Lipid-lowering trials not representative of patients managed in clinical practice

"Certain underrepresenting populations, including older adults and women, might limit the might lead to limited transportability of study findings and uncertainty on possible efficacy and side effects in these groups," Elisavet Moutzouri from Inselspital Bern University Hospital, University of Bern Switzerland, and colleagues wrote in their study.

Cardiovascular disease (CVD) results in high mortality, leading to 8.9 million deaths worldwide by 2019. Primary and secondary CVD prevention measures, such as treatment with lipid‐lowering medication or lifestyle changes, can reduce CVD mortality. Statins are recommended widely as secondary prevention. However, their harms and benefits are not well understood for primary prevention as the statins' net benefit on absolute risk reduction depends on the individual's baseline risk of CVD, and their use is more controversial.

Limited data indicate that some groups of patients might have been excluded in early statin trials. Also, there is not much evidence on the effectiveness of statin treatment in the multimorbid elderly population or those with polypharmacy. Therefore, it is crucial to investigate which patients were included in recent large lipid‐lowering randomized controlled trials (RCTs). As previously observed in RCTs in other research fields, evidence of the effects of statins on CVD risk might have been drawn from trials with selected patient groups that do not represent real‐world demographics.

Against the above background, the research team performed a systematic review and a meta‐analysis to examine the prevalence of different patient groups in these trials.

For this purpose, the researchers retrieved all trials from the Cholesterol Treatment Trialists Collaboration. They searched for large lipid-lowering therapy RCTs, comprising more than 1000 participants, defined as ezetimibe, statins, and PCSK9 inhibitors.

Groups were predefined as women, older adults (>70 or >75 years), heart failure, non‐Whites, immunosuppression, chronic kidney failure, dementia, cancer, chronic obstructive pulmonary disease, treated thyroid disease, atrial fibrillation, multimorbidity (≥ two chronic diseases), mental illness, and polypharmacy. The team counted the number of RCTs that excluded patients of the e predefined groups and meta‐analyzed the prevalence of included patients to obtain pooled estimates.

The study revealed the following findings:

• 42 RCTs comprising 298 605 patients were included. Eighty‐one percent of trials excluded patients with severe and 76% those with moderate kidney failure.
• Seventy‐one percent of trials excluded groups of women, 64% excluded patients with moderate to severe heart failure, 64% those with immunosuppressant conditions, 48% those with cancer, 29% those with dementia, and 29% of trials excluded older adults.
• The pooled prevalence for patients >70 years of age was 25%, 11% for >75 years of age, and 51% for multimorbidity.

Most lipid‐lowering trials excluded the majority of patients managed in clinical. Over 50% of the trials excluded patients with moderate to severe CKD, an immunosuppressant condition, or moderate to severe HF, which could result in biased outcomes and possibly more side effects in these groups.

More than two‐thirds of all studies excluded groups of women, which leads to limited knowledge of the safety and efficacy of lipid‐lowering therapy in women compared with men. One-third of studies excluded older adults, and the prevalence of patients over 75 years of age in overall studies was only 11%.

"Multimorbid patients represented at least 51% of the included population," the researchers stated. "Nevertheless, no study specifically reported the exclusion or inclusion of multimorbid patients or patients with polypharmacy."

"Given that polypharmacy and multimorbidity are common and contribute to adverse events in drug trials, future research should minimize those inadequately justified exclusion criteria, improve equity in cardiovascular research, and promote diversity in the recruitment strategies to warrant a generalizable treatment effect estimation and safety for clinical practice," the researchers concluded.

Reference:

Aeschbacher-Germann M, Kaiser N, Speierer A, Blum MR, Bauer DC, Del Giovane C, Aujesky D, Gencer B, Rodondi N, Moutzouri E. Lipid-Lowering Trials Are Not Representative of Patients Managed in Clinical Practice: A Systematic Review and Meta-Analysis of Exclusion Criteria. J Am Heart Assoc. 2023 Jan 3;12(1):e026551. doi: 10.1161/JAHA.122.026551. Epub 2022 Dec 24. PMID: 36565207.