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Therapeutic rationale of combining therapy with gemfibrozil and simvastatin Patrick O. Curtin and William N. Jones
Received June 13, 2006, and in revised form October 6, 2006. Accepted for publication October 7, 2006.
Abstract
Objectives: To examine specific indications for patients receiving therapy with gemfibrozil plus simvastatin at doses of more than 10 mg daily and determine whether these patient-specific indications met Adult Treatment Panel (ATP) III criteria for combination therapy; and secondarily to identify any complications occurring between August 30, 2002, and May 1, 2003. Design: Retrospective cohort study. Setting: Tertiary care, university-affiliated, Southern Arizona Veterans Affairs Healthcare System from August 30, 2002, to May 1, 2003. Patients: 80 patients with active prescriptions for gemfibrozil at any dose and simvastatin at doses of more than 10 mg daily as of August 30, 2002; and 23 patients who had been prescribed this drug at other institutions. Intervention: Retrospective chart review. Main outcome measures: Frequency of meeting ATP III criteria for combination therapy with gemfibrozil and simvastatin was the primary outcome measure (primary). Results: Of the 80 patients, 45 (56%) met ATP III guidelines for combination therapy. Among the 80 patients started on these drugs at this VA facility, gemfibrozil was added to simvastatin in 61 patients, simvastatin was added to gemfibrozil in 18, and the agents were begun simultaneously for 1 patient. Common errors included combination treatment when LDL cholesterol values could not be calculated (because of serum triglycerides levels exceeding 400 mg/dL); use of gemfibrozil at triglyceride levels lower than the 500 mg/dL with attainment of non–HDL goals; and use of gemfibrozil when triglyceride levels were not measured. One death secondary to rhabdomyolysis occurred in a patient whose care did not meet ATP III guidelines. Conclusion: Combination therapy with simvastatin and gemfibrozil often did not meet ATP III standards. A higher risk of serious adverse events results from combining these drugs, and systems to improve adherence to guidelines may improve the safety of treating dyslipidemic patients. Keywords: Gemfibrozil, statins, dyslipidemias, adverse drug effects, rhabdomyolysis, Adult Treatment Panel III. J Am Pharm Assoc. 2007;47:140–146.
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Patrick O. Curtin, PharmD, BCPS, was Pharmacy Practice Resident, Southern Arizona Veterans Affairs (VA) Health Care System, Tucson, Ariz., at the time this study was conducted; he is currently Staff/Clinical Pharmacist, Department of Veterans Affairs, New Jersey Health Care System, East Orange, N.J. William N. Jones, MS, was Program Manager for Pharmacy Clinical Services, Southern Arizona VA Health Care System, Tucson, Ariz., at the time this study was conducted; he is currently Pharmacy Program Manager for Educational Development and Performance Improvement for the VA Pharmacy Benefits Management Strategic Healthcare Group, and Associate Clinical Professor of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson. Correspondence: Patrick O. Curtin, PharmD, Pharmacy Service (119), New Jersey VA Health Care System, East Orange, NJ 07018. Fax: 973-395-7157. E-mail: patrick. [email protected] Disclosure: Mr. Jones has received grant funding from Merck, Inc., to evaluate dyslipidemias in primary care clinics. The views expressed by the authors are their own and may not reflect those of the Department of Veterans Affairs. Previous presentations: 23rd Annual Western States Conference for Pharmacy Residents, Fellows, and Preceptors, Monterey, Calif., May 22, 2003, and the 2006 APhA Annual Meeting and Exposition, San Francisco, Calif., March 17–21, 2006.
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reating dyslipidemias decreases cardiovascular morbidity and mortality.1–8 Based on this evidence, guidelines were developed in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] III).9 The ATP III identified high low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol, and hypertriglyceridemia as independent risk factors for coronary heart disease (CHD) morbidity, and mortality3,6,10–13 and established specific LDL cholesterol, HDL cholesterol, and triglyceride goals in all patients.8 Different pharmacotherapeutic approaches may be combined to reach the desired endpoints for dyslipidemia. A 3-hydroxy-3-methylglutaryl (HMG)–coenzyme A (CoA) reductase inhibitor (statin) combined with a fibrate is one therapeutic option.
At a Glance Synopsis: In this retrospective chart review of 103 dyslipidemic patients in the Southern Arizona VA Healthcare System with active prescriptions for gemfibrozil and simvastatin in doses of more than 10 mg daily, the prescribing rationale for 44% of patients was not consistent with Adult Treatment Panel (ATP) III criteria. For example, in five patients with serum triglycerides already lower than 500 mg/dL, simvastatin was added to gemfibrozil. ATP III criteria state that the initial primary goal for patients in this category is LDL lowering; gemfibrozil should only be considered after LDL is treated to goal. Similarly, in 21 patients whose triglyceride levels had reached 500 mg/dL, gemfibrozil was added to simvastatin, but the statin perhaps could have been discontinued since hypertriglyceridemia is the primary goal of therapy at that point. Furthermore, LDL cholesterol values could not be calculated in these patients because of the high triglycerides, making it impossible for the clinician to know whether the statin was needed or not. Analysis: A higher risk of serious adverse events results from combining gemfibrozil and simvastatin, as highlighted by an FDA labeling revision to simvastatin in 2002. Myopathy and rhabdomyolysis occur at a higher rate with gemfibrozil–simvastatin combination therapy than with either agent alone. During the period reviewed in the current study, several patients discontinued therapy as a result of stomachaches and myalgias and one patient died from rhabdomyolysis. The finding that approximately 44% of patients’ therapy regimen for this combination did not meet ATP III guidelines suggests that measures should be undertaken to more closely follow established lipid treatment protocols and hence improve the cardiovascular outcomes of dyslipidemic patients.
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The ATP III guidelines state, with caveats, that a fibrate may be used in combination with a statin when triglycerides are between 200 and 499 mg/dL, triglycerides are at least 500 mg/ dL, and HDL cholesterol is less than 40 mg/dL.9 Despite these recommendations, no large randomized controlled trials support combination therapy with a statin and fibrate to decrease cardiovascular morbidity and mortality. However, an increased risk of myopathy and rhabdomyolysis with combination therapy that exceeds either agent alone has been reported.14–16 The Food and Drug Administration (FDA) approved labeling changes related to simvastatin in 2002.17 The new product labeling for simvastatin (Zocor—Merck) states that when the drug is combined with gemfibrozil, its daily dose should not exceed 10 mg. Furthermore, the labeling warns against combining simvastatin with fenofibrate or niacin at doses of 1 gram or more because myopathy may occur and careful assessment of the benefit-torisk ratios is necessary.
