Efficacy and Safety of Lowering LDL Cholesterol in Older Patients

The population of adults aged ≥75 years constitutes approximately 7% of the US population but accounts for 60% deaths due to coronary heart disease. Prevalence and consequences of stroke and peripheral arterial disease in adults aged ≥75 years are similarly disproportionate. Therefore, the meta-analysis by Gencer et al on the benefits of LDL cholesterol reduction in patients aged ≥75 years who qualified for randomized trials, stands out by demonstrating a strong signal of clinical benefit, including reduced cardiovascular death (RR, 0.85 [0.74–0.98]), myocardial infarction (RR, 0.80 [0.71–0.90]), stroke (RR, 0.73 [0.61–0.87]), and coronary revascularization (RR, 0.80 [0.66–0.96]). Notably, benefits were significant in patients being treated for primary as well as secondary prevention, and benefits were similar in trials entailing statins as well as non-statins (ezetimibe and PCSK9 inhibitors). This analysis adds to a growing body of analyses that substantiate utility of statin and non-statin LDL-lowering therapies for older populations for primary and secondary prevention, with absolute risk reduction that is highly beneficial. Nonetheless, this study is fundamentally limited in respects to its generalizability since most statin trials have tended to exclude older adult candidates with cognitive decline, frailty, multimorbidity, polypharmacy, and other geriatric conditions, which are common and which may confound LDL-lowering benefits. Overall, the analysis by Gencer et al corroborates and reinforces the premise that there are some older adults who benefit from LDL-lowering therapies, both for primary and secondary prevention, but it cannot be assumed that this is true for all older adults. The older adult population is highly heterogeneous, and, as the worldwide population continues to grow older, it is increasingly important for trials studying “older patients” to include the full spectrum of older candidates (ie, robust to frail, independent to dependent, including those in long-term care, and inclusive of geriatric clinical complexity). Therefore, despite this excellent analysis by Gencer et al, the recently initiated prospective randomized controlled trial, Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE) of 20,000 adults aged ≥75 years remains distinctively important as it aims to more fully assess utility of statins over a broader range of older patient phenotypes.

Should We Use Lipid-Lowering Agents in the Elderly?

This dilemma has become more common as our elderly population increases. Should we be using a statin and other lipid-lowering therapies in the elderly? Is it worth it? This demographic is not well-represented in clinical trials, and the only way to answer these questions is to combine many trials together so that there will be enough elderly patients to see an effect or not.

The article by Professor Sabatine’s group evaluated 29 trials with 244,090 patients.¹ From this pool, there were 21,492 patients who were at least 75 years of age. Half of them were from statin trials, and the remainder were from ezetimibe or PCSK9 inhibitor trials. The follow-up ranged from 2.2 years to 6.0 years.

The authors found that, in the elderly population, for every 1 mmol/L reduction in LDL cholesterol, there was a 26% reduction in major vascular events (RR, 0.74; 95% CI, 0.61–0.89; P = .019). These rates are very similar to those of the patients who were younger than 75 years of age.

The elderly also had significant reductions in each of the individual endpoints:

• Cardiovascular death (RR, 0.85 [0.74–0.98])
• Myocardial infarction (RR, 0.80 [0.71–0.90])
• Stroke (RR, 0.73 [0.61–0.87])
• Coronary revascularization (RR, 0.80 [0.66–0.96])

There was no difference whether they were on statins, ezetimibe, or a PCSK9-inhibitor. Also, there was no increase in side effects like cancer, hemorrhagic stroke, new-onset diabetes, or neurocognitive adverse events. Therefore, with this 21,000+ database, it would seem that age ≥75 years should not affect our decision as to whether to use lipid-lowering therapies or not.

But what about our primary prevention patients? How long would the benefit take to kick in?

Professor Yourman’s group helped answer this question by evaluating 8 trials with 65,383 patients between the ages of 55 to 69 years who did not have cardiovascular disease (ie, primary prevention).² The age is not as old as we would like, but it is hard to find primary prevention trials with elderly patients in them. The follow-up ranged from 2 to 6 years, which meant the oldest patient at the end of the study was aged 75 years.

The authors evaluated how long it would take to prevent one MACE if 100 people were treated. Their calculation from study data showed that it would take 2.5 years. Therefore, their conclusion was that, if a patient has a life expectancy of more than 2.5 years, then it is worthwhile.

These two studies together basically confirm that there is value in treating our aging population with lipid-lowering agents. Those benefits can be realized over a reasonably short amount of time—so, no more debate and let’s just go ahead and protect our elderly patients.

References

1. Gencer B, Marston NA, Im K, et al. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2020 Nov 21;396(10263):1637-1643. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32332-1/fulltext
2. Yourman LC, Cenzer IS, Boscardin WJ, et al. Evaluation of Time to Benefit of Statins for the Primary Prevention of Cardiovascular Events in Adults Aged 50 to 75 Years: A Meta-Analysis. JAMA Intern Med. 2020 Nov 16. doi:10.1001/jamainternmed.2020.6084. Online ahead of print. https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2773065

Although older adults suffer from higher rates of vascular disease (event rate of 5.7% per year for those over 75 years of age in this meta-analysis), guideline recommendations are equivocal for higher-intensity statin therapy and addition of non-statin alternatives due to lack of evidence in this age group for primary prevention.¹ Gencer et al combine the results of statin trial meta-analyses with results of non-statin trials to show a statistically significant cardiovascular risk reduction among primary and secondary prevention populations over 75 years of age with lipid-lowering therapy—including non-statin lipid-lowering. Questions remain regarding the use of statin therapy in older adults with no prior history of cardiovascular disease, as only two of the studies in the meta-analysis included statin therapy for primary prevention.

Still, this provides compelling evidence to support aggressive lipid-lowering treatment in older individuals and finds no safety signals such as cancer, stroke, diabetes, and neurocognitive adverse events with lower reductions in LDL-C. This is reassurance, particularly for older adults who may care more about cognition than mortality. Ongoing clinical trials, STAREE (NCT02099123) and PREVENTABLE (NCT04262206), both focused specifically on primary prevention in adults over 75 years of age and will provide definitive answers to this question of who to treat for the outcomes that matter most to patients.

Reference

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3168-3209. https://www.sciencedirect.com/science/article/pii/S0735109718390338