Ezetimibe atop statin cuts CV events in elderly ≥75 years
More intensive LDL-lowering by adding ezetimibe to simvastatin in elderly individuals aged ≥75 years significantly reduced recurrent cardiovascular (CV) events without raising safety issues compared with simvastatin alone, a secondary analysis of the IMPROVE-IT* has shown.
In addition, the benefit with ezetimibe addition was 10-fold greater in patients aged ≥75 years vs <75 years, with regard to absolute risk reduction.
“Age was a powerful marker for increased absolute risk of recurrent CVD events that was modifiable with higher intensity therapy to lower lipid levels,” highlighted the researchers.
Due to limited evidence supporting the use of high-intensity therapy for patients >75 years, routine use of such therapy in this elderly population was not recommended in recent lipid management guidelines. [J AmColl Cardiol 2019;73:3168-3209]
“The use of high-intensity therapy to lower lipid levels among elderly individuals remains controversial, at least in part because of persistent uncertainty regarding whether it confers meaningful clinical benefit and is safe in persons of advanced age,” the researchers noted.
“[The study] may have implications for guideline recommendations regarding lowering of lipid levels in the elderly,” they stated.
Greatest CV benefit for ≥75
The multinational, double-blind IMPROVE-IT involved 18,144 patients aged ≥50 years (mean age 64.1 years, 75.7 percent men) recently hospitalized for an ACS** who were randomized to receive ezetimibe 10 mg or placebo, both in addition to simvastatin 40 mg. Of these, 2,798 (15.4 percent) were aged ≥75 years. [JAMA Cardiol 2019;doi:10.1001/jamacardio.2019.2306]
Over 7 years of follow-up, absolute reduction in the primary composite endpoint*** with add-on ezetimibe vs simvastatin monotherapy was greatest among those aged ≥75 years — with the cumulative incidence lowered by 8.7 percent, compared with 0.8 percent and 0.9 percent in the age groups of 65–74 years and <65 years, respectively (hazard ratio [HR], 0.80 vs 0.96 and 0.97; p=0.02 for interaction).
This finding corresponds to a number needed to treat of 11 for patients ≥75 years compared with 125 for those <75 years.
“[These results] strongly support the benefit of intensive therapy to reduce LDL-C levels in elderly individuals with atherosclerotic CV disease. The absolute risk reduction was 10 times greater in the group of patients 75 years and older vs the group of patients younger than 75 years,” wrote Dr Antonio Gotto from Weill Cornell Medicine in New York, New York, US in an accompanying commentary. [JAMA Cardiol 2019;doi:10.1001/jamacardio.2019.2333]
“Furthermore, the end point curves between the drug and placebo groups diverged within the first year for individuals 75 years or older but not until after 2 years in the overall group,” he noted.
Reduction in LDL-C levels was similar across all age groups, with ezetimibe add-on further lowering LDL-C by 15-17 mg/dL vs simvastatin monotherapy in each age group.
In addition, there was no significant increase in the rate of adverse events with the addition of ezetimibe. The incidence of newly diagnosed cancer, cataracts, and neurocognitive events was comparable between the two treatment arms. Not only were the rates of rhabdomyolysis, myopathy, and elevated serum AST and ALT# similar in both treatment arms, they did not increase with age and generally occurred at very low levels.
“Given the favourable tolerability and safety profile observed in IMPROVE-IT, the addition of ezetimibe to statin therapy represents an important alternative to consider for achieving higher-intensity lowering of lipid levels for elderly patients who have difficulty tolerating higher-dose statins,” the researchers pointed out.
LDL-C target: The lower, the better
With increasing age, the risk of recurrent CV events and death also increases; yet, increasing age was associated with less likelihood of receiving intensive lipid-lowering therapy—a phenomenon known as the risk-treatment paradox.
“In light of these observations, continuing to treat elderly patients after an ACS with moderate- rather than higher-intensity therapy to lower lipid levels will represent a missed opportunity to incrementally improve long-term outcomes for this high-risk population,” said the researchers.
They also noted that the elderly is not the only high-risk group who will benefit from ezetimibe; other high-risk groups such as patients with diabetes, prior stroke, or who have undergone CABG## have been shown to benefit as well.
Furthermore, intensive LDL-lowering with other nonstatin therapies such as PCSK9### inhibitors, bile acid sequestrants, and anacetrapib has also been shown to reduce major CV events, Gotto pointed out.
“Collectively, their message is that it is both safe and effective to pursue high-intensity LDL-C reduction therapy,” he stressed.