Objectives A 2002 FDA warning of statin-associated rhabdomyolysis lead to our primary objective: to examine whether patients in the Southern Arizona Veterans Affairs (VA) Healthcare System who were prescribed gemfibrozil and simvastatin at doses of more than 10 mg daily met ATP III recommendations for this combination. Fenofibrate was not included in the analysis because the warning was not as specific as that for gemfibrozil. The secondary objective was to identify any complications that occurred between August 30, 2002, and May 1, 2003, and determine the rate of significant drug–drug interactions. Secondary causes of dyslipidemia, such as uncontrolled diabetes, severe hypothyroidism, and use of various drugs (e.g., oral corticosteroids, beta-blockers, retinoids, oral estrogens), that may have resulted in the prescribing of lipid-lowering therapy were also noted.
Methods This retrospective chart review was approved by the University of Arizona Human Subjects Protection Committee and the Research and Development Committee of the affiliated VA Healthcare System. Patients received care at Southern Arizona VA Healthcare System—a tertiary care, university-affiliated facility. Records for patients with an active prescription for gemfibrozil at any dose and simvastatin at doses more than 10 mg daily as of August 30, 2002, were extracted from the mainframe computer system. The frequency of meeting ATP III criteria for combination therapy with a fibrate and statin was the primary endpoint. Secondary endpoints were the rate of significant drug–drug interactions with amiodarone, verapamil, erythromycin, or fluconazole and reasons for discontinuation between August 30, 2002, and May 1, 2003. Patients who had established care at our institution already prescribed combination therapy were not evaluated for the primary endpoint but were included to observe reasons for discontinuation. w w w.j a p h a . o r g
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Initiation of combination therapy, the prescribed doses, the lipid profile at initiation, and the prescribers’ recorded rationale for using combination therapy were identified by chart review. To accurately compare patients with ATP III guidelines, patient’s LDL cholesterol and non–HDL cholesterol goals were calculated since these values are not a part of the directly measured lipid profile. Secondary causes of dyslipidemia and other potential significant drug–drug interactions with simvastatin were also recorded. Secondary causes of dyslipidemia included uncontrolled diabetes (glycosylated hemoglobin [A1c] >8%), severe hypothyroidism (thyroid-stimulating hormone >10 µU/mL), and use of various drugs such as oral corticosteroids, beta-blockers, retinoids, and oral estrogens. Secondary causes of dyslipidemia alone were not a reason for failing to meet ATP III criteria for receiving combination therapy. Patients who had combination therapy prescribed at our institution were stratified into two groups: those who had therapy initiated before enrolling in our health care system and those whose therapy was started by a local VA prescriber. Subsequently, patients prescribed the combination locally were stratified according to which agent was added second, and then further stratified according to their lipid panel, before initiation of the second agent. Reasons for prescribing were then compared with ATP III guidelines. ATP III guidelines for fibrate–statin combination therapy
Combination therapy with a fibrate and a statin is considered appropriate according to ATP III guidelines in the following patient groups 9: n Triglycerides between 200 and 499 mg/L—LDL cholesterol remains the primary target of therapy in patients with high serum triglycerides. In addition, non–HDL cholesterol becomes a secondary target. A therapeutic goal for non–HDL cholesterol (total minus HDL cholesterol) can be 30 mg/dL higher than the goal for LDL cholesterol. When LDL cholesterol levels are not significantly elevated, the goal for non–HDL cholesterol with a triglyceride-lowering drug usually is within reach. Among these, nicotinic acid is usually the most effective. In patients with contraindications to nicotinic acid or when this drug is poorly tolerated, fibric acid derivatives reduce triglycerides by 40% to 60% and cause a 15% to 25% increase in HDL cholesterol concentrations. Nevertheless, fibrates often raise LDL cholesterol levels by 5% to 30%. This reciprocal increase in LDL cholesterol suggests that fibrates alone do not lower non–HDL cholesterol levels. Therefore, if fibrates are used, combining them with a statin is usually necessary to attain the non–HDL cholesterol goal. n Triglycerides >500 mg/L—Preventing acute pancreatitis is the first priority in patients with severe hypertriglyceridemia; a secondary goal is to reduce CHD risk. Reducing serum triglycerides to less than 500 mg/dL is often considered a successful outcome in patients with extremely high triglycerides. 142 • JAPhA • 4 7: 2 •
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n Isolated low HDL (triglycerides <200 mg/dL, HDL <40 mg/dL, and LDL at goal) —To improve the entire lipoprotein profile, combined use of an LDL-lowering drug with either a fibrate or nicotinic acid is an attractive option for high-risk patients with isolated low HDL.
Statistical analysis
The results are presented descriptively. All interval data are presented as mean ± 1 standard deviation.
Results A total of 103 patients were receiving combination therapy with gemfibrozil and simvastatin at doses of more than 10 mg daily as of August 30, 2002. Of these, 80 (78%) patients had combination therapy instituted by a local VA prescriber, and 23 (22%) patients were receiving continued combination therapy that was initiated at other institutions. Baseline characteristics of the 80 patients started on combination therapy are reported in Table 1. The majority of these patients (n = 61) had gemfibrozil prescribed after simvastatin. Simvastatin was added to gemfibrozil for 18 patients, and 1 individual had both therapies prescribed simultaneously. Overall, 56% of patients met ATP III criteria for receiving combination therapy with both a statin and a fibrate. For secondary causes of dyslipidemia, 9 of 80 patients (11%) had an A1c of more than 8% and none had severe hypothyroidism. Three patients were taking estrogen, and two of these patients had triglyceride levels of 500 mg/dL or more. In addition, 58 patients were prescribed a beta-blocker; however, only 12
Table 1. Baseline characteristics of study patients whose combination gemfibrozil–simvastatin therapy was instituted in the study facility (n = 80) Characteristics Values Age (years), mean ± SD 63 ± 9 Gender—no. men 76 Weight (kg), mean ± SD 97 ± 20 Comorbidities, no. patients (%) No CHD or diabetes 16 (20) Diabetes 15 (18.8) CHD 25 (31.3) CHD and diabetes 24 (30) Simvastatin doses, no. patients (%) 20 mg 42 (52.5) 40 mg 22 (27.5) 80 mg 16 (20) Second therapy added, no. patients (%) Gemfibrozil 61 (76.3) Simvastatin 18 (22.5) Both started simultaneously 1 (1.3) Abbreviation used: CHD, coronary heart disease.
