January 2014 FAQs

What is the latest evidence associating statin use with myopathy?

Background

Statins, or HMG-CoA reductase inhibitors, represent one of the most commonly prescribed medication classes.1 They are indicated for a variety of disease states and have proven mortality-reducing effects in cardiovascular disease and stroke.2,3 These medications are not without risk, and some of the most concerning risks are statin-induced myopathies and rhabdomyolysis. Statin-associated myopathy is rare and has been defined as a measured creatine kinase (CK) greater than 10-times the upper limit of normal in a patient taking a statin medication.4 This has been observed to occur most often within 1 month of statin initiation.5 Symptoms and signs of myopathy can include muscle weakness, decreased strength, elevated CK, and progression to rhabdomyolysis, where muscle breakdown may be so profound that it has the potential to cause acute kidney injury.6

Statin-related myopathies have recently made news with a 2011 Food and Drug Administration (FDA)-issued warning regarding simvastatin 80 mg and a subsequent change in the approved dosing regimen for this drug.7 This warning noted an increased incidence of myopathies, specifically rhabdomyolysis, with the use of 80 mg daily and recommended against initiation of this dose in new patients. The warning further recommended lower maximum doses of simvastatin when used concurrently with certain other drugs, such as amlodipine or diltiazem, which interact with simvastatin metabolism via the cytochrome P450 enzyme system and can increase the risk of statin-associated myopathy by increasing the patient’s exposure to the drug. While the data regarding simvastatin’s myopathy risk are coming to light, the generalizability of this data to other statins is unknown. With generic availability of statins increasing, and the shift to use of higher potency choices within the class, data are needed to determine if the risks seen with simvastatin therapy are a class effect.

Recent Literature

A 2013 publication by Mansi and colleagues attempted to determine the association between statin use and musculoskeletal conditions in a military health-system setting.8 This retrospective study matched a cohort of statin users age 30 to 85 years with non-users by baseline characteristics and co-morbidities. Statin users were defined as patients who had filled a statin prescription for at least 90 days in a 1-year period. Rates of musculoskeletal diseases (including injury), musculoskeletal pain, and arthropathies were collected. Among the nearly 7000 matched pairs, the investigators found a statistically significant odds ratio favoring more total musculoskeletal conditions, more drug-associated pain, and more injury-related diseases among users of statins (Table 1). The authors conclude that statin use is associated with increased likelihood of the diagnosis of musculoskeletal conditions, including pain and injury.

Table 1. Musculoskeletal complaints.8

Abbreviations: CI, confidence interval.

Another recent article, the STOMP study by Parker and colleagues, addressed this same question but in a prospective study.9 Healthy individuals were randomized to atorvastatin 80 mg daily or placebo for 6 months in a double-blind fashion. The investigators measured CK levels, muscle strength, and exercise capacity before and after treatment in 420 subjects. Creatine kinase increased 20.8 units/L on average, but never exceed 10-times the upper limit of normal and was not correlated with any statistically significant concurrent changes in muscle strength or exercise capacity (Table 2). There was a trend toward increased reports of new, unexplained muscle pain with atorvastatin use (23 subjects receiving atorvastatin and 14 receiving placebo). At total of 10 placebo-treated patients met the criteria for myalgia compared with 19 atorvastatin-treated patients (p=0.05). The authors concluded that high-dose atorvastatin has no effect on muscle strength or exercise performance over 6 months in healthy individuals.

Table 2. Absolute changes in aerobic and strength endpoints.9a

a Data presented as point estimates and 95% confidence intervals.

