Statin Benefits Confirmed in Elderly, Along With Harmful Effects of High Cholesterol

Two new studies reinforce the need to treat even those 70 years and older with lipid-lowering drugs to reduce ASCVD risk.

Statin Benefits Confirmed in Elderly, Along With Harmful Effects of High Cholesterol

Two new studies published this week provide yet more data that older adults with high levels of LDL cholesterol, typically excluded from clinical trials, are at a significantly increased risk of cardiovascular events and that they stand to gain a significant benefit from lipid-lowering therapy.

Published November 9, 2020, in the Lancetand slated for presentation at the upcoming virtual American Heart Association scientific sessions, ​​the first study, a meta-analysis that includes nearly a quarter million patients, showed that treating adults aged 75 and older with lipid-lowering therapy, including statins, ezetimibe, and PCSK9 inhibitors, reduced the risk of major atherosclerotic cardiovascular disease (ASCVD) as much as it does in younger patients. The use of lipid-lowering therapy cut the risk of major vascular events by 26% for each 1-mmol/L (roughly 39 mg/dL) reduction in LDL cholesterol, and this magnitude of benefit was not statistically different in the older versus younger patients (P = 0.37 for interaction).

“LDL cholesterol-lowering therapy does work extremely well in older individuals, in this case 75 years or older,” senior investigator Marc Sabatine, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “That’s good news. The benefit was consistent whether it was statin or nonstatin therapy, and the benefit held true for all the components [of the primary endpoint].”

Overall, the risk of cardiovascular death was reduced 15%, myocardial infarction by 20%, stroke by 27%, and coronary revascularization by 20% for each 1-mmol/L reduction in LDL cholesterol among patients 75 years or older.

“All of this is very reassuring from the efficacy point of view that these patients should be treated,” continued Sabatine. “Of note, as has been seen before, the event rates in the elderly patients are higher than in younger individuals. So, if you have a relative risk reduction that is at least as good [as younger patients], and we’re multiplying that by a higher baseline risk, then we’d expect elderly patients to enjoy robust absolute risk reductions.”

There is no reason to think that just because someone is 76 years old versus 74 years old they don’t deserve a high-intensity statin. Marc Sabatine

Borge Nordestgaard, MD, DMSc (Copenhagen University Hospital, Denmark), published the second study along with Martin Bødtker Mortensen, MD, PhD (Aarhus University Hospital, Denmark), showing that higher levels of LDL cholesterol even in the elderly were associated with a higher risk of MI and ASCVD. He told TCTMD that once patients get to a certain age, doctors tend to take their hands the wheel, so to speak.

“Certainly in Europe and I think in the United States, most doctors, once a patient reaches 70 years of age, they have this idea that if they’ve survived to this age without lipid-lowering therapy, then they’re probably super healthy and they can keep going without it,” said Nordestgaard. “I hear it all the time. It’s an impression that’s gotten into their minds, I think.”

At the population level, lipid-lowering in these older patients represents a massive opportunity to prevent cardiovascular events. “We have this inexpensive drug, it costs next to nothing, and it works fantastic,” said Nordestgaard. “It reduces heart attacks, strokes, and can help you live longer—that’s the whole theme of the statin trials—and it’s not being used in the people who could have the most benefit from it.”   

Arbitrary Cutoff in ACC/AHA Cholesterol Guidelines

Despite higher event rates relative to younger patients, elderly patients are far less likely to be included in clinical trials, creating an “evidence gap” when it comes to lipid-lowering therapy, say experts.

In 2018, the American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines also made a distinction for treatment based on age, weakening the recommendation for statin therapy and other agents using 75 years as the cutoff. For example, a high-intensity statin is a class I recommendation for ASCVD patients 75 years or younger, with the addition of ezetimibe a class IIb recommendation if LDL cholesterol remains 70 mg/dL, but the guidelines only award a class IIa recommendation to statin therapy, which can be either a moderate- or high-intensity statin, in ASCVD patients older than 75. There is no guidance on the use of ezetimibe or other agents in older patients.

“We found this puzzling,” said Sabatine. “There is no reason to think that just because someone is 76 years old versus 74 years old they don’t deserve a high-intensity statin, given there is no difference in side effects and we’ve seen the benefits of high- versus low-intensity statin therapy. That led us to examine the issue. Maybe now that more trials have been done, the data set is now robust enough we could eliminate this ageist distinction.”

