Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization

Article Outline

• Abstract
• Methods
  • Setting
  • Patient sample
  • Procedures
  • Analysis
• Results
  • Review of patient cases
    • Drug-drug interactions
    • Re-challenge data
    • Time to onset, symptoms, and resolution
• Discussion
• References
• Copyright

Abstract 

Purpose

To describe the rate, potential causes, symptoms, time to onset, and time to resolution of severe transaminitis associated with increased 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitor (“statin”) usage in a large group model health maintenance organization.

Subjects and methods

Health plan members 18 years of age and older, not receiving chemotherapy, who had received at least 1 statin prescription between January 1, 1997, and December 31, 2001 were eligible. All eligible patients with an alanine aminotransferase greater than 10 times the upper limit of normal at any time during the study period were identified using computerized laboratory records. Medical records were subsequently reviewed in order to determine whether the elevation was attributable to statin therapy.

Results

Alanine aminotransferase had never been measured in 2334 of 25334 (9%) of eligible patients. In the remaining 23000 patients, 62 (0.3%) were identified with an alanine aminotransferase greater than 10 times the upper limit of normal during the 5-year study period. Of these, 17 (0.1% of 23000 patients) had severe transaminitis deemed directly attributable to statin use. All except 4 of these 17 cases were associated with drug interactions. In 16 cases, transaminitis resolved upon statin discontinuation.

Conclusions

In the observed study sample, statin-related severe transaminitis occurred infrequently. These findings support less frequent liver enzyme monitoring for most patients on statins. Continued monitoring remains warranted for patients on concomitant medications or those with comorbid conditions.

Keywords:  3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors , Alanine aminotransferase , Liver

Since lovastatin, the first 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor (“statin”) was launched onto the market in 1987, statins have become one of the most frequently prescribed classes of medications. Although statins appear to be safe, animal and pre-marketing clinical trials have shown signs of liver toxicity, mostly manifesting as minor elevations in alanine aminotransferase and aspartate aminotransferase concentrations.¹ In large clinical trials, alanine aminotransferase elevations of greater than 3 times the upper limit of normal occurred in less than 2% of patients.², ³, ⁴, ⁵, ⁶ The prevalence of severe transaminitis (defined as an alanine aminotransferase level greater than 10 times the upper limit of normal) was even lower.², ³, ⁴, ⁵, ⁶

With statin use increasing, determining the prevalence of severe transaminitis in a real-world setting and whether regular monitoring of liver enzyme levels in all patients is necessary becomes an important clinical question. The objective of this study was to examine the rate, potential causes, symptoms, time to onset, and time to resolution of severe transaminitis associated with statin usage in a large sample of patients in a group model health maintenance organization.

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Methods 

Setting 

This retrospective review was conducted at Kaiser Permanente of Colorado, a large group model health maintenance organization in the western United States with approximately 385000 enrolled members. Approval to conduct the study was obtained from the Institutional Review Board of Kaiser Permanente Northern California.

Patient sample 

All patients 18 years of age and older enrolled in Kaiser Permanente of Colorado between January 1, 1997, and December 31, 2001, who had received at least 1 statin prescription within this period were considered for evaluation. Patients receiving anti-neoplastic therapy were excluded due to the potential for these agents to cause liver enzyme abnormalities. Patients who were no longer Kaiser Permanente members by the end of the study period were also excluded. For any excluded patients in this latter category with an alanine aminotransferase level greater than 10 times the upper limit of normal, the medial record was screened to identify any potential statin-related deaths.

Procedures 

Computerized laboratory and pharmacy data were used to identify all patients with severe transaminitis who were receiving lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, and cerivastatin. Severe transaminitis was defined as an alanine aminotransferase level greater than 10 times the upper limit of normal (>420 IU/L) at any time after the first statin prescription was dispensed.⁷ NCEP III guidelines recommend transaminase monitoring (alanine aminotransferase or aspartate aminotransferase) to assess liver function in patients on statin therapy.⁸ Alanine aminotransferase, rather than aspartate aminotransferase, was chosen as the marker of severe transaminitis as it has demonstrated greater sensitivity and specificity for drug-induced liver dysfunction and is the preferred test at Kaiser Permanente for liver function monitoring in patients on statin therapy.⁹, ¹⁰

Medical records for each patient with alanine aminotransferase levels greater than 10 times the upper limit of normal were reviewed independently by 4 investigators (1 physician and 3 clinical pharmacy specialists). Alternative causes of alanine aminotransferase elevations were examined for each patient along with the presence of comorbid conditions known to affect alanine aminotransferase concentrations. Specifically, these included autoimmune or viral hepatitis, cholelithiasis, fatty liver, and/or pancreatitis. The presence of concomitant medications known to interact with statins was evaluated with particular attention given to medications metabolized through the same metabolic pathways as statins (ie, cytochrome P450 3A4). The timing of events including de-challenge/re-challenge data was evaluated for each case.

