Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Clinical Utility of Coronary CT Angiography: Coronary Stenosis Detection and Prognosis in Ambulatory Patients

INTRODUCTION: Multislice CT coronary angiography (MSCTA) accurately detects stenosis in patients undergoing coronary arteriography, but its accuracy in clinical outpatients is less certain. This study retrospectively analyzed MSCTA performance in a large outpatient cohort and examined 6-month clinical follow-up in those without invasive CA. METHODS: Patients underwent MSCTA for clinical indications including symptoms or noninvasive results being either equivocal or suspected as incorrect by referring clinicians. Standard 16-slice CT scanner techniques were used, and results were analyzed on the basis of both patient and vessel. Patients were treated medically or sent to invasive angiography on the basis of MSCTA results and judgment of referring clinicians. All invasive angiograms were analyzed using quantitative coronary angiography. Six-month clinical follow-up was determined in patients without CA. RESULTS: One thousand fifty-three consecutive patients were referred for MSCTA, resulting in 994 interpretable scans. Mean age was 58+/-13 years, 55% were male, 50% had prior noninvasive testing, and 90% had symptoms. Invasive angiography was performed in 160 patients, with significant stenoses present in 69%. MSCTA demonstrated 87% and 89% accuracy by patient- and vessel-based analysis, respectively, and was most accurate in the left main and right coronary arteries. Only two patients not referred for angiography had significant stenosis in those undergoing 6-month follow-up. CONCLUSIONS: MSCTA accurately detects obstructive coronary stenosis in clinical patients with possible cardiac symptoms, and effectively triages them for invasive angiography. Negative results are highly accurate in ruling out obstructive disease. Six-month prognosis is excellent in patients without significant disease determined by MSCT

Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry

© 2019 [The Author/The Authors] Background and aims: There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH). Methods: CASCADE FH Registry data were analyzed to assess longitudinal changes in medication usage, in low density lipoprotein cholesterol (LDL-C) levels, and the rate of major adverse cardiovascular events (MACE (myocardial infarction, coronary revascularization, stroke or transient ischemic attack) in adults with FH followed in US specialty clinics. Results: The cohort consisted of 1900 individuals (61% women, 87% Caucasian), with mean age of 56 ± 15 years, 37% prevalence of ASCVD at enrollment, mean pretreatment LDL-C 249 ± 68 mg/dl, mean enrollment LDL-C 145 mg/dl and 93% taking lipid lowering therapy. Over follow up of 20 ± 11 months, lipid lowering therapy use increased (mean decrease in LDL-C of 32 mg/dl (p \u3c 0.001)). Only 48% of participants achieved LDL-C \u3c 100 mg/dl and 22% achieved LDL-C \u3c 70 mg/dl; ASCVD at enrollment was associated with greater likelihood of goal achievement. MACE event rates were almost 6 times higher among patients with prior ASCVD compared to those without (4.6 vs 0.8/100 patient years). Also associated with incident MACE were markers of FH severity and conventional ASCVD risk factors. Conclusions: With care in FH specialized clinics, LDL-C decreased, but LDL-C persisted \u3e100 mg/dl in 52% of patients. High ASCVD event rates suggest that adults with FH warrant designation as having an ASCVD risk equivalent. Earlier and more aggressive therapy of FH is needed to prevent ASCVD events

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUND Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-highdensity lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS Among patients who had a previous acute coronary syndrome and who were receiving highintensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

BACKGROUN

Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

Background: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402