Combined Use of Statin and Ezetimibe After Acute Coronary Syndromes

Mohammed Naveed Aijaz, Mercer University College of Pharmacy Class of 2016

Acute coronary syndrome (ACS) is an umbrella term used to describe many conditions where blood flow to the heart has been reduced. Examples of ACS include heart attacks and unstable angina.1 Acute coronary syndromes are considered to be emergencies by the American Heart Association (AHA).2 The primary cause of ACS is reported to be plaque buildup, followed by its eventual rupture and clotting.3 American College of Cardiology Foundation (ACCF) and AHA guidelines suggest that patients who have suffered from an ST-segment elevation (STE) myocardial infarction (MI) or non–ST-segment elevation (NSTE) ACS should receive prophylactic therapy indefinitely with aspirin, a beta-blocker, angiotensin-converting enzyme (ACE) inhibitor, and statin, as these have been suggested to be beneficial in reducing chances of death, stroke, and a secondary heart attack.4,5

It has been suggested that statins reduce low-density lipoproteins (LDL) and risk of cardiovascular events such as heart attacks.6 However, recent reports have brought to light some possible adverse effects associated with use of statins, such as the FDA issued warning of high-doses of simvastatin (80mg) in connection with muscle injury7 and the general use of many different statins in connection with type two diabetes.8 This has led to a search for additional lipid lowering agents to supplement the use of statins. One such agent being studied is ezetimibe, a drug that reduces absorption of cholesterol from the intestinal tract by inhibiting the Niemann–Pick C1–like 1 (NPC1L1) transport protein.9

Title: Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes10
Design Randomized, double blind; N = 18,144
Objective To determine if addition of ezetimibe will further reduce rate of cardiovascular events when added to statin
Study Groups Two groups: patients receiving (1) statin plus ezetimibe (n = 9,067) and (2) statin plus placebo (n = 9,077)
Methods Patients were assigned 40 mg of simvastatin plus 10 mg of ezetimibe or 40 mg of simvastatin and placebo once daily. Patients followed up at 30 days and then every four months thereafter for a minimum of 2.5 years.
Duration October 26, 2005 to July 8, 2010
Primary Outcome Measure Composite of death from cardiovascular disease, a major coronary event, or nonfatal stroke
Baseline Characteristics Patients were over age 50 (average age 64 years old) and had LDL cholesterol of 50 mg per deciliter or higher
Results Kaplan-Meier event rates for primary end point was 32.7% in simvastatin-ezetimibe group and 34.7% in simvastatin monotherapy group (absolute risk reduction, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016)
Adverse Events Common Adverse Events: Elevation of ALT/AST occurred in 2.3% of simvastatin monotherapy group vs. 2.5% of simvastatin-ezetimibe group, cholecystectomy 1.5% vs. 1.5%, gallbladder related adverse events 3.5% vs. 3.1%, rhabdomyolysis 0.2% vs. 0.1%, myopathy 0.1% vs. 0.2%
Serious Adverse Events: Cancer occurred in 10.2% of all patients and death from cancer seen in 3.6% of simvastatin monotherapy group vs. 3.8% of simvastatin-ezetimibe group
Percentage that Discontinued due to Adverse Events: Out of simvastatin-ezetimibe group 10.6% of patients discontinued compared to 10.1% in simvastatin monotherapy group.
Study Author Conclusions In IMPROVE-IT, the addition to statin therapy of a non-statin agent, ezetimibe, which reduces the absorption of cholesterol from the gastrointestinal tract, lowered LDL cholesterol by approximately 24%. The combination of simvastatin and ezetimibe also resulted in a significantly lower risk of cardiovascular events than that with statin monotherapy, with a 2.0-percentage-point lower rate of the primary composite end point of cardiovascular death, major coronary events, or nonfatal stroke (hazard ratio, 0.936). No between-group differences in cardiovascular mortality or in the rate of death from any cause were anticipated or observed in IMPROVE-IT, findings that are consistent with those in trials of intensive-dose versus standard-dose statin therapy. However, significant reductions were observed in the rates of myocardial infarction and ischemic stroke.

This study suggests that ezetimibe added to statin therapy is more effective at reducing cardiovascular events as compared to statin therapy alone. The increased effectiveness of this combined treatment vs. statin monotherapy was only evident after one year of treatment. The results of this study can only be considered relevant toward patients who had had an ACS, as these were the only patients include in the study.

References:

  1. Mayo Clinic Staff. Acute Coronary Syndrome. The Mayo Clinic. http://www.mayoclinic.org/diseases-conditions/acute-coronary-syndrome/basics/causes/con-20033942. Published May 7, 2013. Accessed June 15, 2015.
  2. Acute Coronary Syndrome. American Heart Association. http://www.heart.org/HEARTORG/Conditions/HeartAttack/AboutHeartAttacks/Acute-Coronary-Syndrome_UCM_428752_Article.jsp. Updated March 19, 2013. Accessed June 15, 2015.
  3. Spinler SA, de Denus S. Chapter 7. Acute Coronary Syndromes. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811456. Accessed June 16, 2015.
  4. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACCF/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008;117:296–329.
  5. Jneid H, Andersen JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non–ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2012;126: 875–910.
  6. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-1681
  7. US Food and Drug Administration. Limit Use of 80 mg Simvastatin. FDA.gov. June 8, 2011. Accessed June 16, 2015.
  8. Shah RV, Goldfine AB. Statins and risk of new-onset diabetes mellitus. Circulation. 2012;126(18):e282-4. Doi: 10.1161/CIRCULATIONAHA.112.122135
  9. Bersot TP. Chapter 31. Drug Therapy for Hypercholesterolemia and Dyslipidemia. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com/content.aspx?bookid=374&Sectionid=41266238. Accessed June 16, 2015.
  10. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015; Doi: 10.1056/NEJMoa1410489
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s