Cardiovascular Events
Before alirocumab initiation, 22 CV events and interventions were reported in 16 veterans: 12 percutaneous coronary interventions, 5 coronary artery bypass surgeries (CABG), 4 myocardial infarctions, and 1 transient ischemic attack. One month following alirocumab initiation, 1 veteran underwent a CABG after a non-ST-elevation myocardial infarction (NSTEMI).
Safety and Tolerability
Alirocumab was discontinued in 5 veterans due to 4 cases of intolerance (reported memory loss, lethargy, myalgias, and body aches with dyspnea) and 1 case of persistent LDL-C of < 40 mg/dL. Alirocumab was discontinued after 1 year in 2 patients (persistent LDL-C < 40 mg/dL and reported memory loss) and after 6 months in the veteran who reported lethargy. Alirocumab was discontinued after 4 months in the veteran with myalgias and within 2 months in the veteran with body aches and dyspnea. No other AEs were reported.
Discussion
The Efficacy and Safety of Alirocumab vs Ezetimibe in Statin-Intolerant Veterans With a Statin Rechallenge Arm trial is the first clinical trial to examine the efficacy and safety of alirocumab use in statin-intolerant patients. In the trial, 314 patients were randomized to receive alirocumab, ezetimibe, or an atorvastatin rechallenge.6 At 24 weeks, alirocumab reduced mean (SE) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .01).6 Fewer skeletal-muscle-related events also were noted with alirocumab vs atorvastatin (hazard ratio, 0.61; 95% CI, 0.38-0.99; P = .04).6
In this case series, an LDL-C reduction of > 50% was observed in 9 veterans (42.9%) following 4 weeks of treatment; however, LDL-C reduction of > 50% compared with baseline was sustained in only 6 veterans (28.6%) at week 24. Additionally, LDL-C increases from baseline were observed in 3 veterans; the reasoning for the observed increase was unclear, but this may have been due to nonadherence and dietary factors.4 Although a majority of patients saw a significant and clinically meaningful reduction in LDL-C, the group of patients with an increase in the same may have benefitted from targeted intervention to improve medication and dietary adherence. PCSK9 inhibitor resistance also may have contributed to an increase in LDL-C during treatment.7
Of the 24 patients included, 4 reported AEs resulted in therapy discontinuation. Memory impairment, a rare AE of alirocumab, was reported 1 year following alirocumab initiation. Additionally, lethargy was reported after 6 months of treatment. Myalgia also was reported in a veteran 4 months following treatment, and 1 veteran experienced body aches and dyspnea < 2 months following treatment. The most common AEs associated with alirocumab, as noted in previous safety and efficacy clinical trials, included: nasopharyngitis, injection site reaction, influenza, urinary tract infection, and myalgias.8 Many of these more common AEs may be subclinical and underreported. This small case series, however, detected 4 events severe enough to lead to therapy discontinuation. Although this sample is not representative of all statin-intolerant patients who receive treatment with alirocumab, our findings suggest the need for patient education on potential AEs before therapy initiation and clinician monitoring at follow-up visits.
The ODYSSEY OUTCOMES trial established a CV benefit associated with alirocumab; however, patients included had a recent acute coronary syndrome event and were receiving a high-intensity statin.9 This case series is unique in that before alirocumab initiation, 22 CV events/interventions were reported in the sample of 24 patients. After therapy initiation, 1 patient underwent a CABG after an NSTEMI in the month following initiation. This suggests that cardiac complications are possible after PCSK-9 initiation; however, little information can be gained from 1 patient. Nevertheless, early therapy failure should be investigated in the context of real-world use in statin-intolerant patients. This is a complex task, however, given the difficulties of achieving a balanced study design. Statin intolerance is a clear source of selection bias into treatment with alirocumab as patients in this population have already initiated and failed statin therapy. The prevalence of prior CV events and the time-dependent association between prior and future CV events stand as another complex confounder. Although there is a clear and pressing need to understand the risks and benefits of PCSK9 therapy in statin-intolerant patients, future research in this area will need to cautiously address these important sources of bias.
Overall, the results of this case series support LDL-C reduction associated with alirocumab in the absence of statin therapy. Despite favorable results, use of alirocumab may be limited by cost and its subcutaneous route of administration. Bempedoic acid, an oral, once-daily lipid-lowering agent poses an alternative to PCSK9 inhibitors, but further data regarding CV outcomes with this agent is needed.10,11 Robust randomized controlled trials also are needed to evaluate CV outcomes for alirocumab use in statin-intolerant veterans.
Limitations
Only 24 veterans were included in the study, reflecting 20% of the charts reviewed (80% exclusion rate), and in this small sample, only 1 CV event was observed. Both of these serve as threats to external validity. As the study information was extracted from chart review, the results may be limited by coding or historical bias. Medical information from outside institutions may be missing from medical records. Additionally, results may be skewed by possible documentation errors. Furthermore, the period between previous CV events and alirocumab initiation is unclear as event dates were often not recorded if treatment was received at an outside institution.
Due to the short follow-up period, the case series is limited in its assessment of CV outcomes and safety outcomes. Larger studies over an extended period are needed to assess CV outcomes and safety of alirocumab use in statin-intolerant patients. Also, medication adherence was not assessed. Given the impact of medication adherence on LDL-C reduction, it is unclear what role medication adherence played in the LDL-C reduction observed in this study.4
Conclusions
Alirocumab use in 24 statin-intolerant veterans resulted in a significant reduction in LDL-C at 4 and 24 weeks after initiation. In addition, 1 CV event/intervention was observed following alirocumab initiation, although this should be interpreted with caution due to the retrospective nature of this case series, small sample size, and short follow-up period. Large, long-term studies would better evaluate the CV benefit associated with alirocumab therapy in a veteran population.