Discussion

Despite the limitations inherent in a retrospective study, the study by Mansi and collagues had some strong design features.8 The investigators controlled for potency and dosing of different statins and included all possible musculoskeletal injuries, including those previously validated as drug-related, in their analysis. The data were pulled from a comprehensive database that was unlikely to be missing vital information and included administrative, clinical, and financial data such as prescription fill dates and insurance claims. Due to the use of this database, the study was able to accurately determine claims for musculoskeletal injury in patients prescribed statins and assess the correlated incidence. This study did have other limitations, the largest of which was the large percentage of patients taking maximum doses of a statin (34%), including simvastatin (data not reported). It is possible that up to one-third of patients may have been taking simvastatin 80 mg. Recent literature, as well as warnings issued by the FDA, indicates that this is an unsafe dosing regimen, associated with an increased risk of musculoskeletal injury. Thus, it could be argued that the association between statins and myopathy found in this study is a result of high-dose simvastatin that may not pertain to all statins or lower doses of statins. In addition to this, it can be seen from the baseline characteristics that a significant number of patients receiving statins were also receiving calcium-channel blockers (17%) and/or drugs metabolized via the CYP450 system (7.6%). While this may be representative of the concurrent medication use by the general population, the propensity for drug-drug interactions increasing the risk of myopathy is high, and the investigators do not present any data collection or analysis that would eliminate these interactions from confounding the results.

The STOMP trial succeeded in that it was the first randomized, placebo-controlled study to assess the musculoskeletal side effects of statins.9 Due to this design, the investigators were able to analyze response to the drug in addition to measuring a correlation between myopathy and statin use. This was done by stopping and restarting the statin and measuring resolution and return of symptoms associated with the timing of the drug. The investigators enrolled a large number of patients and excluded those taking drugs which are known to interact with statins or that may alter musculoskeletal function, which would have confounded the results. Of note, however, the patients in the placebo group had a statistically significant higher rate of prescription pain medication use (7.4% versus 2.5%). This may have masked the reporting of new onset muscle pain by the placebo group and could account for a type II error on the part of the investigators, as their study did show a higher incidence of muscle pain reported in the atorvastatin group but failed to find a significant difference. Other limitations of this study include the short duration of treatment time (6 months), the inability to generalize data with atorvastatin to other statins, and the exclusion of patients with underlying musculoskeletal issues, as we then cannot analyze if there is any effect of atorvastatin on exacerbating these disease states.

Conclusion

Both of these studies improve our knowledge of the relationship between statins and musculoskeletal side effects. It appears there is a correlation between statin use and elevation of serum CK values in healthy adults; however, the relationship between these values and symptomatic muscle pain or injury remains unclear. While Mansi and colleagues reported a significant increase in the incidence of myopathies with statin use, they failed to account for a number of confounders and included dosing which we now know to be inappropriate in their study. Parker and colleagues did not see significant differences, but they did not include any patients with co-morbidities and/or underlying musculoskeletal conditions, which makes their patient population less generalizable to practice. From this study, one can conclude that patients without underlying risk factors for musculoskeletal injury, apart from statin use, are unlikely to experience myopathies and elevated CK > 10-times the upper limit of normal with the use of high-dose atorvastatin. Patients with co-morbidities or underlying risk for musculoskeletal injury, which likely represents a large portion of the patients prescribed statins, may have a higher risk, and further studies using approved dosing in these populations should be performed.

References

1. Herper M. America’s most popular drugs. Forbes. http://www.forbes.com/2010/05/11/narcotic-painkiller-vicodin-business-healthcare-popular-drugs.html . Updated May 11, 2010. Accessed December 18, 2013.

2. Taylor F, Huffman T, Acedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;(1):CD004816.

3. Amarenco P, Bogousslavsky J, Callahan III A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549-559.

4. Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137(7):581-585.

5. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients: the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403-414.

6. Pasternak RC, Smith SC, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40(3):567-572.

7. FDA drug and safety communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Updated January 3, 2013. Accessed December 18, 2013.

8. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1-10.

9. Parker B, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127(1):96-103.

Written by:

Nicole Grimmer, PharmD

PGY-1

University of Illinois at Chicago

January 2014

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What are current best practices for prevention of central-line associated bloodstream infections?

