masthead


Frequently Asked Questions

Is the combination of simvastatin and ezetimibe effective for patients with aortic stenosis?

Background
Aortic stenosis (AS) is a narrowing of the aortic valve, which controls blood flow from the left ventricle to the aorta. In AS blood flow is impeded due to the constricted valve; there is increased pressure in the left ventricle, leading to left ventricular hypertrophy. Aortic stenosis affects about 2% of the population >65 years of age and is most commonly caused by calcification of the aortic heart valve.1 Risk factors for AS include age (2-fold increased risk with each decade increase in age), male gender (2-fold excess risk), present smoker, history of hypertension, high lipoprotein (a) levels, and high low-density lipoprotein (LDL) cholesterol levels. AS is generally asymptomatic in early disease, but symptoms of severe AS include shortness of breath on exertion, angina, dizziness, or syncope, as well as the characteristic systolic murmur.2,3 After the onset of symptoms, survival prognosis is approximately 2 to 3 years without surgical intervention. Aortic valve replacement (AVR) is the treatment of choice for patients with symptomatic AS because presently, medical management has not proven to prevent or delay the disease process.2

Progression of AS shares a number of similarities with atherosclerosis, including lipid accumulation and inflammation.1 Several retrospective reports have shown the beneficial effects of angiotensin converting enzyme inhibitors in AS, but data are still conflicting about the effect of statin therapy.2,3 In 2005, a small prospective, randomized, placebo-controlled trial in patients with calcific aortic valve disease failed to demonstrate a benefit of atorvastatin in reducing disease progression over a median of 2 years. This trial had its limitations and to truly determine the role of statin therapy in patients with AS there was a need for larger, long-term, randomized, controlled trials.4

Literature Summary
In recent years ezetimibe has been studied extensively alone and in combination with other lipid lowering therapies. Ezetimibe alone has been proven to reduce total cholesterol (TC), LDL, Apo B, and triglycerides (TG), and increase high-density lipoprotein (HDL) in patients with primary hyperlipidemia.5 When co-administered with fenofibrate, it significantly lowered TC, LDL, Apo B, and non-HDL compared to fenofibrate administered alone. Ezetimibe has also shown efficacy in combination with a statin in patients with homozygous familial hypercholesterolemia (HoFH) for the reduction of TC and LDL. These parameters (TC, LDL, Apo B, and TG) are classified as surrogate markers and cannot be substituted for clinical endpoints.

The first clinical trial to study the effect of ezetimibe and a statin using an endpoint besides lipid values was the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial.6 [See ENHANCE FAQ] The ENHANCE primary outcome was focused on the result of changes in carotid-artery intima-media thickness in patients with HoFH. It was concluded that therapy with combination ezetimibe and the highest recommended dose of simvastatin did not significantly reduce intima-media thickness versus simvastatin treatment alone, despite statistically significant decreases in lipid endpoints (LDL and C-reactive protein).

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was a multicenter, double-blind, randomized, and placebo-controlled study conducted in 173 study sites in 7 European countries.7 The SEAS investigators chose to study the non-surrogate endpoint of reduction of aortic-valve and ischemic events in patients with AS. Patients were included if they were between the ages of 45 and 85 years and met the diagnosis of asymptomatic mild-to-moderate AS. Patients were excluded if they had an indication for statin treatment (LDL >232 mg/dL), other significant valvular heart disease, or diabetes mellitus, among others. Patients underwent randomization after a 4-week placebo/diet run-in period to either ezetimibe/simvastatin 10/40 mg daily (n=944) or placebo (n=929). The primary outcome of the study was a composite of major cardiovascular events including death from cardiovascular causes, aortic-valve replacement, congestive heart failure as a result of progression of aortic-valve stenosis, nonfatal myocardial infarction, hospitalization for unstable angina, coronary-artery bypass grafting (CABG), percutaneous coronary intervention (PCI), and nonhemorrhagic stroke. Secondary outcomes were a number of aortic-valve events (including AVR), ischemic events, progression of AS, and the safety of the study medications.