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patients were on high doses of these drugs (≥100 mg daily of atenolol or equivalent), and 9 of them had triglyceride levels of 500 mg/dL or more. No complications were observed in any of the four patients receiving amiodarone, verapamil, erythromycin, or fluconazole. Gemfibrozil added to simvastatin therapy
Among the 61 patients for whom gemfibrozil was added to a simvastatin regimen, only two had isolated low HDL. One patient had diabetes and the other CHD; therefore, both met ATP III guidelines for the addition of gemfibrozil to simvastatin. Another 21 of these 61 patients had of serum triglyceride concentrations in the very high range (500 mg/dL or more), and 12 of these patients had other potential confounding factors that may have contributed to high triglycerides (Figure 1). The LDL cholesterol in these patients was unknown because direct measurements were not performed and calculations are not accurate when triglyceride levels exceed 400 mg/dL. In patients with very high hypertriglyceridemia, triglyceride lowering is the primary goal of therapy because of the possibility of pancreatitis; LDL lowering becomes a secondary goal. Thus, the prescribing rationale for these 21 patients was classified as not meeting ATP III guidelines because correcting hypertriglyceridemia was not the primary goal. Another 36 of these 61 patients had serum triglyceride levels between 200 and 499 mg/dL. LDL and non–HDL cholesterol are the primary treatment targets in these patients, and other causes of hypertriglyceridemia need evaluation. However, 3 patients (8%) had diabetes and A1c more than 8%, and 7 patients (19%) achieved their non–HDL goal before gemfibrozil was prescribed. According to ATP III guidelines, no further lipid-lowering therapy was required for the 7 patients who had attained their non–HDL goal. Thus, the prescribing rationale for these patients did not meet ATP III criteria. One (approximately
Research
1% of all patients evaluated) of these 7 patients died from rhabdomyolysis when gemfibrozil was added to simvastatin 80 mg daily when the LDL value was 58 mg/dL. Two remaining patients had gemfibrozil added to simvastatin therapy. One patient had an LDL cholesterol level <100 mg/dL, triglycerides of <200 mg/dL, and an HDL cholesterol of 45 mg/dL. The second patient had a triglyceride level of <200 mg/dL, an HDL cholesterol value of 32 mg/dL, and an LDL cholesterol level of 167 mg/dL. These two patients were also classified as not meeting ATP III criteria. Simvastatin added to gemfibrozil therapy
Eight patients whose triglycerides had exceeded 500 mg/dL were controlled to a lower triglyceride level when simvastatin was added to gemfibrozil (Table 2); this prescribing rationale was considered appropriate, based on ATP III criteria. In contrast, five patients with serum triglycerides that had always been lower than 500 mg/dL had simvastatin added to gemfibrozil. The prescribing rationale for these five patients did not meet ATP III criteria, which specify LDL lowering as the initial primary goal of therapy; the statin would be the preferred first-line agent, with gemfibrozil considered only after LDL cholesterol was treated to goal. Five patients who were taking gemfibrozil and for whom triglyceride status was unknown had established care at our institution. We could not determine whether these patients met ATP III criteria. Safety evaluation
Of the 103 patients prescribed the combination of gemfibrozil plus simvastatin in doses of more than 10 mg daily, 20 (19%) discontinued therapy (3 because of muscle aches; 2, upset stomach; 4, lack of efficacy; 1, increased serum transaminase values; 1, death from rhabdomyolysis as a direct result of the
21 patients with triglycerides >500 mg/dL
3 patients with diabetes mellitus and A1c >8%
7 patients taking beta-blockers in doses ≥100mg atenolol or equivalent
2 patients taking estrogen
Figure 1. Complicating factors among patients with very high serum triglyceride levels who had gemfibrozil added to simvastatin therapy Abbreviation used: A1c, glycosylated hemoglobin.
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Table 2. Presenting features of patients who had simvastatin added to gemfibrozil therapy (n = 18) Feature at time of initiation of simvastatin Triglycerides previously ≥500 mg/dL a Triglycerides previously <500 mg/dL Triglyceride status unknownb
No. patients 8 5 5
These patients meet Adult Treatment Panel (ATP) III criteria. Unable to determine whether patient meets ATP III criteria.
a b
combination; and 7, unknown) (Table 3). The patient who died as a result of rhabdomyolysis was prescribed the combination when his LDL cholesterol value was 58 mg/dL and triglycerides 327 mg/dL. The progress notes at the time of initiation of therapy reflected a need to aggressively lower triglycerides. According to ATP III criteria, the patient should not have received therapy because the non–HDL cholesterol targets already had been attained. The patient had previously been treated with simvastatin and gemfibrozil and had reported myalgias and stopped gemfibrozil on his own. The symptoms were noted in the progress notes, but unfortunately, a possible adverse drug reaction was not recorded in the medical record. After gemfibrozil was reinstituted, myalgias caused the patient to seek urgent care, and a diagnosis of acute sinusitis was made. The possible adverse reaction was not recognized, and the patient was treated with doxycycline and then trimethoprim/sulfamethoxazole by a non–VA practitioner. The patient also had atrial fibrillation and was treated with warfarin. Following completion of the trimethoprim/sulfamethoxazole course, the patient developed hemoptysis, and his international normalized ratio was found to be 13. He was admitted to the hospital to manage his hemorrhage. Although the patient had again stopped simvastatin and gemfibrozil combination therapy, the orders remained active in his chart and were reinstituted upon admission. Over a few days, the patient became progressively weaker and complained of myalgias. A creatine kinase value of more than 10,000 units/L was reported, and rhabdomyolysis was diagnosed. Although simvastatin and gemfibrozil were immediately stopped, the patient’s condition worsened. He developed acute renal failure, fulminant hepatitis, and respiratory failure. Despite efforts to correct these conditions, the patient died. Although this death cannot be unequivocally attributed to the combination of gemfibrozil–simvastatin therapy, the clinical course meets the criteria for a definite adverse drug reaction. Symptoms were temporally related to drug administration, having appeared during combination therapy, subsided upon dechallenge, and worsened during rechallenge. In addition, the patient’s clinical course was consistent with myopathy associated with the warning concerning use of this drug combination.
