A meta-analysis of medications directed against PCSK9 in familial hypercholesterolemia.

BACKGROUND AND AIMS: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. METHODS: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. RESULTS: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). CONCLUSIONS: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.

Outcomes following repair of anomalous coronary artery from the pulmonary artery in infants: results from a procedure-based national database.

BACKGROUND: Anomalous coronary artery from the pulmonary artery (ACAPA) is a very rare congenital anomaly that often occurs during infancy. Patients can present in a critical condition. METHODS: We analysed procedure-related data from a national audit database for the period 2000-2013. RESULTS: A total of 120 patients <1 year had repair of isolated ACAPA using a coronary transfer or the tunnel (Takeuchi) operation. Seven patients (6.8%) required a mitral valve procedure at index and eight patients (7.8%) had a mitral valve repair/replacement during follow-up, including mitral reoperations. Follow-up data (>30 days) were available in 102 patients and the mean follow-up time was 4.7 years. The 30-day overall mortality was 1.9%, higher for neonates (16.7% vs 1%, p=0.1) and after postoperative extracorporeal membrane oxygenation (ECMO) (20% vs 1%, p=0.09). At 10 years the survival estimate is 95.1%, freedom from coronary and mitral reintervention being 95.9% and 91.2%, respectively. Use of postoperative ECMO was a risk factor for long-term mortality (p<0.001). Risk factors for coronary reintervention were age under 30 days (p=0.06) and the need for postoperative ECMO (p=0.02). Age under 30 days (p=0.002) was a risk factor for mitral reintervention. CONCLUSIONS: To our knowledge this is the largest series to date. These preliminary national results show that early outcomes are good and medium-term attrition acceptable. Poor outcomes are correlated with early presentation, also with the need for postoperative circulatory support.