<0.0001). Relative risk reductions with evolocumab were similar in patients with and without prior PCI (MACE: HR, 0.84 [0.77-0.91] versus HR, 0.88 [0.77-1.01]; Pinteraction 0.51; major coronary events: HR, 0.82 [0.75-0.90] versus HR, 0.88 [0.75-1.04]; Pinteraction 0.42). Absolute risk reductions for MACE were 2.0% versus 0.9% (Pinteraction 0.14) and for major coronary events 2.0% versus 0.7% (Pinteraction 0.045). In those with prior PCI, the effect of evolocumab on coronary revascularization (HR, 0.76 [0.69-0.85]) was directionally consistent across types of revascularization procedures: coronary artery bypass grafting (HR, 0.71 [0.54-0.94]); any PCI (HR, 0.77 [0.69-0.86]); PCI for de novo lesions (HR, 0.76 [0.66-0.88]); and PCI for stent failure or graft lesions (HR, 0.76 [0.63-0.91]). CONCLUSIONS: Evolocumab reduces the risk of MACE in patients with prior PCI including the risk of coronary revascularization, with directionally consistent effects across several types of revascularization procedures, including coronary artery bypass grafting and PCI for stent or graft failure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex.

BACKGROUND: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level data. METHODS: We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs [95% CIs]) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. RESULTS: A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 [3.01%] versus 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74-0.89]), death (2276/29 312 [7.76%] versus 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87-0.97]), and intracranial bleeding (184/29 270 [0.63%] versus 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37-0.56]), but no statistically different hazard of major bleeding (1479/29 270 [5.05%] versus 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74-1.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 [3.96%] versus 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95-1.19]) but a lower hazard of intracranial bleeding (55/12 985 [0.42%] versus 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21-0.37]), death (1082/13 049 [8.29%] versus 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83-0.97]), and major bleeding (564/12 985 [4.34%] versus 1733/29 187 [5.94%]; HR, 0.63 [95% CI, 0.45-0.88]). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (P=0.01) and lower creatinine clearance (P=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (P=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction P=0.02) and lower-dose DOACs (interaction P=0.01) versus warfarin. CONCLUSIONS: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.

Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.

AIMS: We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients. CONCLUSIONS: In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.

LEGACY: Phase 2a Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamic Effects of the Anti-EL (Endothelial Lipase) Antibody MEDI5884 in Patients With Stable Coronary Artery Disease.

OBJECTIVE: Functional HDL (high-density lipoprotein) particles that facilitate cholesterol efflux may be cardioprotective. EL (endothelial lipase) hydrolyzes phospholipids promoting catabolism of HDL and subsequent renal excretion. MEDI5884 is a selective, humanized, monoclonal, EL-neutralizing antibody. We sought to determine the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of MEDI5884 in patients with stable coronary artery disease. Approach and Results: LEGACY was a phase 2a, double-blind, placebo-controlled, parallel-design trial that randomized 132 patients with stable coronary artery disease receiving high-intensity statin therapy to 3 monthly doses of 1 of 5 dose levels of MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary end point was the safety and tolerability of MEDI5884 through the end of the study (day 151). Additional end points included change in HDL cholesterol and cholesterol efflux from baseline to day 91, hepatic uptake of cholesterol at day 91, changes in various other lipid parameters. The incidence of adverse events was similar between the placebo and MEDI5884 groups. In a dose-dependent manner, MEDI5884 increased HDL cholesterol up to 51.4% (P<0.0001) and global cholesterol efflux up to 26.2% ([95% CI, 14.3-38.0] P<0.0001). MEDI5884 increased HDL particle number up to 14.4%. At the highest dose tested, an increase in LDL (low-density lipoprotein) cholesterol up to 28.7% (P<0.0001) and apoB (apolipoprotein B) up to 13.1% (P=0.04) was observed with MEDI5884. However, at the potential target doses for future studies, there was no meaningful increase in LDL cholesterol or apoB. CONCLUSIONS: Inhibition of EL by MEDI5884 increases the quantity and quality of functional HDL in patients with stable coronary artery disease on high-intensity statin therapy without an adverse safety signal at the likely dose to be used. These data support further clinical investigation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03351738.