The meta-analysis included data from 29 primary and secondary prevention trials, with 24 of those studies included as part of the Cholesterol Treatment Trialists’ Collaboration (CTTC) meta-analysis published in 2019. The five additional trials included the large cardiovascular outcomes studies testing the PCSK9 inhibitors in FOURIER and ODYSSEY OUTCOMES, IMPROVE-IT with ezetimibe, EWTOPIA, which specifically randomized patients 75 years or older to statin therapy, and the Treat Stroke to Target study. Of the 244,090 patients, 21,492 were at least 75 years old.       

In addition to efficacy, the researchers observed no signal of harm with treatment in the older patients, with no evidence of cancer, hemorrhagic stroke, new-onset diabetes, or neurocognitive adverse events documented in the meta-analysis. Sabatine said data have shown that high-intensity statins are tolerated just as well as less intensive therapy, and there really isn’t any reason for a patient to be on a low-intensity statin.

“We hope that this study will highlight the fact that these patients can enjoy a substantial benefit from starting therapy,” said Sabatine. He noted that once a person reaches 65, it’s expected they’d have another 20 years of life. For the 75-year-old patient, the horizon of life isn’t a couple of years, he said, “it’s going to be a decade-plus.”

In the previous CTTC meta-analysis, the benefit of statin therapy in older adults was attenuated in those without vascular disease. Sabatine acknowledged that the majority of clinical events—more than 75%—occurred in patients with preexisting cardiovascular disease, but said they observed no evidence of a treatment difference in those with and without established ASCVD. One possible reason for the disparate findings might be that their group excluded four trials that exclusively enrolled patients with heart failure or dialysis while the CTTC meta-analysis included them.    

In an editorial, Frederick Raal, MBBCh, PhD, and Farzahna Mohamed, MBBCh (both University of the Witwatersrand, Johannesburg, South Africa), point out that older patients have a high burden of risk factors for ASCVD and that pill burden and polypharmacy become issues in this population. For this reason, physician judgement and shared decision-making, taking into account functional status, independence, and quality of life, are critical when weighing the risks and benefits of statins in this older group. 

Elevated LDL and Risk of MI/ASCVD

In the second study, Nordestgaard and Mortensen analyzed LDL-cholesterol levels in 91,131 individuals without established cardiovascular disease enrolled in the Copenhagen General Population Study and the associated risk of MI and ASCVD. Of these, 12% of subjects were 70 to 79 years old and 3% were older than 80 years.

In the entire cohort of individuals aged 20 to 100 years old, each 1-mmol/L increase in LDL cholesterol was associated with a 34% increased risk of MI and a 16% increased risk of ASCVD, and these risks were observed across all age groups. For the older patients, specifically those aged 70-79 and 80-100 years, each 1-mmol/L increase in LDL cholesterol was associated with significant a 25% and 28% increased risk of MI, respectively, and a significant 12% and 16% increased risk of ASCVD.

We have this inexpensive drug, it costs next to nothing, and it works fantastic. Borge Nordestgaard

When investigators compared clinical outcomes among those aged 80-100 years old with LDL cholesterol levels ≥ 5.0 mmol/L versus those with LDL levels < 3.0 mmol/L, these older patients had a nearly threefold higher risk of MI (HR 2.99; 95% CI 1.71-5.23) and twofold higher risk of ASCVD (HR 1.90; 95% CI 1.27-2.83).

Overall, MI and ASCVD event rates per 1,000 person-years for every 1-mmol/L increase in LDL cholesterol were highest for those aged 70 to 100 years old. For example, there were 2.5 MIs per 1,000 person-years for each 1-mmol/L increase in LDL cholesterol for those aged 80 to 100 years versus 0.6, 0.5, and 0.7 events per 1,000 person-years for those aged 20-49, 50-59, and 60-69 years old, respectively. Correspondingly, the number needed to treat (NNT) over 5 years to prevent one MI was 80 and 145 for those aged 80-100 and 70-79 years, respectively, if prescribed a moderate-intensity statin. The NNT to prevent one MI in those aged 20-49, 50-59, and 60-69 years was 1,107, 439, and 261, respectively.

STAREE and PREVENTABLE

To TCTMD, Michael Nanna, MD (Duke University Medical Center, Durham, NC), who wasn’t involved in the meta-analysis but who investigated statin dosing in older adults in the Patient and Provider Assessment of Lipid Management (PALM) registry, said the benefits of lipid-lowering therapy for secondary prevention are well established now, and the new report reemphasizes its role for lowering risk of ASCVD. However, the role of lipid-lowering therapy in older adults without preexisting ASCVD is “still in question,” he said.  

