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Adding ezetimibe to statins in the elderly – should we bother?

13th August 2019, Dr Chee L Khoo

Although persons 75 years or older account for 6% of the population, they account for more than 65%of all deaths due to cardiovascular disease (CVD) (1). We know from numerous trials that intensive treatment to reduce lipid levels reduces CV events in patients after they have an ACS (2). What about elderly patients (>75 years old)? Do they benefit from intensifying treatment after an ACS? Only problem is that the evidence supporting the benefit is limited. We often have to depend on sub-analysis of an older cohort of patients in a bigger randomised controlled trial. This is exactly what a recently post-hoc study did. Their results surprised me. Let me share that with you.

Older patients (i.e. patients older than 75 years old) are often the forgotten group. There are very limited studies enrolling older patients. Most clinical trials exclude patients older than 70 or 75 years old even though as a group, these patients have a higher cardiovascular event rate and you would think that the number to treat would be smaller than the number to treat for younger patients.

Epidemiological studies which show the strong positive association between elevated lipid levels and adverse CV events in younger patients peters out when we reach the elderly and in some studies, the association actually reversed (3-6). Some studies show that the efficacy of treatment to reduce CV events in the older patients becomes attenuated. Others like the Cholesterol Treatment Trialists’ meta-analysis, found that the efficacy of treatment was consistent across the all age groups including the elderly but there were only 2400 patients older than 75 years (2). As you can see, many studies have so few patients in the trial over 75 years old that the studies were just not powered to show that intensifying treatment is superior over standard care.

Bach R et al performed a secondary analysis of the IMPROV-IT trial data (7). The original Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) was a multi-centre prospective randomised double-blind clinical trial designed to evaluate the effect of adding ezemitibe (Vytorin®) to simvastatin in patients with stabilised acute coronary syndrome. They found that adding ezetimibe to simvastatin cause a further reduction in LDL-cholesterol and led to improved cardiovascular outcomes compared with simvastatin alone.

Within each age group, the LDL-C level achieved was 15 to17mg/dL (~0.4mmol/L) lower with simvastatin-ezetimibe than with simvastatin monotherapy.  Age did not affect the lipid lowering of adding of ezetimibe to simvastatin. As expected, as the patients aged, the rate of the primary end point increased across the age groups. In patients on simvastatin only, the rate increased by 30.8% in patients <65 years old, 35% in patients between 65-74 years old and 47.6% for patients >75 years.

For patients >75 years, the rate of CV death, nonfatal MI, unstable angina leading to hospitalisation, coronary revascularisation after day 30, or nonfatal stroke was lower with simvastatin-ezetimibe within the first 12 months, and the curves continued to diverge during the 7 years of follow-up. See Figure 1.

Treatment with simvastatin-ezetimibe resulted in an absolute reduction of the primary composite end point. For patients < 65 years the absolute reduction for patients 65 – 74 years was 0.8% and for patients > 75 years, the absolute reduction was 8.7%. The number to treat to prevent 1 primary event with simvastatin-ezetimibe is 125 for patients under 75 years and 11 for patients >75 years.

Side effects of rhabdomyolysis, myopathy or abnormal LFTs did not increase with age nor increase by adding ezetimibe to simvastatin. The rates of newly diagnosed cancer, cataracts and neuro-cognitive events increased with age but were not more frequent in patients on simvastatin-ezetimibe compared with simvastatin monotherapy. The rates of haemorrhagic stroke were low and did not differ between the treatment groups.

Patients who already have an ACS are highly likely to have more cardiovascular events. As the patient ages, that rate increases further. Thus, many of our older patients are at significant risk of a cardiovascular event. High dose statins may not be enough and adding ezetimibe to a statin may reduce those statistics.

References:

  1. Mozaffarian D, Benjamin EJ, Go AS, et al; Writing Group Members; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38-e360.
  2. Fulcher J, O’Connell R, VoyseyM, et al; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):1397-1405. doi:10.1016/ S0140-6736(14)61368-4
  3. Ulvenstam G, Bergstrand R, Johansson S, et al. Prognostic importance of cholesterol levels after myocardial infarction. Prev Med. 1984;13(4):355-366. doi:10.1016/0091-7435(84)90027-6
  4. Kronmal RA, Cain KC, Ye Z, Omenn GS. Total serum cholesterol levels and mortality risk as a function of age: a report based on the Framingham data. Arch Intern Med. 1993;153(9):1065-1073. doi:10.1001/archinte.1993.00410090025004
  5. Krumholz HM, Seeman TE, Merrill SS, et al. Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA. 1994;272(17):1335-1340. doi:10.1001/jama.1994. 03520170045034
  6. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 2001;358(9279):351-355. doi:10.1016/ S0140-6736(01)05553-2

Bach R, Cannon CP, Giugliano RP, et al. Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiology July 17, 2019

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