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Table 3. Reasons for discontinuation of one or both agents during combination gemfibrozil–simvastatin therapy (n = 20) Reasons for discontinuation Death Muscle aches Upset stomach Increased transaminases Prescriber deemed unnecessary Lack of efficacy Unknown
No. patients (%) 1 (1) 3 (2.9) 2 (1.9) 1 (1) 2 (1.9) 4 (3.9) 7 (6.8)
Discussion To our knowledge, this is the first study to examine prescribing criteria in patients receiving both gemfibrozil and a statin. Our retrospective chart review demonstrates that almost 45% patients who received gemfibrozil and simvastatin at doses of more than 10 mg daily did not meet ATP III guidelines for use of combination therapy. This finding has important medicolegal implications because the product labeling was changed in 2002 to reflect safety concerns with the combination of gemfibrozil and simvastatin. Many patients in this review had secondary causes of dyslipidemia that were not controlled, including approximately 11% having uncontrolled diabetes. Additionally, 19% of the patients on the combination stopped therapy for problems that were potentially related to these drugs. Three patients stopped taking the medications because of muscle aches, and another patient died because of rhabdomyolysis. This may underestimate the actual rate of myalgias because a majority of patients who were on combination therapy as of August 31, 2002, had been taking the combination for more than 1 year; these patients were more likely to tolerate the combination. However, we assessed simvastatin at doses more than 10 mg daily—a level at which the rate of myopathy and rhabdomyolysis is reported to be higher.16 In another retrospective review, Taher et al.18 reviewed the records of all patients referred to a cardiovascular risk reduction clinic over a 7.5-year period and identified 106 patients taking a statin–fibrate combination. During a mean follow-up of 18.5 months, 20% of patients discontinued combination therapy (8% because of myalgias). Various statins were examined in the Taher et al. study, and the discontinuation rate was similar to that of our study. Similar studies have reported a incidence of myopathy that is lower than the 8% reported by Taher et al.19–21 A recent systematic review22 examined all of the published safety data on statins, including cohort studies, randomized trials, voluntary notifications to regulatory authorities, and published case reports. The incidence of rhabdomyolysis in two cohort studies was 10 times greater when gemfibrozil was combined with statin therapy versus statin therapy alone (35 Jour nal of the A mer ican Phar macists A ssociation
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versus 3.4 per 100,000 person–years), and the case-fatality rate was 10%. As targets for lipid-lowering therapy become increasingly lower,23 combination therapy is often required to reach lipid goals. However, no large randomized controlled clinical trials have been conducted to support a decrease in any cardiovascular morbidity and mortality by targeting multiple endpoints of dyslipidemia therapy. Additionally, two recent trials that used HMG-CoA reductase inhibitors to achieve an LDL of around 70 mg/dL included patients with triglycerides of less than 600 mg/dL and excluded the use of any other lipid-lowering agents.24,25 Furthermore, evidence for treating high cholesterol with a fibrate plus a statin to reduce cardiovascular risk is not straightforward, and a major limitation of all fibrate trials is that efficacy is assessed in different populations. Hence, determining which lipid parameter to target, and to what goal, is difficult. The Bezafibrate Infarction Prevention Study Group6 treated patients with total cholesterol between 180 and 250 mg/dL, HDL cholesterol of 45 mg/dL or less, and triglycerides of 300 mg/dL or less with bezafibrate or placebo. There was no difference in the primary endpoint of fatal or nonfatal myocardial infarction or sudden death. A post hoc analysis showed that patients with triglyceride levels of more than 200 mg/dL had almost a 40% relative risk reduction in the primary endpoint; however, this has not been well investigated in subsequent trials. The Helsinki Heart Study26 investigated 4,081 men, without CHD and with a non–HDL cholesterol value of 200 mg/dL or more, who were randomized to gemfibrozil or placebo. Therapy resulted in a 34% relative risk reduction in the frequency of CHD after 5 years of treatment. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial3 evaluated 2,531 men with a history of CHD and isolated low HDL cholesterol (mean, 32 mg/dL). Patients were randomized to gemfibrozil 600 mg or placebo twice daily. Gemfibrozil resulted in a 22% relative risk reduction in nonfatal myocardial infarction and CHD-related death (P = 0.006). In a meta-analysis, Bucher et al.27 included all trials that reported mortality outcomes. In the fibrate trials, the overall risk ratio for death by CHD in treatment groups was 0.98 (95% CI 0.78–1.24), not a significant reduction. Post hoc analysis of previous studies has shown that patients with features of metabolic syndrome benefit most from fibrate therapy. As a result, the Fenofibrate Intervention and Event Lowering in Diabetes study28 was conducted to assess the effect of fenofibrate in 9,795 patients with diabetes aged 50 to 75 years. Patients with a total cholesterol concentration of 115 to 251 mg/dL and a total-to-HDL cholesterol ratio more than 4 or a plasma triglyceride value of 88 to 442 mg/dL were included. Of the patients enrolled 22% had cardiovascular disease. After a median follow-up of 5 years, no differences were observed for the combined primary endpoint of either nonfatal myocardial infarction or death from CHD.
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Limitations Because this study used a retrospective chart review method, we could not determine whether all patient-specific factors for combination therapy met current guidelines. Also, we did not determine whether patients with triglyceride values between 200 and 499 mg/dL had previously received niacin. ATP III guidelines recommend niacin as first-line treatment in this patient population, and the combination of niacin and a statin may have a lower risk of rhabdomyolysis. Because only adverse reactions occurring between August 30, 2002, and May 1, 2003, were captured and many patients had already received the combination for more than 1 year, the adverse reaction rate with fibric acid derivatives and HMG-CoA reductase inhibitors may have been lower than if we had considered only patients beginning therapy with the combination. However, we assessed simvastatin at doses (>10 mg daily) for which the rate of myopathy and rhabdomyolysis is reportedly higher.16
Conclusion In our clinical setting, gemfibrozil and simvastatin at doses of more than 10 mg daily frequently did not meet current guidelines. The FDA-approved product labeling for simvastatin was changed in 2002 to increase clinician awareness of the risk associated with this combination. Toxicity can be fatal, and the benefit and safety of combining lipid-lowering agents needs to be addressed in future clinical trials. Our study shows that many patients who are receiving combination therapy with simvastatin at doses more than 10 mg daily and gemfibrozil do not fit current consensus guidelines. Without any other compelling evidence with using this combination, patient safety may be compromised. We suggest that this combination therapy be carefully addressed in light of the lack of evidence supporting the therapy and the potential serious risks associated with higher doses of simvastatin. Although fenofibrate is less likely to cause a drug–drug interaction,29 these results suggest that the prescribing guidelines for combination therapy are often not followed. Pharmacists should seek to improve drug therapy safety and effectiveness by ensuring that this combination is appropriately prescribed. References
1. Scandinavian Simvastatin Survival Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–9. 2. Shepherd J, Cobb SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study. N Engl J Med. 1995;333:1301–7. 3. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410–8. 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;279:1615–22.
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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;339:1349–57. 6. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) Study. Circulation. 2000;102:21–7. 7. 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. 8. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998;97:1440–5. 9. Executive Summary of the 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). JAMA. 2001;285:2486–97. 10. Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–47. 11. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 1989;79:8–15. 12. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B–12B. 13. Assman G, Schulte H, Funke H, von Eckardstein A. The emergence of triglycerides as a significant independent risk factor in coronary artery disease. Eur Heart J. 1998;19(suppl M):M8–14.
14. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after atorvastatin with gemfibrozil. Am J Cardiol. 1998;81:368–9. 15. Van Puijenbroek EP, Du Buf-Vereijken PW, Spooren PF, Van Doormaal JJ. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. J Intern Med. 1996;240:403–4. 16. Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother. 2002;36:288– 95. 17. Zocor [package insert]. Whitehouse Station, N.J.: Merck; 2002. 18. Taher TH, Dzavik V, Reteff EM, et al. Tolerability of statin–fibrate and statin–niacin combination therapy in dyslipidemic patients at high risk for cardiovascular events. Am J Cardiol. 2002;89:390–4. 19. Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol. 1997;80:608–13. 20. Ellen RL, McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol. 1998:81(suppl):60B–65B. 21. Murdock DK, Murdock AK, Murdock RW, et al. Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J.1999;138:151–5. 22. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(suppl):52C–60C. 23. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227– 39.
