In the JournalsPerspective

High-intensity statin therapy confers improved outcomes in older patients with ACS

High-intensity therapy with simvastatin and ezetimibe contributed to a greater benefit compared with monotherapy with simvastatin in patients hospitalized for ACS, especially in those aged 75 years or older, according to a secondary analysis of the IMPROVE-IT trial published in JAMA Cardiology.

“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,” Richard G. Bach, MD, FACC, professor of medicine in the cardiovascular division at Washington University School of Medicine in St. Louis, and colleagues wrote.

As Cardiology Today previously reported, the addition of ezetimibe to simvastatin was associated with better clinical outcomes in high-risk patients with ACS compared with simvastatin alone.

Secondary analysis

This secondary analysis included all 18,144 patients (mean age, 64 years; 76% men) that were enrolled in the trial who were hospitalized within 10 days for ACS, had an LDL of at least 50 mg/dL and a maximum of 125 mg/dL or 100 mg/dL depending on whether they were receiving prescription therapy. Patients were assigned 40 mg simvastatin with 10 mg ezetimibe once per day or 40 mg simvastatin once per day with placebo.

The primary efficacy endpoint was a composite of CVD death, nonfatal stroke or major adverse cardiac event, which was defined as unstable angina leading to hospitalization, nonfatal MI or coronary revascularization after 30 days.

Of the patients in the trial, 28.5% were aged 65 to 74 years and 15.4% were aged at least 75 years at randomization.

Patients younger than 65 years assigned simvastatin and ezetimibe had lower rates of the primary endpoint compared with those assigned simvastatin and placebo (0.9%; HR = 0.97; 95% CI, 0.9-1.05). This was also seen in patients aged 65 to 74 years (0.8%; HR = 0.96; 95% CI, 0.87-1.06). The greatest absolute risk reduction was in patients aged at least 75 years (8.7%; HR = 0.8; 95% CI, 0.7-0.9; P for interaction = .02).

High-intensity therapy with simvastatin and ezetimibe contributed to a greater benefit compared with monotherapy with simvastatin in patients hospitalized for ACS, especially in those aged 75 years or older, according to a secondary analysis of the IMPROVE-IT trial published in JAMA Cardiology.
Source: Adobe Stock

There was no increase in the rate of adverse events in younger or older patients when simvastatin and ezetimibe was compared with simvastatin and placebo.

“These results have implications for guideline recommendations regarding therapy to lower lipid levels in elderly individuals,” Bach and colleagues wrote.

Shared decision - making

“While the results reported by Bach et al are part of a post-hoc analysis, they provide valuable information for both the patient and the practitioner,” Antonio M. Gotto Jr., MD, DPhil, dean emeritus at Weill Cornell Medicine, wrote in a related editorial. “They strongly support the benefit of intensive therapy to reduce LDL-C levels in elderly individuals with atherosclerotic cardiovascular disease.” – by Darlene Dobkowski

Disclosures: The IMPROVE-IT trial was supported by Merck and Co. Bach reports he received grants from CSL Behring, Merck & Co. and Myokardia and personal fees from Armaron Bio, Novo Nordisk and Pharmacosmos. Gotto reports he received personal fees from Esperion Therapeutics, consults for Kowa Pharmaceuticals and serves on the data safety monitoring board for Akcea Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures.

High-intensity therapy with simvastatin and ezetimibe contributed to a greater benefit compared with monotherapy with simvastatin in patients hospitalized for ACS, especially in those aged 75 years or older, according to a secondary analysis of the IMPROVE-IT trial published in JAMA Cardiology.

“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,” Richard G. Bach, MD, FACC, professor of medicine in the cardiovascular division at Washington University School of Medicine in St. Louis, and colleagues wrote.

As Cardiology Today previously reported, the addition of ezetimibe to simvastatin was associated with better clinical outcomes in high-risk patients with ACS compared with simvastatin alone.

Secondary analysis

This secondary analysis included all 18,144 patients (mean age, 64 years; 76% men) that were enrolled in the trial who were hospitalized within 10 days for ACS, had an LDL of at least 50 mg/dL and a maximum of 125 mg/dL or 100 mg/dL depending on whether they were receiving prescription therapy. Patients were assigned 40 mg simvastatin with 10 mg ezetimibe once per day or 40 mg simvastatin once per day with placebo.