All cases were classified as either unrelated or possibly related to statin therapy according to predetermined definitions.¹⁰ Cases that were determined to be possibly related to statin therapy were then scored using the Naranjo probability scale for assessing drug-related adverse reactions.¹¹ The Naranjo criteria, which have been validated for the assessment of drug-induced adverse events, consider the onset, course of reaction, and possible disease and drug alternatives.¹¹ A score of greater than 9 indicates a high probability of drug-induced adverse events, 5–8 is probable, 1–4 is possible, and less than 1 is doubtful.¹¹

Cases in which alanine aminotransferase elevation preceded statin initiation were considered unrelated to statin therapy. Instances of negative re-challenge, defined as a retrial of the same or different statin after an initial alanine aminotransferase elevation in which subsequent alanine aminotransferase results remained within normal limits, were also considered unrelated to statin therapy.¹⁰ However, if a re-challenge with the same or different statin resulted in an alanine aminotransferase elevation greater than 42 IU/L upon subsequent testing, it was considered related.¹⁰ In cases in which an alanine aminotransferase elevation resulted in statin discontinuation, laboratory data were examined to determine the clinical course after drug cessation. In situations in which the alanine aminotransferase did not decrease by at least 50% 2 months after statin discontinuation, the elevation was considered unrelated to the statin. A period of 1 month is suggested for the evaluation of drug-induced liver disorders; however, we chose 2 months to allow sufficient time for laboratories to be completed.¹⁰ Unanimous agreement among the reviewing investigators was required for an episode of transaminitis to be considered related to statin therapy.

Analysis 

Results were summarized using common methods such as calculating medians, maximum and minimum values, means, standard deviations, and percentages. Percentages refer to the proportion of the total evaluable study sample that had alanine aminotransferase measurements available unless otherwise noted. Means are reported with accompanying standard deviations.

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Results 

A total of 30830 patients received at least 1 prescription for a statin during the 5-year study period (Figure 1). Of these patients, a total of 4651 (15%) were no longer active Kaiser Permanente members at the end of the study period and 845 (3%) were receiving antineoplastic therapy and were excluded. Of the remaining 25334 evaluable patients, 2334 (9%) had no alanine aminotransferase measurements. The average duration of statin use in this group was 2.8 ± 1.8 years; range 0.08 to 5.0 years. Table 1 describes the baseline characteristics of the remaining 23000 patients.

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• Figure 1. 

  Patient disposition. ALT = alanine aminotransferase; ULN = upper limit of normal.

Table 1. Baseline characteristics of the 23000 patients who had alanine aminotransferase measured at least once after initiation of a statin

Patient Characteristics	n = 23 000
Average age (years)	62.4 ± 11.5
Age range (years)	21 to 99
Women (%)	44.9
Average statin duration (years)	3.9 ± 1.6
Median statin dose mg per day (min, max)
Lovastatin	10(10,40)
Simvastatin	40(5,80)
Atorvastatin	20(10,80)
Pravastatin	20(10,40)
Fluvastatin	20(20,40)
Median number of days to first ALT⁎ (min, max)	88(0,2526)

There were 361 patients (2%) with alanine aminotransferase levels between 3 and 10 times the upper limit of normal (average 192 ± 72 IU/L) during the 5-year study period (Figure 1). Elevated alanine aminotransferase values returned to normal upon subsequent testing in 235 (65%) of these patients but remained elevated (average 174.9 ± 54 IU/L) in 91 (25%). Thirty-five of these patients (10%) did not have repeat alanine aminotransferase testing.