A clinical trial testing whether lowering LDL-cholesterol levels with statin therapy in older primary prevention patients is coming, although the results are not expected for a number of years. In Australia, the STAREE trial will randomize approximately 18,000 patients older than 70 years to atorvastatin 40 mg or placebo for the prevention of major vascular events. The National Institutes of Health (NIH)-sponsored PREVENTABLE trial is also testing whether atorvastatin 40 mg in 20,000 adults without preexisting disease can reduce the risk of new dementia or disability. Cardiovascular mortality is a secondary endpoint.

Those trials, said Nanna, will provide clarity on the benefits and risks of primary prevention statin therapy in the older population. Nordestgaard, for his part, is certain that statins will help these older patients without ASCVD. “When I ask my doctor friends if they give statins to their parents they say, ‘Of course,’” said Nordestgaard. “The evidence is so overwhelming. When you ask me if I’d treat a patient [with statins], I’d say that if it were my own mother, father, or aunt, the answer is clearly yes.”

Sabatine made a similar statement, and while he said there are limited data supporting primary-prevention lipid-lowering therapy in elderly patients, he doesn’t think physicians should treat elderly patients any differently than they would a younger patient. The STAREE trial will add more yet more evidence, Sabatine added. “But in the meantime, I would say that all the data would point to the fact that the therapies are effective and safe and while it will be good to have large dedicated trials, I would not wait for them and I would treat my elderly patients just as aggressively as I would my younger patients.”

Michael O’Riordan is the Associate Managing Editor for TCTMD and a Senior Journalist. He completed his undergraduate degrees at Queen’s…

Read Full Bio
Disclosures
  • Nordestgaard and Nanna report no relevant conflicts of interest.
  • Gencer reports grant funding to his institution from the Geneva University Hospital, Eugenio Litta and Athemis Foundations.
  • Sabatine reports grant support to his institution from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Roche Diagnostics, and Takeda; he reports personal fees from Alnylam, Bristol Myers Squibb, CVS Caremark, Dynamix, Esperion, Ionis, and MyoKardia.
  • Raal reports research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.

Comments

1

Marco Tullio Suadoni

10 months ago
The post rely heavily on a study recently published in The Lancet, where Baris Gencer and colleagues[1]⁠ report their meta-analysis on efficacy and safety of lowering LDL cholesterol in patients aged 75 years or older. They pooled data from 29 randomised lipid-lowering statins, ezetimibe, and PCSK9 inhibitors trials. They conclude that lowering lipids reduces cardiovascular events and death in patients aged 75 years or older as effectively as in younger adults. However, their meta-analysis has methodological weaknesses, and is ineffective in supporting meaningful clinical decision-making. Pooled studies population, intervention, comparison, and outcomes[2]⁠ were widely heterogeneous. Employing random-effects meta-analysis to take into account obvious heterogeneity is inappropriate. Subgroup meta-analyses and examining relationships between study characteristics effect sizes would be indicated.[3]⁠ Composite endpoints further mix the evidence. They are meaningful when individual components are of similar importance to patients, occur with similar frequency, and share similar relative risk reduction.[4]⁠ It was not the case in the meta-analysis. Risk-of-bias assessment was not discussed: the conclusions in the risk-of-bias table are questionable. For example, the EWTOPIA[5]⁠ ezetimibe trial had 40% attrition rate. It stopped early due to non-cardiovascular death competing risk. All-cause mortality in the ezetimibe arm had an increasing trend. Committee members who stopped the trial were not independent as the trial report stated, but financially tied with ezetimibe manufacturer and distributors. These factors would warrant high-risk. In conclusion, effect estimates and precision from the meta-analysis are inapplicable in joint informed decision making between the discerning patient and the conscientious clinician considering a specific therapy for specific goals. Funding declaration This comment had no funding. However, I obtained access to the literature cited through the library online service of Edinburgh Napier University, Edinburgh, Scotland, where I have just completed a MSc funded by Burdett Trust for Nursing, grant no. 448. Conflict of interest declaration No conflict to declare. References 1 Gencer B, Marston NA, Im KA, et al. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials. Lancet 2020; 396: 1637–43. 2 Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to evidence-based decisions. Am Coll Physicians J Club 1995; 123: A12-3. 3 Higgins J, Thomas J, Chandler J, et al., editors. 10.10.1 What is heterogeneity? In: Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019. 10.10 Heterogeneity. 4 McCoy CE. Understanding the use of composite endpoints in clinical trials. West J Emerg Med 2018; 19: 631–4. 5 Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial. Circulation 2019; 140: 992–1003.