St. Valentine’s Day Berries • Loveland, Ohio • February 2007 • Dennis Worthen, PhD
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Therapeutic rationale of combining therapy with gemfibrozil and simvastatin Patrick O. Curtin and William N. Jones
Received June 13, 2006, and in revised form October 6, 2006. Accepted for publication October 7, 2006.
Abstract
Objectives: To examine specific indications for patients receiving therapy with gemfibrozil plus simvastatin at doses of more than 10 mg daily and determine whether these patient-specific indications met Adult Treatment Panel (ATP) III criteria for combination therapy; and secondarily to identify any complications occurring between August 30, 2002, and May 1, 2003. Design: Retrospective cohort study. Setting: Tertiary care, university-affiliated, Southern Arizona Veterans Affairs Healthcare System from August 30, 2002, to May 1, 2003. Patients: 80 patients with active prescriptions for gemfibrozil at any dose and simvastatin at doses of more than 10 mg daily as of August 30, 2002; and 23 patients who had been prescribed this drug at other institutions. Intervention: Retrospective chart review. Main outcome measures: Frequency of meeting ATP III criteria for combination therapy with gemfibrozil and simvastatin was the primary outcome measure (primary). Results: Of the 80 patients, 45 (56%) met ATP III guidelines for combination therapy. Among the 80 patients started on these drugs at this VA facility, gemfibrozil was added to simvastatin in 61 patients, simvastatin was added to gemfibrozil in 18, and the agents were begun simultaneously for 1 patient. Common errors included combination treatment when LDL cholesterol values could not be calculated (because of serum triglycerides levels exceeding 400 mg/dL); use of gemfibrozil at triglyceride levels lower than the 500 mg/dL with attainment of non–HDL goals; and use of gemfibrozil when triglyceride levels were not measured. One death secondary to rhabdomyolysis occurred in a patient whose care did not meet ATP III guidelines. Conclusion: Combination therapy with simvastatin and gemfibrozil often did not meet ATP III standards. A higher risk of serious adverse events results from combining these drugs, and systems to improve adherence to guidelines may improve the safety of treating dyslipidemic patients. Keywords: Gemfibrozil, statins, dyslipidemias, adverse drug effects, rhabdomyolysis, Adult Treatment Panel III. J Am Pharm Assoc. 2007;47:140–146.
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Patrick O. Curtin, PharmD, BCPS, was Pharmacy Practice Resident, Southern Arizona Veterans Affairs (VA) Health Care System, Tucson, Ariz., at the time this study was conducted; he is currently Staff/Clinical Pharmacist, Department of Veterans Affairs, New Jersey Health Care System, East Orange, N.J. William N. Jones, MS, was Program Manager for Pharmacy Clinical Services, Southern Arizona VA Health Care System, Tucson, Ariz., at the time this study was conducted; he is currently Pharmacy Program Manager for Educational Development and Performance Improvement for the VA Pharmacy Benefits Management Strategic Healthcare Group, and Associate Clinical Professor of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson. Correspondence: Patrick O. Curtin, PharmD, Pharmacy Service (119), New Jersey VA Health Care System, East Orange, NJ 07018. Fax: 973-395-7157. E-mail: patrick. [email protected] Disclosure: Mr. Jones has received grant funding from Merck, Inc., to evaluate dyslipidemias in primary care clinics. The views expressed by the authors are their own and may not reflect those of the Department of Veterans Affairs. Previous presentations: 23rd Annual Western States Conference for Pharmacy Residents, Fellows, and Preceptors, Monterey, Calif., May 22, 2003, and the 2006 APhA Annual Meeting and Exposition, San Francisco, Calif., March 17–21, 2006.
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reating dyslipidemias decreases cardiovascular morbidity and mortality.1–8 Based on this evidence, guidelines were developed in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] III).9 The ATP III identified high low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol, and hypertriglyceridemia as independent risk factors for coronary heart disease (CHD) morbidity, and mortality3,6,10–13 and established specific LDL cholesterol, HDL cholesterol, and triglyceride goals in all patients.8 Different pharmacotherapeutic approaches may be combined to reach the desired endpoints for dyslipidemia. A 3-hydroxy-3-methylglutaryl (HMG)–coenzyme A (CoA) reductase inhibitor (statin) combined with a fibrate is one therapeutic option.
At a Glance Synopsis: In this retrospective chart review of 103 dyslipidemic patients in the Southern Arizona VA Healthcare System with active prescriptions for gemfibrozil and simvastatin in doses of more than 10 mg daily, the prescribing rationale for 44% of patients was not consistent with Adult Treatment Panel (ATP) III criteria. For example, in five patients with serum triglycerides already lower than 500 mg/dL, simvastatin was added to gemfibrozil. ATP III criteria state that the initial primary goal for patients in this category is LDL lowering; gemfibrozil should only be considered after LDL is treated to goal. Similarly, in 21 patients whose triglyceride levels had reached 500 mg/dL, gemfibrozil was added to simvastatin, but the statin perhaps could have been discontinued since hypertriglyceridemia is the primary goal of therapy at that point. Furthermore, LDL cholesterol values could not be calculated in these patients because of the high triglycerides, making it impossible for the clinician to know whether the statin was needed or not. Analysis: A higher risk of serious adverse events results from combining gemfibrozil and simvastatin, as highlighted by an FDA labeling revision to simvastatin in 2002. Myopathy and rhabdomyolysis occur at a higher rate with gemfibrozil–simvastatin combination therapy than with either agent alone. During the period reviewed in the current study, several patients discontinued therapy as a result of stomachaches and myalgias and one patient died from rhabdomyolysis. The finding that approximately 44% of patients’ therapy regimen for this combination did not meet ATP III guidelines suggests that measures should be undertaken to more closely follow established lipid treatment protocols and hence improve the cardiovascular outcomes of dyslipidemic patients.
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The ATP III guidelines state, with caveats, that a fibrate may be used in combination with a statin when triglycerides are between 200 and 499 mg/dL, triglycerides are at least 500 mg/ dL, and HDL cholesterol is less than 40 mg/dL.9 Despite these recommendations, no large randomized controlled trials support combination therapy with a statin and fibrate to decrease cardiovascular morbidity and mortality. However, an increased risk of myopathy and rhabdomyolysis with combination therapy that exceeds either agent alone has been reported.14–16 The Food and Drug Administration (FDA) approved labeling changes related to simvastatin in 2002.17 The new product labeling for simvastatin (Zocor—Merck) states that when the drug is combined with gemfibrozil, its daily dose should not exceed 10 mg. Furthermore, the labeling warns against combining simvastatin with fenofibrate or niacin at doses of 1 gram or more because myopathy may occur and careful assessment of the benefit-torisk ratios is necessary.