Introduction

In 2012, The Joint Commission released a document entitled Preventing Central Line-Associated Bloodstream Infections: A Global Challenge, a Global Perspective.1 This monograph provides an in-depth discussion of the epidemiology and risk factors for central line-associated bloodstream infections (CLABSI) with an emphasis on initiatives and best practices aimed at prevention of these events. The Joint Commission estimates that 3 million central line catheters are used yearly in the United States, with 250,000 subsequent cases of CLABSI. The majority of CLABSI occurs outside of the intensive care unit setting and may lengthen hospitalization by up to 3 weeks. Per the Centers for Disease Control and Prevention (CDC), the estimated cost for a CLABSI is $16,550, and other authors have noted an associated mortality rate of 12.3%. The widespread and substantial burden of CLABSI warrants significant provider concern and attention to effective preventative measures.

The Joint Commission CLABSI toolkit

As a companion to the original monograph, in November 2013 The Joint Commission debuted a CLABSI prevention toolkit on its website with a goal of widely disseminating information that may help healthcare organizations reduce the occurrence, morbidity, mortality, and financial burden of CLABSI.2 Recommendations involving pharmacologic and antiseptic prevention techniques are provided in Chapter 3 and are summarized below. The toolkit website contains links to relevant sections of the original monograph or resources from other professional organizations that support the recommendations.

Table 1. Summary of CLABSI Prevention Strategies from The Joint Commission.1,2

Abbreviations: CDC=Centers for Disease Control and Prevention; CLABSI=central line-associated bloodstream infections; USP=United States Pharmacopoeia; HO=World Health Organization.

Other recommendations for CLABSI prevention

A major consensus document on the prevention of CLABSI that includes recommendations from numerous national professional organizations including the CDC, Infectious Diseases Society of America (IDSA), Infusion Nurses Society (INS), and other major medical and nursing groups was released in 2011.3 A previous FAQ from our group summarizes these best practices ( http://dig.pharm.uic.edu/faq/2011/May/faq3.aspx).

Conclusion

The US healthcare system and its patients are plagued by substantial negative effects from CLABSI. Fortunately, recommendations from The Joint Commission and other groups may help prevent CLABSI and their associated burden from occurring. These recommendations include appropriate hand hygiene, skin preparation prior to catheter insertion, frequent dressing changes and skin antisepsis, and removal of central line catheters at the first sign of infection.

References

1. The Joint Commission. Preventing Central Line-Associated Bloodstream Infections: A Global Challenge, a Global Perspective. May 2012. http://www.jointcommission.org/preventing_clabsi/. Accessed December 9, 2013.

2. The Joint Commission. CLABSI Toolkit – Preventing Central-Line Associated Bloodstream Infections: Useful Tools, An International Perspective. http://www.jointcommission.org/Topics/Clabsi_toolkit.aspx. Accessed December 9, 2013.

3. O'Grady NP, Alexandar M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52(9):e162-e193.

January 2014

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What are the key features of the new cholesterol treatment guidelines?

Introduction

In 2002, the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) was released. 1 Uptake of the guideline recommendations into clinical practice was relatively widespread. Since the original release of ATP III, only a minor “update” was published – a summary of implications from recent clinical trials – in 2004.2 On November 12, 2013, fully revised guidelines for the treatment of high blood cholesterol in adults (ATP IV) were released by the American College of Cardiology-American Heart Association (ACC-AHA) Task Force on Practice Guidelines.3 This revision contains key features that may significantly impact lipid management, with some recommendations already resulting in controversy among healthcare providers.

Key Features

In contrast to the previous ATP III guidelines, which focused on patient-specific lipid-level goals dependent upon risk level, the new guidelines undertook a vastly different approach.4 The expert panel in ATP IV relied heavily on data from randomized controlled trials involving fixed doses of statins in patients at risk for atherosclerotic cardiovascular disease. Utilizing this approach, the expert panel identified 4 patient subgroups for which the benefits of statin therapy outweigh the risks. These 4 subgroups include:

1. those with clinically evident atherosclerotic disease,

2. patients with low-density lipoprotein (LDL) cholesterol levels ≥ 190 mg/dL,

3. patients, 40 to 75 years of age, with diabetes and an LDL level of 70 to 189 mg/dL,

4. or those, 40 to 75 years of age, with a 10-year risk of atherosclerotic cardiovascular disease of ≥ 7.5% and an LDL level of 70 to 189 mg/dL.

