Measuring benefits vs. harm: The complexity of dosing statin therapy

It is well established that serum levels of LDL correlate directly with the incidence of CV events. There is a robust body of literature demonstrating that statins can substantially reduce the rates of death and recurrent MI in patients with a history of CVD.

The benefits of high-intensity statin therapy in the setting of acute coronary syndrome were established by the PROVE-IT trial, which demonstrated that 2 years of therapy with atorvastatin 80 mg is superior to pravastatin 40 mg (Pravachol, Teva Pharmaceuticals) in reducing the rate of recurrent major adverse cardiac events.

Long To

Douglas L. Jennings

Risk-benefit profile

Several studies have attempted to define the risk–benefit profile of high-intensity statin therapy outside setting of ACS. The TNT study demonstrated that atorvastatin 80 mg prevented more recurrent non-fatal MI and stroke compared with atorvastatin 10 mg in patients with stable CAD. However, there was a trend toward higher rates of death related to non-CV causes with high-intensity statin therapy in this trial. To clarify these findings, the IDEAL study was designed to determine whether atorvastatin 80 mg would safely reduce the rate of major adverse coronary events when compared with simvastatin 20 mg (Zocor, Merck) in patients with stable CAD. Results from this study indicated that, although rates of recurrent MI were significantly reduced with intensive statin therapy, there were no significant differences in CV or all-cause mortality.

Although the TNT and IDEAL studies showed reductions in recurrent CV events with high-intensity statin therapy, there was a consistent dose-related increase in serum liver transaminase levels and rates of myopathy. To address these lingering safety concerns, the SEARCH trial was designed to further assess the efficacy and safety of high-dose statin therapy in patients with stable CVD. In this trial, major adverse cardiac events occurred in 24.5% of participants allocated simvastatin 80 mg vs. 25.7% of those allocated 20 mg, corresponding to a nonsignificant 6% RR reduction (P=.10). There were no apparent differences in deaths attributed to vascular (9.4% vs. 9.5%) or nonvascular (6.6% vs. 6.6%) causes.

In line with the safety analysis of the TNT and IDEAL studies, the SEARCH trial showed a higher rate of adverse events with high-intensity statin therapy. The rate of myopathy in patients randomly assigned to simvastatin 80 mg was 53 (1%) compared with two patients (0.03%) randomly assigned to simvastatin 20 mg. This rate was highest in the first year after randomization (four in 1,000) and continued to decrease in subsequent years (one in 1,000). Asymptomatic myopathy was identified in 82 (1.4%) patients assigned to simvastatin 80 mg vs. 12 (0.2%) assigned simvastatin 20 mg. Of the 58 asymptomatic myopathy patients allowed to remain on high-dose simvastatin, 12 (21%) went on to develop definite myopathy. Rhabdomyolysis was identified in seven patients taking simvastatin 80 mg compared with zero with simvastatin 20 mg. Because patients in these studies were monitored closely, the rate of rhabdomyolysis is expected to be lower compared with the general population, and the severity is attenuated since occurrences were caught early.

Based on these results, the FDA now recommends that simvastatin 80 mg should not be initiated in patients who have not previously received lower doses of simvastatin for at least 1 year. Additionally, as drug–drug interactions likely contributed to the increased rate of myopathy in the high-intensity statin group, the package insert for simvastatin was revised to include new recommendations for dose adjustments of simvastatin in the setting of therapy with strong CYP3A4 inhibitors (Table).

Besides liver injury and myopathy, there is now concern regarding new-onset diabetes with long-term use of high-dose statin therapy. A recent meta-analysis found that patients receiving high-dose statin during a period of 4.9 years of therapy were more likely to develop new-onset diabetes than those receiving moderate-dose statin (OR=1.12; 95% CI, 1.04-1.22). Currently, the mechanisms behind this adverse effect are not fully understood.

Rosuvastatin (Crestor, AstraZeneca), the newest and most potent agent in this class, represents a potential option for high-intensity statin therapy. To date, no clinical studies have been published for this agent in patients with stable CAD. Preliminary results from the SATURN trial indicate that rosuvastatin 40 mg is not superior to atorvastatin 80 mg in reducing atheroma volume.

Overall, the results of the SEARCH, TNT and IDEAL studies indicate that high-intensity statin therapy in patients with chronic, stable CAD is associated with a modest decrease in recurrent vascular events without a significant reduction in CV mortality. These benefits are offset by a potential risk for liver injury, myopathy and new-onset diabetes, as well as increased drug costs.

Advice for clinicians

Clinicians caring for those with a distant history of CAD should carefully assess each patient to ensure that the potential benefit of high-intensity statin therapy outweighs the potential harm.

If the decision is made to pursue high-intensity statin therapy, atorvastatin 80 mg would be the preferred regimen, given the aforementioned safety concerns with simvastatin 80 mg. Patients who receive high-intensity statin therapy should be closely monitored for signs and symptoms of myopathy, liver injury and new-onset diabetes.

Long To, PharmD, is PGY2 pharmacology resident in the department of pharmacy services at Henry Ford Hospital. Douglas L. Jennings, PharmD, BCPS, is clinical pharmacy specialist at Henry Ford Hospital and adjunct assistant professor in the department of pharmacy practice at Wayne State University.

Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board. For suggestions of future topics for this column, contact Dr. Cooper-DeHoff at dehoff@cop.ufl.edu.

For more information:

• Cannon CP. N Engl J Med. 2004;350:1495-1504.
• Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2010;376:1670-1681.
• LaRosa JC. N Engl J Med. 2005;352:1425-1435.
• Pedersen TR. JAMA. 2005;294:2437-2445.
• Preiss D. JAMA. 2011;305:2556-2564.
• SEARCH Collaborative Group. Lancet. 2010;376:1658-1669.
• Zocor (simvastatin) [package insert]. Whitehouse Station, NJ: Merck & Co. Inc; revised October 2011.

Disclosure: Drs. To and Jennings report no relevant financial disclosures.