Objectives A 2002 FDA warning of statin-associated rhabdomyolysis lead to our primary objective: to examine whether patients in the Southern Arizona Veterans Affairs (VA) Healthcare System who were prescribed gemfibrozil and simvastatin at doses of more than 10 mg daily met ATP III recommendations for this combination. Fenofibrate was not included in the analysis because the warning was not as specific as that for gemfibrozil. The secondary objective was to identify any complications that occurred between August 30, 2002, and May 1, 2003, and determine the rate of significant drug–drug interactions. Secondary causes of dyslipidemia, such as uncontrolled diabetes, severe hypothyroidism, and use of various drugs (e.g., oral corticosteroids, beta-blockers, retinoids, oral estrogens), that may have resulted in the prescribing of lipid-lowering therapy were also noted.
Methods This retrospective chart review was approved by the University of Arizona Human Subjects Protection Committee and the Research and Development Committee of the affiliated VA Healthcare System. Patients received care at Southern Arizona VA Healthcare System—a tertiary care, university-affiliated facility. Records for patients with an active prescription for gemfibrozil at any dose and simvastatin at doses more than 10 mg daily as of August 30, 2002, were extracted from the mainframe computer system. The frequency of meeting ATP III criteria for combination therapy with a fibrate and statin was the primary endpoint. Secondary endpoints were the rate of significant drug–drug interactions with amiodarone, verapamil, erythromycin, or fluconazole and reasons for discontinuation between August 30, 2002, and May 1, 2003. Patients who had established care at our institution already prescribed combination therapy were not evaluated for the primary endpoint but were included to observe reasons for discontinuation. w w w.j a p h a . o r g
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Initiation of combination therapy, the prescribed doses, the lipid profile at initiation, and the prescribers’ recorded rationale for using combination therapy were identified by chart review. To accurately compare patients with ATP III guidelines, patient’s LDL cholesterol and non–HDL cholesterol goals were calculated since these values are not a part of the directly measured lipid profile. Secondary causes of dyslipidemia and other potential significant drug–drug interactions with simvastatin were also recorded. Secondary causes of dyslipidemia included uncontrolled diabetes (glycosylated hemoglobin [A1c] >8%), severe hypothyroidism (thyroid-stimulating hormone >10 µU/mL), and use of various drugs such as oral corticosteroids, beta-blockers, retinoids, and oral estrogens. Secondary causes of dyslipidemia alone were not a reason for failing to meet ATP III criteria for receiving combination therapy. Patients who had combination therapy prescribed at our institution were stratified into two groups: those who had therapy initiated before enrolling in our health care system and those whose therapy was started by a local VA prescriber. Subsequently, patients prescribed the combination locally were stratified according to which agent was added second, and then further stratified according to their lipid panel, before initiation of the second agent. Reasons for prescribing were then compared with ATP III guidelines. ATP III guidelines for fibrate–statin combination therapy
Combination therapy with a fibrate and a statin is considered appropriate according to ATP III guidelines in the following patient groups 9: n Triglycerides between 200 and 499 mg/L—LDL cholesterol remains the primary target of therapy in patients with high serum triglycerides. In addition, non–HDL cholesterol becomes a secondary target. A therapeutic goal for non–HDL cholesterol (total minus HDL cholesterol) can be 30 mg/dL higher than the goal for LDL cholesterol. When LDL cholesterol levels are not significantly elevated, the goal for non–HDL cholesterol with a triglyceride-lowering drug usually is within reach. Among these, nicotinic acid is usually the most effective. In patients with contraindications to nicotinic acid or when this drug is poorly tolerated, fibric acid derivatives reduce triglycerides by 40% to 60% and cause a 15% to 25% increase in HDL cholesterol concentrations. Nevertheless, fibrates often raise LDL cholesterol levels by 5% to 30%. This reciprocal increase in LDL cholesterol suggests that fibrates alone do not lower non–HDL cholesterol levels. Therefore, if fibrates are used, combining them with a statin is usually necessary to attain the non–HDL cholesterol goal. n Triglycerides >500 mg/L—Preventing acute pancreatitis is the first priority in patients with severe hypertriglyceridemia; a secondary goal is to reduce CHD risk. Reducing serum triglycerides to less than 500 mg/dL is often considered a successful outcome in patients with extremely high triglycerides. 142 • JAPhA • 4 7: 2 •
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n Isolated low HDL (triglycerides <200 mg/dL, HDL <40 mg/dL, and LDL at goal) —To improve the entire lipoprotein profile, combined use of an LDL-lowering drug with either a fibrate or nicotinic acid is an attractive option for high-risk patients with isolated low HDL.
Statistical analysis
The results are presented descriptively. All interval data are presented as mean ± 1 standard deviation.
Results A total of 103 patients were receiving combination therapy with gemfibrozil and simvastatin at doses of more than 10 mg daily as of August 30, 2002. Of these, 80 (78%) patients had combination therapy instituted by a local VA prescriber, and 23 (22%) patients were receiving continued combination therapy that was initiated at other institutions. Baseline characteristics of the 80 patients started on combination therapy are reported in Table 1. The majority of these patients (n = 61) had gemfibrozil prescribed after simvastatin. Simvastatin was added to gemfibrozil for 18 patients, and 1 individual had both therapies prescribed simultaneously. Overall, 56% of patients met ATP III criteria for receiving combination therapy with both a statin and a fibrate. For secondary causes of dyslipidemia, 9 of 80 patients (11%) had an A1c of more than 8% and none had severe hypothyroidism. Three patients were taking estrogen, and two of these patients had triglyceride levels of 500 mg/dL or more. In addition, 58 patients were prescribed a beta-blocker; however, only 12
Table 1. Baseline characteristics of study patients whose combination gemfibrozil–simvastatin therapy was instituted in the study facility (n = 80) Characteristics Values Age (years), mean ± SD 63 ± 9 Gender—no. men 76 Weight (kg), mean ± SD 97 ± 20 Comorbidities, no. patients (%) No CHD or diabetes 16 (20) Diabetes 15 (18.8) CHD 25 (31.3) CHD and diabetes 24 (30) Simvastatin doses, no. patients (%) 20 mg 42 (52.5) 40 mg 22 (27.5) 80 mg 16 (20) Second therapy added, no. patients (%) Gemfibrozil 61 (76.3) Simvastatin 18 (22.5) Both started simultaneously 1 (1.3) Abbreviation used: CHD, coronary heart disease.