Baseline characteristics included a mean patient age of 68 ± 10 years, 39% female, mean blood pressure of 145 ± 20/82 ± 10 mm Hg (51% hypertensive); 55% were current or previous smokers, most were overweight (mean body mass index 26.9 kg/m2), and mean TC was 222 ± 39 mg/dL.8 Further breakdown showed that baseline LDL was 139 ± 36 mg/dL, HDL was 58 ± 17 mg/dL, and TG were 126 ± 61 mg/dL. The median duration of follow-up was 52.2 months and there was no statistically significant difference in the incidence of the primary composite outcome in the ezetimibe/simvastatin group verses the placebo group (35.3% vs. 38.2%, hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.83 to 1.12, p=0.59).7 There was no difference between the groups in the incidence of aortic-valve events (32.6% vs. 35.1%, HR 0.97, 95% CI 0.83 to 1.14, p=0.73). There were significantly fewer patients with the secondary composite outcome of ischemic cardiovascular events in the ezetimibe/simvastatin group compared to the placebo group (15.7% vs. 20.1%, HR 0.78, 95% CI 0.63 to 0.97, p=0.02). This was determined to be due to the effect of a significant reduction in the need for CABG, with 69 patients in the ezetimibe/simvastatin group, as compared with 100 patients in the placebo group, undergoing the procedure (7.3% vs. 10.8%, HR 0.68, 95% CI 0.50 to 0.93, p=0.02). Another finding was a mean percent reduction in LDL cholesterol of 53.8% in the ezetimibe/simvastatin group and 3.8% in the placebo group over the duration of the study period. In the subsidiary safety analyses, cancer was observed more frequently among patients in the ezetimibe/simvastatin group than among those assigned to placebo (105 [11.1 %] vs. 70 [7.5%], p=0.01). In addition, there were also slightly more cancer deaths (39 [4.1%] vs. 23 [2.5%], HR 1.67, 95% CI 1.00 to 2.79, unadjusted p=0.05). Cancers that had been diagnosed before randomization recurred in 8 of these patients (3 in the ezetimibe/simvastatin group and 5 in the placebo group), and 1 patient had a cancer that developed in a previous trial before the addition of ezetimibe (Simvastatin in Aortic Stenosis [SAS] study). These apparent differences were not related to any particular type of cancer, did not become significantly larger with more prolonged treatment, and the risk of incident cancer was not associated with the degree of LDL-cholesterol lowering.

The authors concluded that long-term, intensive LDL cholesterol lowering with ezetimibe/simvastatin 10/40 mg daily in patients with mild-to-moderate, asymptomatic AS had no overall effect on the course of aortic-valve stenosis but did reduce the risk of ischemic cardiovascular events, especially the need for CABG.7 In addition, the higher incidence of cancer in the ezetimibe/simvastatin group was unexpected and requires further exploration on the basis that long-term statin therapy has not been associated with an increased risk of cancer, and the observed differences in cancer in the SEAS study were based on small numbers and could have occurred as a result of chance [See ezetimibe and cancer FAQ].

Conclusion
The SEAS trial is 1 of a few studies that have investigated a clinically relevant outcome of ezetimibe use as opposed to strictly measuring the surrogate endpoint of lowering LDL cholesterol. The findings of the SEAS trial are consistent with previous studies in AS patients who have used lipid-lowering therapy in an attempt to slow the progression of the disease in finding that this treatment has no significant overall effect on the course of aortic-valve stenosis. With respect to the safety analyses that generated a hypothesis about ezetimibe increasing cancer risk, it is important to note that the SEAS trial had several limitations, 1 being the small size of the study. It is possible that the increased risk of cancer events seen in the ezetimibe/simvastatin treatment group could have occurred as a result of chance. Ongoing trials will determine whether ezetimibe is safe and effective in considerably more patients. Ezetimibe in combination with simvastatin currently has an unknown place in therapy for the treatment of AS, but it seems prudent to encourage patients whose LDL cholesterol levels remain elevated despite treatment with an optimal dose of a statin to intensify their efforts at dietary control and exercise first before adding other treatment therapies such as niacin, fibrates, or bile acid sequestrants. The addition of ezetimibe should be reserved for patients who are not adequately controlled with diet and exercise, a statin alone, or those who cannot tolerate any secondary agents.

References

  1. Stewart BF, Siscovick D, Lind BK. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol. 1997;29(3):630-634.
  2. Bonow RO, Carabelloi BA, Chatterjee K, et al. ACC/AHA 2006 practice guidelines for the management of patients with valvular heart disease: executive summary. ACC/AHA Practice Guidelines. J Am Coll Cardiol. 2006;48(3):598–675.
  3. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease. European Society of Cardiology Guidelines. Eur Heart J. 2007;28(2):230-268.
  4. Cowell SJ, Newby DE, Prescott RJ, et al for the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005;352(23):2389-2397.
  5. Zetia [package insert]. Kenilworth (NJ): Schering Corporation; 2008.
  6. Kastelein JP, Akdim F, Stroes ES, et al for the ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358(14):1431-1443.
  7. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343-1356.
  8. Rossebø AB, Pedersen TR, Allen C, et al. Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Am J Cardiol. 2007;99(7):970-973.

By: Natalie Fedeczko, PharmD