Alirocumab post-heart transplant lowers LDL cholesterol but not coronary plaque progression

Key takeaways:

• PCSK9 inhibition with alirocumab did not reduce the primary endpoint of coronary plaque progression.
• LDL levels were reduced substantially among heart transplant recipients assigned alirocumab.

NEW ORLEANS — In the CAVIAR trial, adding alirocumab to statin therapy soon after heart transplantation safely lowered LDL cholesterol, but did not impact coronary artery plaque progression.

The CAVIAR trial tested the safety and efficacy of the PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron), in addition to statin therapy, to prevent cardiac allograft vasculopathy, which is “an accelerated form of atherosclerosis” that can occur in patients after heart transplantation and is an important cause of mortality after transplant, William F. Fearon, MD, professor of medicine and chief of interventional cardiology at Stanford University School of Medicine, said during a press conference at the American Heart Association Scientific Sessions.

Dyslipidemia is “a major contributor” to the development of cardiac allograft vasculopathy, Fearon said.

“PCSK9 inhibition with alirocumab early after heart transplantation safety and significantly reduced total cholesterol, LDL cholesterol, lipoprotein(a) and apolipoprotein B levels when added to rosuvastatin therapy,” Fearon said during the presentation.

The study included 114 post-heart transplant patients randomly assigned to alirocumab plus rosuvastatin or rosuvastatin alone.

LDL cholesterol levels decreased significantly from baseline to 1 year in those on alirocumab (from 72.7 mg/dL to 31.5 mg/dL; P < .001), whereas there was no change in those on rosuvastatin alone (from 69 mg/dL to 69.2 mg/dL; P = .92).

However, alirocumab did not reduce the development of cardiac allograft vasculopathy compared with rosuvastatin alone.

The primary endpoint of CAVIAR — change in coronary artery plaque volume from baseline to 1 year based on serial intravascular ultrasound — was not significantly different between the two groups (P = .86). Fearon said “the lack of significant plaque progression in the placebo arm reduced the study’s power to detect a difference with alirocumab.”

Plaque volume increased numerically from baseline to 1 year, from 176.3 mm3 to 184.5 mm3 among those assigned alirocumab (P = .23) and from 173.7 mm3 to 183.1 mm3 among those assigned rosuvastatin alone (P = .15), according to results simultaneously published in Circulation.

There were no adverse events related to alirocumab that occurred during the study, according to the researchers.

CAVIAR included patients within 6 months of heart transplantation. The patients’ mean age was about 53 years, most (80%) were men and approximately half were white.

Before randomization and then at 1 year, patients underwent an invasive coronary angiogram, including IVUS with near-infrared spectroscopy, coronary physiologic assessment with fractional flow reserve, coronary flow reserve and the index of microcirculatory resistance. Lipid and biomarker levels were also determined.

“Longer-term therapy in transplant recipients who have higher baseline LDL cholesterol levels might still be beneficial for reducing cardiac allograft vasculopathy and clinical events,” Fearon said.

Patients in both groups had a baseline LDL level of about 70 mg/dL.

During a discussion of the trial following the press conference, Amanda R. Vest, MBBS, MPH, FAHA, section head of heart failure and transplant cardiology at Cleveland Clinic, also noted the short study length, but said “it doesn’t dissuade us from using these metabolic medications.”

Vest cited a prior small trial of evolocumab (Repatha, Amgen), which she said showed a “similar phenomenon” to the CAVIAR trial of improving lipid profiles but no difference in coronary plaque volume at 1 year.

Also, Vest and colleagues presented a moderated digital poster at this year’s AHA Scientific Sessions that showed LDL level at 1 year after heart transplant “does not really predict outcomes in the way we would expect,” she said. Patients with an LDL level below 70 mg/dL had worse outcomes.

“At the end of the day, the contributions toward the development of cardiac allograft vasculopathy in our heart transplant recipients from the traditional risk factors, such as hyperlipidemia, may be fairly modest. Although we want to optimize metabolic health to help our patients survive and thrive, maybe simple lowering of the LDL, at least in the short term, is not going to have that huge an impact,” Vest said.

More research is needed to define optimal LDL targets after heart transplantation and strategies for cardiac allograft vasculopathy prevention. Vest cited early animal studies suggest that GLP-1 receptor antagonism could potentially help attenuate cardiac allograft vasculopathy.

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