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patients were on high doses of these drugs (≥100 mg daily of atenolol or equivalent), and 9 of them had triglyceride levels of 500 mg/dL or more. No complications were observed in any of the four patients receiving amiodarone, verapamil, erythromycin, or fluconazole. Gemfibrozil added to simvastatin therapy
Among the 61 patients for whom gemfibrozil was added to a simvastatin regimen, only two had isolated low HDL. One patient had diabetes and the other CHD; therefore, both met ATP III guidelines for the addition of gemfibrozil to simvastatin. Another 21 of these 61 patients had of serum triglyceride concentrations in the very high range (500 mg/dL or more), and 12 of these patients had other potential confounding factors that may have contributed to high triglycerides (Figure 1). The LDL cholesterol in these patients was unknown because direct measurements were not performed and calculations are not accurate when triglyceride levels exceed 400 mg/dL. In patients with very high hypertriglyceridemia, triglyceride lowering is the primary goal of therapy because of the possibility of pancreatitis; LDL lowering becomes a secondary goal. Thus, the prescribing rationale for these 21 patients was classified as not meeting ATP III guidelines because correcting hypertriglyceridemia was not the primary goal. Another 36 of these 61 patients had serum triglyceride levels between 200 and 499 mg/dL. LDL and non–HDL cholesterol are the primary treatment targets in these patients, and other causes of hypertriglyceridemia need evaluation. However, 3 patients (8%) had diabetes and A1c more than 8%, and 7 patients (19%) achieved their non–HDL goal before gemfibrozil was prescribed. According to ATP III guidelines, no further lipid-lowering therapy was required for the 7 patients who had attained their non–HDL goal. Thus, the prescribing rationale for these patients did not meet ATP III criteria. One (approximately
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1% of all patients evaluated) of these 7 patients died from rhabdomyolysis when gemfibrozil was added to simvastatin 80 mg daily when the LDL value was 58 mg/dL. Two remaining patients had gemfibrozil added to simvastatin therapy. One patient had an LDL cholesterol level <100 mg/dL, triglycerides of <200 mg/dL, and an HDL cholesterol of 45 mg/dL. The second patient had a triglyceride level of <200 mg/dL, an HDL cholesterol value of 32 mg/dL, and an LDL cholesterol level of 167 mg/dL. These two patients were also classified as not meeting ATP III criteria. Simvastatin added to gemfibrozil therapy
Eight patients whose triglycerides had exceeded 500 mg/dL were controlled to a lower triglyceride level when simvastatin was added to gemfibrozil (Table 2); this prescribing rationale was considered appropriate, based on ATP III criteria. In contrast, five patients with serum triglycerides that had always been lower than 500 mg/dL had simvastatin added to gemfibrozil. The prescribing rationale for these five patients did not meet ATP III criteria, which specify LDL lowering as the initial primary goal of therapy; the statin would be the preferred first-line agent, with gemfibrozil considered only after LDL cholesterol was treated to goal. Five patients who were taking gemfibrozil and for whom triglyceride status was unknown had established care at our institution. We could not determine whether these patients met ATP III criteria. Safety evaluation
Of the 103 patients prescribed the combination of gemfibrozil plus simvastatin in doses of more than 10 mg daily, 20 (19%) discontinued therapy (3 because of muscle aches; 2, upset stomach; 4, lack of efficacy; 1, increased serum transaminase values; 1, death from rhabdomyolysis as a direct result of the
21 patients with triglycerides >500 mg/dL
3 patients with diabetes mellitus and A1c >8%
7 patients taking beta-blockers in doses ≥100mg atenolol or equivalent
2 patients taking estrogen
Figure 1. Complicating factors among patients with very high serum triglyceride levels who had gemfibrozil added to simvastatin therapy Abbreviation used: A1c, glycosylated hemoglobin.
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Table 2. Presenting features of patients who had simvastatin added to gemfibrozil therapy (n = 18) Feature at time of initiation of simvastatin Triglycerides previously ≥500 mg/dL a Triglycerides previously <500 mg/dL Triglyceride status unknownb
No. patients 8 5 5
These patients meet Adult Treatment Panel (ATP) III criteria. Unable to determine whether patient meets ATP III criteria.
a b
combination; and 7, unknown) (Table 3). The patient who died as a result of rhabdomyolysis was prescribed the combination when his LDL cholesterol value was 58 mg/dL and triglycerides 327 mg/dL. The progress notes at the time of initiation of therapy reflected a need to aggressively lower triglycerides. According to ATP III criteria, the patient should not have received therapy because the non–HDL cholesterol targets already had been attained. The patient had previously been treated with simvastatin and gemfibrozil and had reported myalgias and stopped gemfibrozil on his own. The symptoms were noted in the progress notes, but unfortunately, a possible adverse drug reaction was not recorded in the medical record. After gemfibrozil was reinstituted, myalgias caused the patient to seek urgent care, and a diagnosis of acute sinusitis was made. The possible adverse reaction was not recognized, and the patient was treated with doxycycline and then trimethoprim/sulfamethoxazole by a non–VA practitioner. The patient also had atrial fibrillation and was treated with warfarin. Following completion of the trimethoprim/sulfamethoxazole course, the patient developed hemoptysis, and his international normalized ratio was found to be 13. He was admitted to the hospital to manage his hemorrhage. Although the patient had again stopped simvastatin and gemfibrozil combination therapy, the orders remained active in his chart and were reinstituted upon admission. Over a few days, the patient became progressively weaker and complained of myalgias. A creatine kinase value of more than 10,000 units/L was reported, and rhabdomyolysis was diagnosed. Although simvastatin and gemfibrozil were immediately stopped, the patient’s condition worsened. He developed acute renal failure, fulminant hepatitis, and respiratory failure. Despite efforts to correct these conditions, the patient died. Although this death cannot be unequivocally attributed to the combination of gemfibrozil–simvastatin therapy, the clinical course meets the criteria for a definite adverse drug reaction. Symptoms were temporally related to drug administration, having appeared during combination therapy, subsided upon dechallenge, and worsened during rechallenge. In addition, the patient’s clinical course was consistent with myopathy associated with the warning concerning use of this drug combination.
