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Adding PCSK9 inhibitor to rosuvastatin after acute MI improves coronary plaque reduction

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08/06/2022
Reuters Health - 08/06/2022 - Adding alirocoumab (AL) to high-intensity statin therapy after urgent percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI) or non-STEMI leads to significantly greater coronary plaque regression in non-infarct-related coronary arteries, new data suggests.

The findings are from the PACMAN-AMI Randomized Clinical Trial, which enrolled 300 patients admitted with acute MI at nine European centers from May 2017 through October 2020. Patients were placed on rosuvastatin 20 mg daily as a high intensity statin, and then randomized to begin biweekly subcutaneous alirocumab 150 mg within 24 hours of the PCI (148 patients) or placebo (152 patients). The mean age was 58 years, with 83% males versus 78.3% in the AL and placebo groups, respectively.

After culprit lesion intervention during the acute PCI/stenting procedure, intravascular ultrasonography, near-infrared spectroscopy, and optical coherence tomography were performed in the two non-infarct coronary arteries, with repeat elective studies performed after 52 weeks. Eligible patients were required to have two non-infarct related arteries (IRA) with non-obstructed disease, diameter stenosis >20% and <50%.

Dr. Lorenz Raber of Bern University Hospital in Switzerland and co-investigators reported in JAMA that patients receiving alirocumab, a potent PCSK9 inhibitor, had significantly greater plaque reduction in the non-infarct arteries at the time of follow-up, beyond the improvement seen with statins alone.

The study showed a primary efficacy endpoint of change in mean percent atheromata volume (PAV): -2.13% versus -0.92%, with between-group difference, -1.21% (95% CI, -1.78% to -0.65%; P <0.001). Mean change in minimal fibrous cap thickness was also improved, with 62.67um improvement with AL versus 33.19um with placebo (95% CI, 11.75-47.55; p=0.001).

As this was a study regarding the impact of PCSK9 inhibition on plaque reduction in AMI, patients who were statin naïve were required to have a low-density lipoprotein cholesterol (LDL) level >125 mg/dl, or if they were on a stable statin for at least 4 weeks, an LDL >70 mg/dl. Patients in both groups were required to continue rosuvastatin 20 mg daily, with no change in type or dose of statin during the course of the study. Statin adherence remained high, with rosuvastatin usage at 52 weeks 90.6%.

Regarding the protocol of static dosing of rosuvastatin 20 mg daily plus AL versus placebo, Dr. Raber told Reuters Health by email, "The control arm received guideline conform high-intensity statin therapy (rosuvastatin 20mg). The effect on additional LDL-C lowering by either 40mg rosuvastatin (instead of 20mg) or adding ezetimibe is limited, justifying not to require up-titration for the 52 week study period. The study aim was to mechanistically study the effects of intensive LDL-C lowering by alirocumab. Importantly: an up-titration guided by LDL-C would have led to immediate unblinding, which would have put the overall study conduction at risk."

There was a significant improvement of LDL beyond statin use with AL. At baseline, mean LDL levels were 152 mg/dl. At the 52 week mark, mean LDL-C Level in the AL group was 23.6 mg/dl, as compared to 74.4 mg/dl in the placebo group. The rosuvastatin group had mean 76.5 mg/dL decrease, as opposed to a 131.2 mg/dL reduction in the AL group, giving a 54 mg/dl difference between treatment groups.

Patients receiving AL also had significantly greater reductions in triglycerides (- 13.2 mg/dL versus +15 mg/dL), lipoprotein(a) (-2.5 mg/dL versus +8.3 mg/dL) and apolipoprotein B, with no difference in C-reactive protein levels.

The authors note, "The extent of PAV regression (2.13%) in the active treatment group of this trial was larger than observed on previous reports and the mean LDL-C levels achieved (23.6 mg/dl) were lower compared with previous intravascular ultrasonography trials of statins."

The groups were equally divided between STEMI (53%) and NSTEMI (47%), with previous use of statins in 11.5% and 13.2 % of the AL and placebo groups, respectively, and baseline rates of high-intensity-statin use of 7.4% and 5.9%. AL patients were more likely to be smokers (52% versus 43%), although more placebo patients had diabetes (8.1% of the AL patients versus 12.5% of the placebo group). Of note, this was a naïve intervention group, with previous MI/PCI in only 1.4% of AL patients and 3% of the placebo group. Roughly 10% to 12% in each group had been taking anti-platelet drugs, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).

The study was too small to allow for determination of statistically significant changes in clinical events based on group assignment. Numbers in the AL and placebo groups, respectively, were 2 versus 1 for all-cause mortality, 2 versus 0 for cardiac death, 2 versus 3 for MI, and perhaps more interesting, 12 vs 28 for ischemic-driven coronary revascularization.

"Indeed," Dr. Raber said, "there was a significant reduction in coronary revascularization events in the non-infarct related vessels in favor of alirocumab. This is consistent with the the ODYSSEY trial."

For two reasons, he added, the difference may be more pronounced in PACMAN AMI. "We enrolled an enriched population with angiographic evidence of plaques in the two non-infarct related arteries," and "We had a protocol-mandated repeat angiography, which is known to inflate revascularization numbers."

In a JAMA podcast (https://bit.ly/3Msr469), Dr. Pamela Morris of the Medical University of South Carolina, who chaired the American College of Cardiology's recent Annual Scientific Sessions, commented, "My takeaway from this study is, number 1, begin early therapy for these very high-risk patients. And also implement aggressive lowering of LDL cholesterol in patients who've had an acute coronary syndrome and are at very high risk for a recurrent cardiovascular event."

SOURCE: https://bit.ly/3xdbHZN and https://bit.ly/396x5Ii JAMA, online April 3, 2022.

By Austin Kutscher MD FACC



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