Key Points
- The CAVIAR trial enrolled recent heart transplant recipients to receive either receive alirocumab 150 mg subcutaneously every 2 weeks or placebo, in addition to rosuvastatin (target 20 mg daily).
- Alirocumab safely reduced LDL-C by more than 50% when added to rosuvastatin in heart transplant recipients; however, nonsignificant reduction in plaque progression was observed at 1 year compared with placebo
- Findings suggest further LDL-C lowering below 70 mg/dL may not improve early CAV outcomes
Cardiac allograft vasculopathy (CAV) remains a leading cause of late morbidity and mortality following heart transplantation (HT). Dyslipidemia is a key contributor, and statins improve both lipid levels and survival after HT. However, submaximal statin dosing and drug interactions often limit optimal lipid lowering. Proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors, such as alirocumab, have shown potent LDL-C reduction and slowed atherosclerosis progression in non-transplant populations, but their safety and efficacy in preventing CAV have not been well established.
The Cardiac Allograft Vasculopathy Inhibition with AliRocumab (CAVIAR) Trial was an investigator-initiated, NIH-funded, prospective, multicenter, double-blind, placebo-controlled, randomized trial (ClinicalTrials.gov: NCT03537742) presented at the American Heart Association Scientific Sessions in New Orleans, LA, with simultaneous publication in Circulation. In this study conducted between 2019 and 2024, 114 recent HT recipients (mean age 53 years) were randomized 1:1 to receive alirocumab 150 mg subcutaneously every 2 weeks or placebo, in addition to rosuvastatin (target 20 mg daily). Participants underwent baseline and 1-year coronary angiography, fractional flow reserve (FFR), coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and intravascular ultrasound with near-infrared spectroscopy (NIRS-IVUS). The primary endpoint was change in coronary plaque volume at 1 year.
LDL-C decreased from 72.7 ± 31.7 mg/dL to 31.5 ± 20.7 mg/dL with alirocumab (p<0.001), while it remained unchanged with placebo (69.0 ± 22.4 to 69.2 ± 28.1 mg/dL, p=0.92). Lipoprotein(a) and apolipoprotein B were also significantly reduced in the alirocumab group. Despite substantial lipid lowering, plaque volume increased similarly in both groups (alirocumab: 176.3 to 184.5 mm³, p=0.23; placebo: 173.7 to 183.1 mm³, p=0.15), with no difference in the change between arms (mean ratio of 1.01, 95% CI 0.89-1.14, p=0.86). Coronary physiological indices (FFR, CFR, IMR) and NIRS-derived lipid core burden did not differ significantly. No safety concerns or excess adverse events were reported.
The CAVIAR trial demonstrated that PCSK9 inhibition with alirocumab is safe and highly effective for lipid lowering after HT but did not reduce plaque progression or improve coronary physiology at 1 year when added to potent statin therapy. The absence of benefit may be related to the already low baseline LDL-C (about 70 mg/dL), minimal plaque progression in the placebo group, or the multifactorial, immune-mediated nature of CAV beyond cholesterol metabolism. These results are aligned with prior data from the EVOLVD trial of evolocumab, reinforcing that further LDL-C lowering may not translate to short-term CAV benefit. Longer-term studies may clarify whether PCSK9 inhibition confers outcome advantages in higher-risk or higher-LDL subgroups. The conclusion is best summarized by trial investigator William Fuller Fearon, MD: “These results support PCSK9 inhibitors for patients who have high LDL cholesterol levels in conjunction with statin therapy, however, we need more studies testing treatment with PCSK9 inhibitors with longer term follow-up with more participants to confirm if PCSK9s can reduce the development of cardiac allograft vasculopathy.”