For patients within these subgroups, high-intensity statin therapy is generally recommended.4 According to the guidelines, high-intensity statin therapy reduces LDL levels by ≥ 50% on average. The expert panel recommends atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg once daily as appropriate agents for high-intensity therapy. In patients who cannot tolerate high-intensity therapy or those with diabetes and a 10-year risk of atherosclerotic cardiovascular disease < 7.5%, moderate-intensity statin therapy is recommended. Moderate-intensity therapy reduces LDL levels by approximately 30% to < 50% on average. Recommended statin dosage regimens for moderate-intensity therapy include atorvastatin 10 to 20 mg, rosuvastatin 5 to 10 mg, simvastatin 20 to 40 mg, pravastatin 40 to 80 mg, lovastatin 40 mg, extended-release fluvastatin 80 mg, fluvastatin 40 mg, and pitavastain 2 to 4 mg. All recommended moderate-intensity dosage regimens should be given once daily except for immediate-release fluvastatin, which is administered twice daily.

The new guidelines also identify patients for whom current clinical data do not support the use of statin therapy and for whom no treatment recommendation is made. These patients include:

1. those on hemodialysis,

2. those > 75 years of age, unless atherosclerotic cardiovascular disease is present,

3. and those with New York Heart Association class II to IV heart failure.

Finally, the expert panel stated that there is no clinical evidence “to support the use of non-statin cholesterol-lowering drugs, either combined with statin therapy or in statin-intolerant patients”.4 Basically, the panel could find no randomized controlled trials that demonstrated a further reduction in atherosclerotic cardiovascular disease events in these situations.3

Practice Implications

Healthcare providers who manage patients with high cholesterol may see considerable changes in practice parameters as a result of the new treatment recommendations.4 These include:

1. not prescribing lipid-lowering therapy in certain patient populations,

2. elimination of routine LDL level assessments due to the fact that target levels are no longer an emphasis of the guidelines,

3. avoiding non-statin therapy in statin-tolerant patients,

4. more conservative prescribing of statin therapy in patients > 75 years of age with no evidence of atherosclerotic disease,

5. reduced utilization of surrogate laboratory markers (i.e., C-reactive protein, calcium scores),

6. and implementation of a new risk calculator that may result in a greater number of patients receiving statin therapy.

Controversy

There has been some controversy regarding the revised guidelines since their release, primarily involving the new risk calculator.4 This calculator has not been prospectively evaluated regarding its accuracy in predicting cardiovascular risk and currently appears to overestimate risk. This overestimation may lead to certain patients being falsely labeled as candidates for statin therapy.

Conclusion

The new cholesterol treatment guidelines have been long awaited and shift the focus of treatment away from targeting specific LDL goals to identifying those patients in need of high-intensity, moderate-intensity, or no statin therapy. These guidelines will result in considerable changes in the practice of lipid management; however, this revision is not without controversy. The new risk calculator within the guidelines tends to overestimate risk and may result in an increase in the number of patients receiving statin therapy, sometimes inappropriately. A prospective assessment of the risk calculator is needed to verify its accuracy.

References

1. National Institutes of Health. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf. Accessed December 6, 2013.

2. Grundy SM, Cleeman JI, Bairey Merz N, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239.

3. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol. 2013; doi:10.1016/j.jacc.2013.11.002.

4. Keaney JF, Curfman GD, Jarcho JA. A pragmatic view of the new cholesterol treatment guidelines. N Engl J Med. 2013; Nov 27. [Epub ahead of print].

January 2014

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