Long-Term Ticagrelor in Patients With Prior Coronary Stenting in the PEGASUS-TIMI 54 Trial.

Background Coronary stent type and risk of stent thrombosis remain important factors affecting recommended duration of dual antiplatelet therapy. We investigated the efficacy and safety of long-term ticagrelor in patients with prior coronary stenting enrolled in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial. Methods and Results Patients in PEGASUS-TIMI 54 had a myocardial infarction 1 to 3 year prior and were randomized 1:1:1 to ticagrelor 60 or 90 mg BID or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events). Stent thrombosis was prospectively adjudicated (Academic Research Consortium definition). Baseline characteristics were compared by most recent stent type (bare metal versus drug-eluting stent and first- versus later-generation drug-eluting stent). Treatment arms were compared using Cox proportional hazards models. Of 21 162 patients randomized, 80% (n=16 891) had prior coronary stenting. Following randomization, myocardial infarction was the most frequent ischemic event in patients with prior stenting in the placebo arm, occurring in 5.2% of patients (Type 1: 4.1%), followed by cardiovascular death (2.3%), stroke (1.7%), and stent thrombosis (0.9%). Ticagrelorpooled reduced major adverse cardiovascular events (7.0% versus 8.0%; hazard ratio [HR], 0.85; 95% CI, 0.75-96) regardless of stent type (bare metal stent versus drug-eluting stent: pinteraction=0.767; first versus later generation: pinteraction=0.940). The rate of any stent thrombosis was numerically lower with ticagrelorpooled (0.7% versus 0.9%; HR, 0.73; 95% CI, 0.50-1.05) and Thrombolysis in Myocardial Infarction major bleeding was increased (HR, 2.65; 95% CI, 1.90-3.68). Conclusions Long-term ticagrelor reduces major adverse cardiovascular events in patients with prior myocardial infarction and coronary stenting regardless of stent type, with the benefit driven predominantly by reduction in de novo events. Nonfatal major bleeding is increased with ticagrelor. Registration Information clinicaltrials.gov. Identifier: NCT01225562.

Edoxaban versus Warfarin in Patients with Atrial Fibrillation at the Extremes of Body Weight: An Analysis from the ENGAGE AF-TIMI 48 Trial.

BACKGROUND: The effects of anticoagulants at extremes of body weight (BW) are not well described. The aim of this study was to analyze the pharmacokinetics/pharmacodynamics and clinical outcomes in patients randomized to warfarin, higher dose edoxaban (HDER), and lower dose edoxaban (LDER) regimens at extremes of BW in ENGAGE AF-TIMI 48. METHODS AND RESULTS: We analyzed three BW groups: low BW (LBW: <5th percentile, ≤55 kg, N = 1,082), middle BW (MBW: 45th-55th percentile, 79.8-84 kg, N = 2,153), and high BW (HBW: >95th percentile, ≥120 kg, N = 1,093). In the warfarin arm, LBW patients had higher rates of stroke/systemic embolism (SSE: 6.5 vs. 4.7 in MBW vs. 1.6% in HBW, P trend < 0.001), major bleeding (MB: 9.3 vs. 7.7 vs. 6.5%, P trend = 0.08), and worse net clinical outcome of systemic embolic event, MB, or death (31.5 vs. 19.1 vs. 16.0%, P trend < 0.0001). The time-in-therapeutic range with warfarin was lowest in LBW patients (63.0 vs. 69.3 vs. 70.1% patients, P trend < 0.001). The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across BW groups. The risk of SSE was similar between HDER and warfarin for each of the three weight groups (P int = 0.52, P int-trend = 0.86). MB was reduced by LDER versus warfarin (P int = 0.061, P int-trend = 0.023), especially in LBW patients. Net clinical outcomes were improved by HDER versus warfarin (P int = 0.087, P int-trend = 0.027), especially in LBW patients. CONCLUSION: Patients with LBW in ENGAGE AF-TIMI 48 had in general a more fragile clinical status and poorer international normalized ratio control. The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across extremes of BW, resulting in similar efficacy compared with warfarin, while major or clinically relevant non-MB and net outcomes were most favorable with edoxaban as compared to warfarin in LBW patients.

Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization.

OBJECTIVES: This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization. BACKGROUND: PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall. METHODS: FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG). RESULTS: In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years). CONCLUSIONS: Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

Effect of Evolocumab on Type and Size of Subsequent Myocardial Infarction: A Prespecified Analysis of the FOURIER Randomized Clinical Trial.

Importance: The PCSK9 inhibitor evolocumab reduced major vascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, yet the types and sizes of myocardial outcomes in FOURIER have not been previously explored. Objective: To assess the types and sizes of myocardial infarction (MI) and the effect of evolocumab on MI by subtype. Design, Setting, and Participants: A prespecified analysis of a multicenter double-blind randomized clinical trial. Patients were randomized to evolocumab or placebo and followed up for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Clinical end points were evaluated by the Thrombolysis in Myocardial Infarction clinical events committee. Rates presented are 3-year Kaplan-Meier estimates. Data were collected from 2013 to 2016 and analyzed from June 2017 to December 2019. Main Outcomes and Measures: Myocardial infarction was defined based on the third universal MI definition, and further classified according to MI type (universal MI subclass, ST-segment elevation myocardial infarction [STEMI] vs non-STEMI) and by MI size (determined by peak troponin level). Results: A total of 27 564 patients were randomized, with a mean (SD) age of 62.5 (9.0) years, and 20 795 (75%) were male. Of these, 1107 patients experienced a total of 1288 MIs. Most MIs (68%) were atherothrombotic (type 1), with 15% from myocardial oxygen supply-demand mismatch (type 2) and 15% percutaneous coronary intervention-related (type 4). Sudden death (type 3) and coronary artery bypass grafting-related (type 5) accounted for a total of 21 MIs (<2%). Evolocumab significantly reduced the risk of first MI by 27% (4.4% vs 6.3%; hazard ratio [HR], 0.73; 95% CI, 0.65-0.82; P < .001), type 1 by 32% (2.9% vs 4.5%; HR, 0.68; 95% CI, 0.59-0.79; P < .001), and type 4 by 35% (0.8% vs 1.1%; HR, 0.65; 95% CI, 0.48-0.87; P = .004), with no effect on type 2 (0.9% vs 0.8%; HR, 1.09; 95% CI, 0.82-1.45; P = .56). Most MIs (688 [59.8%]) had troponin levels greater than or equal to 10 times the upper limit of normal. The benefit was highly significant and consistent regardless of the size of MI with a 34% reduction in MIs with troponin level greater than or equal to 10 times the upper limit of normal (2.6% vs 3.7%; HR, 0.66; 95% CI, 0.56-0.77; P < .001) and a 36% reduction in the risk of STEMI (1.0% vs 1.5%; HR, 0.64; 95% CI, 0.49-0.84; P < .001). Conclusions and Relevance: Low-density lipoprotein cholesterol lowering with evolocumab was highly effective in reducing the risk of MI. This reduction with evolocumab included benefit across multiple subtypes of MI related to plaque rupture, smaller and larger MIs, and both STEMI and non-STEMI. These data are consistent with the known benefit of low-density lipoprotein cholesterol lowering and underscore the reduction in clinically meaningful events. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial.

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%. Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease. Interventions: Patients were randomized 1:1 to evolocumab or placebo. Design, Setting, and Participants: Exploratory analysis of the FOURIER trial, which enrolled 27 564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020. Main Outcomes and Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model. Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P = .002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P = .001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P = .14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. Conclusions and Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.