Safety profile of proprotein convertase subtilisin/kexin type 9 inhibitors alirocumab and evolocumab: an updated meta-analysis and meta-regression.

BACKGROUND: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. METHODS: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. RESULTS: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). CONCLUSION: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

Impact of Chronic Kidney Disease on the Outcomes of Patients Undergoing Percutaneous Left Atrial Appendage Occlusion: Insights from a Large National Database.

BACKGROUND: Studies exploring the effectiveness and safety of percutaneous left atrial appendage occlusion (pLAAO) in patients with chronic kidney disease (CKD) are limited. OBJECTIVES: We aimed to analyze trends and outcomes following pLAAO in patients with CKD. METHODS: We utilized the National Inpatient Sample (NIS) to identify hospitalizations for pLAAO from 2016-2020 and further identified cases with concomitant CKD. The primary outcome was mortality, and secondary outcomes were cerebrovascular accidents, major bleeding, vasopressor requirements, percutaneous coronary intervention, cardiac arrest, acute respiratory failure, transfusion, length of stay (LOS), and total hospital charges. Multivariable logistic regression was performed to further adjust for covariates. RESULTS: A total of 89,309 pLAAO procedures from 2016 to 2020 were identified, of which 21,559 (24.1%) reported concomitant CKD, with males comprising the majority (62.2%). An increasing trend in pLAAO procedures was seen from 2.24 to 13.9 per 10,000 patients from 2016 to 2020. Despite patients with CKD having a higher rate of most comorbidities, there was no difference in mortality (non-CKD vs. CKD, 0.07% vs. 0.42%; aOR: 1.3, 95% CI: 0.4 - 4.4, p=0.686) and complications for CKD and non-CKD patients, while CKD patients had longer LOS and higher total hospital charge. No significant sex differences in outcomes among CKD patients were observed except for a longer LOS in females. CONCLUSION: Despite generally having more comorbidities, outcomes of patients with CKD following pLAAO are similar to those without CKD, suggesting that pLAAO can be offered as a safe option for the treatment of AF in eligible patients with CKD.

Sex differences in trends and outcomes of acute myocardial infarction with mechanical complications in the United States.

BACKGROUND: Mechanical complications (MC) are rare but significant sequelae of acute myocardial infarction (AMI). Current data on sex differences in AMI with MC is limited. METHODS: We queried the National Inpatient Sample database to identify adult patients with the primary diagnosis of AMI and MC. The main outcome of interest was sex difference in-hospital mortality. Secondary outcomes were sex differences in the incidence of acute kidney injury (AKI), major bleeding, use of inotropes, permanent pacemaker implantation (PPMI), performance of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), surgery (VSD repair and MV surgery), pericardiocentesis, use of mechanical circulatory support (MCS), ischemic stroke, and mechanical ventilation. RESULTS: Among AMI-MC cohort, in-hospital mortality was higher among females compared to males (41.24% vs 28.13%: aOR 1.39. 95% CI 1.079-1.798; p = 0.01). Among those who had VSD, females also had higher in-hospital mortality compared to males (56.7% vs 43.1%: aOR 1.74, 95% CI 1.12-2.69; p = 0.01). Females were less likely to receive CABG compared to males (12.03% vs 20%: aOR 0.49 95% CI 0.345-0.690; p < 0.001). CONCLUSION: Despite the decreasing trend in AMI admission, females had higher risk of MC and associated mortality. Significant sex disparities still exist in AMI treatment.