The CLEAR Outcomes trial is a phase 3 trial that randomized 13,970 participants with statin intolerance. The investigators implemented a rigorous approach in selecting study participants by including those with statin intolerance that involved disabling symptoms on two or more statins, including one agent at the lowest prescribed dose. Further, they established a contractual agreement with the patient and their provider that they understood and agreed with the statements: “they were statin intolerant and aware of the benefits of statins in reducing the risk of cardiovascular events, including death, as well as acknowledge that many patients who are unable to receive an administered statin can receive a different statin or dose.”
Statin-associated muscle symptoms (SAMS) account for 73% of the causes of statin intolerance and represent the leading cause of statin-associated down-titration and discontinuation. The consequences of disruption in the use of statins in very high-risk patients with myocardial infarction include 50% higher odds of myocardial infarction, 51% higher odds of hospitalization for a coronary heart disease event in the two years after hospitalization for an acute myocardial infarction, and higher health care expenditures. In high-risk patients, statin intolerance leading to discontinuation has been associated with higher mortality rates.
Due to the lack of a diagnostic test for SAMS, the evaluation of patient-reported symptoms is subjective. An accurate diagnosis requires good clinical understanding of symptoms that are unexpected by routine activities. This was the basis of our SAMS clinical index score developed in 2014. In cardiovascular outcomes trials with statins, an adverse event attributed to statin myopathy requires muscle symptoms and an elevated creatinine kinase or mild rhabdomyolysis. These criteria for statin myopathy represents a more advanced manifestation of SAMS and ignores the symptoms of myalgia and myopathy that may be disabling for that individual. Within the context of clinical trials of statin therapy, statin myopathy is uncommon. However, the burden of SAMS in clinical practice is much higher, affecting 15–20% of treated individuals. Multiple reasons account for these higher numbers, including symptom-based diagnosis that does not require an elevated creatinine kinase level and treatment of all high-risk patients regardless of pre-existing musculoskeletal conditions and comorbidities and concomitant pharmacotherapy that may affect statin metabolism.
The use of bempedoic acid for six months was accompanied by a 21.1% reduction in LDL cholesterol and a 21.6% reduction in C-reactive protein. The primary endpoint was a four-component composite of major adverse cardiovascular events that encompasses death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke events, or coronary revascularization. These events were 13% lower in the active treatment group than in the placebo group (11.7% versus 13.3%. Overall, 62 patients needed to be treated to avoid one major adverse cardiovascular event. Treatment with bempedoic acid was accompanied by more episodes of acute gout (3.1% versus 2.1%) and cholelithiasis (2.2% versus 1.2%). Lesser increases in hemoglobin A1c were observed with bempedoic acid than with placebo, which is a finding that favorably differs from adverse events of statin treatment in clinical trials.
A challenge to the success of this trial was the conduct during the COVID-19 pandemic. Despite these immense hurdles, vital status was obtained in 95.3%. By the end of the trial, there was a diminution in the LDL cholesterol lowering efficacy between the treatment groups due to drop-in cholesterol lowering therapy in the placebo group. The use of non-study LDL cholesterol lowering therapy may have contributed to a lesser than expected reduction in major adverse cardiovascular events.
This precedent-setting trial should serve as the basis for studying other non-statin therapies in patients reporting intolerable symptoms leading to treatment discontinuation. For example, short-term studies of LDL cholesterol lowering efficacy have been conducted with proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs). In these studies, PCSK9 mAbs have been efficacious and well tolerated in patients with statin muscle intolerance. By providing options to our patients, we help reduce their LDL cholesterol and future risk of a cardiovascular event.
To conclude, the investigators and sponsor require accolades for conducting a trial in patients with statin intolerance. As clinicians, we enter a dialogue with our patients to provide solutions for their health and well-being. We show them respect!
Dr. Rosenson reports research funding to his institution from Amgen, Arrowhead, Lilly, Novartis and Regeneron, consulting fees from Amgen, Arrowhead, Lilly, Lipigon, Novartis, CRISPR Therapeutics, Precision BioSciences, Verve, Ultragenyx Pharmaceutical, Inc. and Regeneron, non-promotional speaking fees from Amgen, Kowa and Regeneron, royalties from Wolters Kluwer (UpToDate), and stock holdings in MediMergent, LLC.
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