The primary efficacy endpoint was a composite of CVD death, nonfatal stroke or major adverse cardiac event, which was defined as unstable angina leading to hospitalization, nonfatal MI or coronary revascularization after 30 days.

Of the patients in the trial, 28.5% were aged 65 to 74 years and 15.4% were aged at least 75 years at randomization.

Patients younger than 65 years assigned simvastatin and ezetimibe had lower rates of the primary endpoint compared with those assigned simvastatin and placebo (0.9%; HR = 0.97; 95% CI, 0.9-1.05). This was also seen in patients aged 65 to 74 years (0.8%; HR = 0.96; 95% CI, 0.87-1.06). The greatest absolute risk reduction was in patients aged at least 75 years (8.7%; HR = 0.8; 95% CI, 0.7-0.9; P for interaction = .02).

High-intensity therapy with simvastatin and ezetimibe contributed to a greater benefit compared with monotherapy with simvastatin in patients hospitalized for ACS, especially in those aged 75 years or older, according to a secondary analysis of the IMPROVE-IT trial published in JAMA Cardiology.
Source: Adobe Stock

There was no increase in the rate of adverse events in younger or older patients when simvastatin and ezetimibe was compared with simvastatin and placebo.

“These results have implications for guideline recommendations regarding therapy to lower lipid levels in elderly individuals,” Bach and colleagues wrote.

Shared decision - making

“While the results reported by Bach et al are part of a post-hoc analysis, they provide valuable information for both the patient and the practitioner,” Antonio M. Gotto Jr., MD, DPhil, dean emeritus at Weill Cornell Medicine, wrote in a related editorial. “They strongly support the benefit of intensive therapy to reduce LDL-C levels in elderly individuals with atherosclerotic cardiovascular disease.” – by Darlene Dobkowski

Disclosures: The IMPROVE-IT trial was supported by Merck and Co. Bach reports he received grants from CSL Behring, Merck & Co. and Myokardia and personal fees from Armaron Bio, Novo Nordisk and Pharmacosmos. Gotto reports he received personal fees from Esperion Therapeutics, consults for Kowa Pharmaceuticals and serves on the data safety monitoring board for Akcea Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Udho Thadani

    Udho Thadani

    This secondary post-hoc analysis of the data from the IMPROVE–IT trial shows that in patients above the age of 75 years who were stable following an episode of ACS, lowering the LDL values to well below 70 mg/dL with a combination of simvastatin 40 mg per day plus ezetimibe 10 mg per day was more effective than monotherapy with simvastatin 40 mg per day and posed no safety concerns. These findings are in line with a recent meta-analysis, published in 2018 (Sabatine MS, et al. JAMA Cardiol. 2018;doi:10.1001/jamacardio.2018.2258.), showing that irrespective of the agents used to lower LDL, the lower the LDL values achieved, the lower the major coronary event rates were.

    These findings have important implications for clinical practice, as older patients (75 years and above) can now be reassured regarding the efficacy and safety of lipid-lowering therapy with a combination of simvastatin 40 mg per day and ezetimibe 10 mg per day, provided there are no contraindications to the use of simvastatin. Unfortunately, many older patients are taking many other medications which may have important interaction with simvastatin. These patients may be taking a more potent statin, and thus the guidance regarding combination treatment in these patients remains unclear and cannot be addressed from the results of the IMPROVE-IT trial.

    One must keep in mind that this was a retrospective subgroup analysis of IMROVE-IT trial and showed a clear benefit of combination therapy only in patients above age 75 years and not such a clear-cut benefit in lower age groups. One is thus left wondering regarding the usefulness of combination therapy in patients below the age of 75 years. Other large randomized trials of lipid-lowering therapy have shown a clear-cut benefit of lowering LDL to low values irrespective of the age groups studied.

    One still needs an adequately powered, large randomized controlled outcome trial in patients aged 75 and above to confirm the findings that lower LDLs achieved will definitely translate into better clinical outcomes and no long-term adverse side effects in patients above the age of 75 years.

    • Udho Thadani, MD, MRCP, FRCPC, FACC, FAHA, FCCS
    • Cardiology Today Editorial Board Member
      University of Oklahoma Health Sciences Center and VA Medical Center

    Disclosures: Thadani reports he is a local principal investigator for studies unrelated to statins in which his institution received funding from various pharmaceutical companies, the NIH and the VA and has consulted for Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck and other pharmaceutical companies.