Sixty-two patients (0.3%) with alanine aminotransferase greater than 10 times the upper limit of normal were identified and their medical records were reviewed. Elevated alanine aminotransferase levels in 46 of the 62 (74%) patients were determined to be unrelated to statin use. Eleven of the 46 patients were not on a statin at the time alanine aminotransferase was elevated. One or more of the following causes identified as responsible for the alanine aminotransferase elevation was present in a further 29 patients: cholelithiasis (n = 15), viral or autoimmune hepatitis (n = 8), fatty liver (n = 1), pancreatitis (n = 1), severe congestive heart failure (n = 1), triamterene/ hydrochlorothiazide use (n = 1), sertraline use (n = 1), and cancer (n = 1). Medical records were unavailable in two patients. In 4 cases the precipitating factor was unclear due to complicated history such as diverticulitis, suspected but unconfirmed cholelithiasis, gaps in patient’s medical record or the lack of re-challenge data after statin discontinuation. The remaining 16 (26% of cases) patients had severe transaminitis considered to be directly related to statin use. Table 2 provides a summary for these 16 cases and an additional case of a patient who expired shortly after starting a statin. Baseline alanine aminotransferases prior to initiation of statin therapy were normal (<42 IU/L) for 14 patients; two patients had values slightly higher than normal (46 and 54 IU/L); and for one patient the baseline values were not available due to new membership status. Using the Naranjo scale, we determined that 16 of the 17 cases were probable or highly probable for statin-related toxicity. In only one case was the alanine aminotransferase determined not likely to be related to the statin (Table 2).

Table 2. Summary of 17 cases with alanine aminotransferase greater than 10 times the upper limit of normal

Review of patient cases 

Of the 16 cases considered related to statin therapy, 13 (81%) were associated with drug interactions (Table 2). Seven patients had potential drug-drug interactions caused by agents that share common metabolic pathways with statins (ie, cyclosporine, erythromycin, cimetidine, and indinavir). Two patients were taking drugs for which liver enzyme elevation has been reported as an adverse effect in the literature (ie, propoxyphene with acetaminophen, naproxen, and codeine with acetaminophen) in addition to the statin therapy. Eight patients were on a combination of statin and another agent with either the potential to elevate liver enzymes (ie, propafenone) or inhibit the CYP 3A4 metabolic pathway (ie, verapamil, diltiazem, fluoxetine, digoxin, or gemfibrozil).¹²

Of the 16 patients with alanine aminotransferase greater than 10 times the upper limit of normal attributable to statin use, 6 were not re-challenged. Ten patients were re-challenged with the same (n = 7) or different statin (n = 3) at least once. Out of 7 re-challenged with the same statin, 4 patients had no recurrent alanine aminotransferase elevation. Three had a positive re-challenge. These 3 patients and 3 others were tried on a different statin. Five out of the 6 patients tolerated the alternative statin without subsequent alanine aminotransferase elevation. One patient had severe alanine aminotransferase elevation when re-challenged with the initial statin as well as an alternative statin. This was a 74-year-old woman on multiple medications, including verapamil, digoxin, and warfarin. She was hospitalized twice with symptoms of myositis and alanine aminotransferase and creatine kinase elevations. At the time of the first hospitalization, she was on simvastatin 80 mg daily and gemfibrozil 600 mg twice a day; however, during the second hospitalization she was receiving lovastatin 80 mg daily as monotherapy. Both the alanine aminotransferase and creatine kinase elevations resolved when statins were discontinued.

One death was identified as potentially, though not likely, statin related. The patient, an 80-year-old woman with no documented history of liver disease or prior statin usage, was started on simvastatin 40 mg daily as well as lisinopril 10 mg daily. Three weeks later, she was admitted to hospital with multiorgan failure, including myocardial infarction, liver failure, and severe coagulopathy. She expired after several days in the hospital.

Table 2, Table 3 describe time to alanine aminotransferase elevation, presence or absence of symptoms of liver damage, and the time for alanine aminotransferase to return to normal limits. Of the 17 patients, 11 (65%) experienced severe transaminitis within 2 days to 4 weeks, 3 (18%) within 8 weeks, and the remaining 3 (18%) between 16 weeks and more than 5 years after the changes in patient’s drug regimen were made (Table 3). There did not appear to be any correlation between statin dosage and the time of onset of alanine aminotransferase elevation.

Table 3. Time to onset of alanine aminotransferase greater than 10 times the upper limit of normal from statin initiation/dose change or addition of concomitant medication

Ten out of 17 patients were symptomatic at the time of abnormal laboratory findings with symptoms ranging from mild (yellow skin tint, itching, urine and stool discoloration) to severe (rhabdomyolysis, liver failure, coagulopathy). Six patients presented with no symptoms of liver damage. Data were not available for 1 patient. With the exception of the 1 fatality, alanine aminotransferase levels returned to normal for all patients within 2 to 8 weeks.

