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Cardiac Allograft Vasculopathy Inhibition With Alirocumab: The CAVIAR Trial
William F Fearon1,2, Kosei Terada1, Kuniaki Takahashi1
1Division of Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, CA (W.F.F., K.T., K.T., A.S., H.I.L., C.A.L., T.H., K.S., A.Y., J.W.K., Y.H., J.T., K.K.K.).
Insights
Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibition with alirocumab safely lowers LDL cholesterol post-heart transplant. However, it did not reduce coronary plaque progression compared to statin therapy alone.
Area of Science:
- Cardiology
- Immunology
- Pharmacology
Background:
- Cardiac allograft vasculopathy (CAV) is a leading cause of mortality after heart transplantation (HT).
- Dyslipidemia significantly contributes to CAV development.
- The role of PCSK9 inhibition in preventing early CAV post-HT remains unclear.
Purpose of the Study:
- To evaluate the safety and efficacy of alirocumab plus rosuvastatin versus rosuvastatin alone in preventing CAV early after HT.
- To assess the impact of PCSK9 inhibition on coronary plaque volume and microvascular function post-HT.
Main Methods:
- A prospective, multicenter, double-blind randomized trial involving 114 HT recipients.
- Participants received either alirocumab or placebo alongside rosuvastatin.
- Invasive coronary assessments (angiography, FFR, CFR, IMR, IVUS-NIRS) and lipid levels were measured at baseline and 1 year.
Main Results:
- Alirocumab significantly reduced LDL cholesterol levels, while placebo did not.
- Coronary artery plaque volume numerically increased in both groups, with no significant difference between alirocumab and placebo.
- No significant changes were observed in FFR, CFR, or IMR with alirocumab addition.
Conclusions:
- PCSK9 inhibition with alirocumab is safe and effectively lowers LDL cholesterol post-HT.
- Alirocumab did not reduce coronary artery plaque progression at 1 year compared to rosuvastatin alone in patients with low baseline LDL-C.
Background:
Cardiac allograft vasculopathy is an important cause of mortality after heart transplantation (HT). Dyslipidemia is a major contributor to the development of cardiac allograft vasculopathy. The safety and effectiveness of proprotein convertase subtilisin/kexin 9 inhibition to lower cholesterol and to prevent cardiac allograft vasculopathy early after HT are not well established.
Methods:
In this investigator-initiated, prospective, multicenter, double-blind randomized trial, participants were randomized early after HT to receive either alirocumab or placebo in addition to rosuvastatin. Before randomization and at 1 year, all participants underwent invasive coronary assessment, including angiography, fractional flow reserve, coronary flow reserve, the index of microcirculatory resistance, and intravascular ultrasound with near-infrared spectroscopy. Lipid values were assessed at baseline and at prespecified intervals. The primary end point was the change in coronary artery plaque volume from baseline to 1 year after HT based on serial intravascular ultrasound.
Results:
A total of 114 HT recipients were included (57 assigned to alirocumab and 57 assigned to placebo). Baseline characteristics were well matched between the 2 groups. The low-density lipoprotein cholesterol levels decreased significantly from baseline to 1 year in the alirocumab arm (72.7±31.7 to 31.5±20.7 mg/dL; P<0.001) and did not change with placebo (69.0±22.4 to 69.2±28.1 mg/dL; P=0.92). Plaque volume increased numerically in both groups from baseline to 12 months (alirocumab, 176.3±95.2 to 184.5±105.4 mm³; P=0.23; placebo 173.7±96.7 to 183.1±109.8 mm3; P=0.15). The change in plaque volume (mean difference in differences) did not differ between groups (1.01 [0.89-1.14]; P=0.86). Fractional flow reserve, coronary flow reserve, and the index of microcirculatory resistance did not change significantly with the addition of alirocumab. There were no significant adverse events related to alirocumab.
Conclusions:
Proprotein convertase subtilisin/kexin 9 inhibition with alirocumab in addition to statin therapy early after HT safely lowers low-density lipoprotein cholesterol but did not reduce coronary artery plaque progression after 1 year compared with rosuvastatin alone in patients with a low baseline low-density lipoprotein cholesterol.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03537742.
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