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Table 3. Reasons for discontinuation of one or both agents during combination gemfibrozil–simvastatin therapy (n = 20) Reasons for discontinuation Death Muscle aches Upset stomach Increased transaminases Prescriber deemed unnecessary Lack of efficacy Unknown
No. patients (%) 1 (1) 3 (2.9) 2 (1.9) 1 (1) 2 (1.9) 4 (3.9) 7 (6.8)
Discussion To our knowledge, this is the first study to examine prescribing criteria in patients receiving both gemfibrozil and a statin. Our retrospective chart review demonstrates that almost 45% patients who received gemfibrozil and simvastatin at doses of more than 10 mg daily did not meet ATP III guidelines for use of combination therapy. This finding has important medicolegal implications because the product labeling was changed in 2002 to reflect safety concerns with the combination of gemfibrozil and simvastatin. Many patients in this review had secondary causes of dyslipidemia that were not controlled, including approximately 11% having uncontrolled diabetes. Additionally, 19% of the patients on the combination stopped therapy for problems that were potentially related to these drugs. Three patients stopped taking the medications because of muscle aches, and another patient died because of rhabdomyolysis. This may underestimate the actual rate of myalgias because a majority of patients who were on combination therapy as of August 31, 2002, had been taking the combination for more than 1 year; these patients were more likely to tolerate the combination. However, we assessed simvastatin at doses more than 10 mg daily—a level at which the rate of myopathy and rhabdomyolysis is reported to be higher.16 In another retrospective review, Taher et al.18 reviewed the records of all patients referred to a cardiovascular risk reduction clinic over a 7.5-year period and identified 106 patients taking a statin–fibrate combination. During a mean follow-up of 18.5 months, 20% of patients discontinued combination therapy (8% because of myalgias). Various statins were examined in the Taher et al. study, and the discontinuation rate was similar to that of our study. Similar studies have reported a incidence of myopathy that is lower than the 8% reported by Taher et al.19–21 A recent systematic review22 examined all of the published safety data on statins, including cohort studies, randomized trials, voluntary notifications to regulatory authorities, and published case reports. The incidence of rhabdomyolysis in two cohort studies was 10 times greater when gemfibrozil was combined with statin therapy versus statin therapy alone (35 Jour nal of the A mer ican Phar macists A ssociation
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versus 3.4 per 100,000 person–years), and the case-fatality rate was 10%. As targets for lipid-lowering therapy become increasingly lower,23 combination therapy is often required to reach lipid goals. However, no large randomized controlled clinical trials have been conducted to support a decrease in any cardiovascular morbidity and mortality by targeting multiple endpoints of dyslipidemia therapy. Additionally, two recent trials that used HMG-CoA reductase inhibitors to achieve an LDL of around 70 mg/dL included patients with triglycerides of less than 600 mg/dL and excluded the use of any other lipid-lowering agents.24,25 Furthermore, evidence for treating high cholesterol with a fibrate plus a statin to reduce cardiovascular risk is not straightforward, and a major limitation of all fibrate trials is that efficacy is assessed in different populations. Hence, determining which lipid parameter to target, and to what goal, is difficult. The Bezafibrate Infarction Prevention Study Group6 treated patients with total cholesterol between 180 and 250 mg/dL, HDL cholesterol of 45 mg/dL or less, and triglycerides of 300 mg/dL or less with bezafibrate or placebo. There was no difference in the primary endpoint of fatal or nonfatal myocardial infarction or sudden death. A post hoc analysis showed that patients with triglyceride levels of more than 200 mg/dL had almost a 40% relative risk reduction in the primary endpoint; however, this has not been well investigated in subsequent trials. The Helsinki Heart Study26 investigated 4,081 men, without CHD and with a non–HDL cholesterol value of 200 mg/dL or more, who were randomized to gemfibrozil or placebo. Therapy resulted in a 34% relative risk reduction in the frequency of CHD after 5 years of treatment. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial3 evaluated 2,531 men with a history of CHD and isolated low HDL cholesterol (mean, 32 mg/dL). Patients were randomized to gemfibrozil 600 mg or placebo twice daily. Gemfibrozil resulted in a 22% relative risk reduction in nonfatal myocardial infarction and CHD-related death (P = 0.006). In a meta-analysis, Bucher et al.27 included all trials that reported mortality outcomes. In the fibrate trials, the overall risk ratio for death by CHD in treatment groups was 0.98 (95% CI 0.78–1.24), not a significant reduction. Post hoc analysis of previous studies has shown that patients with features of metabolic syndrome benefit most from fibrate therapy. As a result, the Fenofibrate Intervention and Event Lowering in Diabetes study28 was conducted to assess the effect of fenofibrate in 9,795 patients with diabetes aged 50 to 75 years. Patients with a total cholesterol concentration of 115 to 251 mg/dL and a total-to-HDL cholesterol ratio more than 4 or a plasma triglyceride value of 88 to 442 mg/dL were included. Of the patients enrolled 22% had cardiovascular disease. After a median follow-up of 5 years, no differences were observed for the combined primary endpoint of either nonfatal myocardial infarction or death from CHD.
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Limitations Because this study used a retrospective chart review method, we could not determine whether all patient-specific factors for combination therapy met current guidelines. Also, we did not determine whether patients with triglyceride values between 200 and 499 mg/dL had previously received niacin. ATP III guidelines recommend niacin as first-line treatment in this patient population, and the combination of niacin and a statin may have a lower risk of rhabdomyolysis. Because only adverse reactions occurring between August 30, 2002, and May 1, 2003, were captured and many patients had already received the combination for more than 1 year, the adverse reaction rate with fibric acid derivatives and HMG-CoA reductase inhibitors may have been lower than if we had considered only patients beginning therapy with the combination. However, we assessed simvastatin at doses (>10 mg daily) for which the rate of myopathy and rhabdomyolysis is reportedly higher.16
Conclusion In our clinical setting, gemfibrozil and simvastatin at doses of more than 10 mg daily frequently did not meet current guidelines. The FDA-approved product labeling for simvastatin was changed in 2002 to increase clinician awareness of the risk associated with this combination. Toxicity can be fatal, and the benefit and safety of combining lipid-lowering agents needs to be addressed in future clinical trials. Our study shows that many patients who are receiving combination therapy with simvastatin at doses more than 10 mg daily and gemfibrozil do not fit current consensus guidelines. Without any other compelling evidence with using this combination, patient safety may be compromised. We suggest that this combination therapy be carefully addressed in light of the lack of evidence supporting the therapy and the potential serious risks associated with higher doses of simvastatin. Although fenofibrate is less likely to cause a drug–drug interaction,29 these results suggest that the prescribing guidelines for combination therapy are often not followed. Pharmacists should seek to improve drug therapy safety and effectiveness by ensuring that this combination is appropriately prescribed. References
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14. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after atorvastatin with gemfibrozil. Am J Cardiol. 1998;81:368–9. 15. Van Puijenbroek EP, Du Buf-Vereijken PW, Spooren PF, Van Doormaal JJ. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. J Intern Med. 1996;240:403–4. 16. Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother. 2002;36:288– 95. 17. Zocor [package insert]. Whitehouse Station, N.J.: Merck; 2002. 18. Taher TH, Dzavik V, Reteff EM, et al. Tolerability of statin–fibrate and statin–niacin combination therapy in dyslipidemic patients at high risk for cardiovascular events. Am J Cardiol. 2002;89:390–4. 19. Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol. 1997;80:608–13. 20. Ellen RL, McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol. 1998:81(suppl):60B–65B. 21. Murdock DK, Murdock AK, Murdock RW, et al. Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J.1999;138:151–5. 22. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(suppl):52C–60C. 23. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227– 39.
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