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Discussion 

Clinical trials with statins have demonstrated that approximately 1% to 3% of patients develop alanine aminotransferase greater than 3 times the upper limit of normal.², ³, ⁴, ⁵, ⁶ In agreement with that, our study found that of over 23000 patients with alanine aminotransferase levels drawn while on statin therapy, only 1.6% developed alanine aminotransferase greater than 3 times the upper limit of normal, and fewer (0.3%) had levels greater than 10 times the upper limit of normal. Upon review of the 0.3% of patients, very few cases (less than 0.1% of the 23000 with alanine aminotransferase levels drawn) were deemed to be actually related to statin therapy.

Our data are consistent with other studies in the literature.¹, ¹³, ¹⁴, ¹⁵, ¹⁶ A recent review of animal toxicology as well as pre- and post-marketing clinical trials of lovastatin found no direct correlation between the increased use of lovastatin over the past 15 years and the incidence of drug-related serious liver disease.¹ In fact, serious liver disease due to lovastatin was less common than that associated with NSAIDs.¹ Smith et al reviewed the medical charts of 194 primary care patients receiving statins within a 1-year time period and reported that only 1% developed alanine aminotransferase greater than 3 times the upper limit of normal.¹⁵ Moreover, none of these cases were deemed to be statin-related. A recent study by Chalasani et al found that individuals with elevated baseline liver enzymes were not at increased risk for hepatotoxicity from statin therapy.¹⁶

The elevation of liver enzymes observed in the clinical trials may actually be related to cholesterol-lowering per se rather than a direct hepatotoxic effect of statins.¹ Cholesterol lowering may increase hepatocyte membrane permeability, resulting in an increase in liver enzyme leakage.¹ Animal toxicology data and the fact that liver enzyme elevation has been reported with other classes of cholesterol-lowering medications support this theory.¹, ¹⁷

Considering the remarkable clinical benefits of statins, the widespread use of these agents, and the potentially nontoxic nature of liver transaminitis, our results question the clinical utility of routine liver function monitoring in all statin users. Previous studies have also questioned the value of routine monitoring of liver function tests and whether monitoring prevents serious liver damage.¹, ¹⁵ Furthermore, given the fact that statins are being evaluated for over-the-counter status, the practice of routine liver enzyme monitoring will be less likely to occur in clinical practice.

A good screening tool should be capable of detecting the target condition prior to the onset of symptoms. Current treatment guidelines recommend liver enzyme monitoring every 6 to 8 weeks after the initiation of statin therapy, every 3 to 6 months for the first year, and periodically thereafter.⁸ In our study, the majority of patients (65%) with alanine aminotransferase greater than 10 times the upper limit of normal experienced severe liver enzyme elevation within the first month after statin initiation, dose adjustment, and/or addition of medications with potential to interact with statins. Ten out of 17 patients (58%) were symptomatic at the time of the test. Thus, in the majority of our patients, testing detected enzyme elevation only after the patient became symptomatic.

Our results suggest that routine liver enzyme monitoring is likely most appropriate in patients at risk for severe transaminitis, such as those with multiple comorbid conditions and/or who are receiving concomitant medications.¹² We identified 1 death that was potentially, though not likely, simvastatin related. The patient’s medical chart provided little detail other than the patient was an 80-year-old statin-naïve woman with history of congestive heart failure, who presented with liver failure and myocardial infarction 3 weeks after initiation of simvastatin 40 mg daily. Considering that this was a single case out of 30000 statin users and the retrospective nature of this analysis, we cannot rule out other cases of liver failure and death, such as organ failure secondary to a myocardial infarction or a rare idiosyncratic reaction.

Elevations of liver enzymes, alanine aminotransferase in particular, are not specific to statin therapy. Enzyme elevation can be associated with conditions such as gallbladder disease, infectious liver disease, passive hepatic congestion secondary to congestive heart failure, nonalcoholic fatty liver associated with diabetes, obesity, and dyslipidemia. In our study, 15 out of 17 cases of statin-related alanine aminotransferase greater than 10 times the upper limit of normal presented with medical comorbid conditions that could have been the contributing factor to alanine aminotransferase elevation.

We chose to evaluate only patients with alanine aminotransferase greater than 10 times the upper limit of normal rather than patients with alanine aminotransferase greater than 3 times the upper limit of normal. Our decision was based on the fact that alanine aminotransferase greater than 10 times the upper limit of normal is the range that has been defined as serious.⁷ In fact, it is possible that discontinuation of lipid-lowering therapy simply based upon mildly elevated alanine aminotransferase levels (ie, 1 to 3 times the upper limit of normal) could be more detrimental by increasing the risk of death from heart disease and strokes than simply continuing therapy. Future studies are needed to evaluate the impact of discontinuation of statins with alanine aminotransferase greater than 3 times the upper limit of normal and the rate of recurrent coronary events with this practice.

Our study has some limitations. We could not assess the impact of other factors such as alcohol use or the use of over-the-counter and herbal products from this retrospective chart review. About 9% of patients started on statin never had alanine aminotransferase measured, suggesting that the actual number of patients with severe transaminitis may be even greater. However, it is likely that the number of patients missed is very small because most patients with this degree of transaminase elevation in our study were symptomatic. There were insufficient data to compare alanine aminotransferase elevations with different statins because the majority of our patients were on lovastatin or simvastatin. A study specifically designed to compare statins is needed to determine whether some agents have a lower risk of transaminitis than others.

The present study suggests that very few patients develop severe transaminitis as a direct result of statin therapy. The majority of patients who developed severe transaminitis either had comorbid conditions or were receiving concomitant medications with the potential to interact with the statin. These data would suggest that routine liver enzyme monitoring in patients without significant comorbid conditions or concomitant therapies may not be necessary. More aggressive monitoring of liver function tests and possibly earlier than recommended by current guidelines is likely warranted in patients on multiple medications with comorbid conditions or if a potentially interacting drug is added to a patient’s drug regimen. In patients who develop elevations in liver function tests, the tests typically return to normal after the statin is discontinued. Furthermore, most patients who fail one statin due to liver enzyme elevation can be successfully re-challenged with the same or different statin.

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References 

1. Tolman KG . The liver and lovastatin . Am J Cardiol. . 2002;89:1374–1380
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (140 KB)
   • CrossRef
2. Scandinavian Simvastatin Study Group . Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease (the Scandinavian Simvastatin Survival Study (4S)) . Lancet . 1994;344:1383–1389
   • View In Article
   • Abstract
3. Sacks FM , Pfeffer MA , Lemuel AM , et al.   The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels . N Engl J Med. . 1996;335:1001–1009
   • View In Article
   • MEDLINE
   • CrossRef
4. Downs JR , Clearfield M , Weis S , et al.   Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS . JAMA . 1998;279:1615–1622
   • View In Article
   • MEDLINE
   • CrossRef
5. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group . Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels . N Engl J Med. . 1998;339:1349–1357
   • View In Article
   • MEDLINE
   • CrossRef
6. Heart Protection Study Collaborative Group . MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals (a randomized placebo-controlled trial) . Lancet . 2002;360:7–22
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (207 KB)
   • CrossRef
7. PhRMA/FDA/AASLD Drug-induced hepatotoxicity white paper post-marketing considerations. Available from: http://www.fda.gov/cder/livertox/ [cited 2004 Apr 29].
   • View In Article
8. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults . Executive Summary of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) . JAMA . 2001;285:2486–2497
   • View In Article
   • MEDLINE
   • CrossRef
9. Dujovne CA . Side effects of statins (hepatitis versus “transaminitis”—myositis versus “CPKitis”) . Am J Cardiol. . 2002;89:1411–1413
   • View In Article
   • Full Text
   • Full-Text PDF (46 KB)
   • CrossRef
10. Benichou C . Criteria of drug-induced liver disorders. Report of an international consensus meeting . J Hepatol. . 1990;11:272–276
    • View In Article
    • MEDLINE
    • CrossRef
11. Naranjo CA , Busto U , Sellers EM , et al.   A method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther. . 1981;30:239–245
    • View In Article
    • MEDLINE
    • CrossRef
12. Williams D , Feely J . Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors . Clin Pharmacokinet. . 2002;41:343–370
    • View In Article
    • MEDLINE
    • CrossRef
13. Newman CB , Palmer G , Silbershatz H , Szarek M . Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients . Am J Cardiol. . 2003;92:670–676
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (109 KB)
    • CrossRef
14. Ballantyne CM , Corsini A , Davidson MH , et al.   Risk of myopathy with statin therapy in high-risk patients . Arch Intern Med. . 2003;163:553–564
    • View In Article
    • MEDLINE
    • CrossRef
15. Smith CC , Bernstein LI , Davis RB , et al.   Screening for statin-related toxicity . Arch Intern Med. . 2003;163:688–692
    • View In Article
    • MEDLINE
    • CrossRef
16. Chalasani N , Aljadhey H , Kesterson J , Murray MD . Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity . Gastroenterology . 2004;126:1287–1292
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (88 KB)
    • CrossRef
17. MacDonald JS , Gerson RJ , Kornbrust DJ , et al.   Pre-clinical evaluation of lovastatin . Am J Cardiol. . 1988;62:16J–27J
    • View In Article
    • MEDLINE