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Metformin and Thiazolidinedione Use in Medicare Patients With Heart Failure
Frederick A. Masoudi, MD, MSPH;
Yongfei Wang, MS;
Silvio E. Inzucchi, MD;
John F. Setaro, MD;
Edward P. Havranek, MD;
JoAnne M. Foody, MD;
Harlan M. Krumholz, MD, SM
JAMA. 2003;290:81-85.
ABSTRACT
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Context According to package inserts, metformin is contraindicated in diabetic patients receiving drug treatment for heart failure therapy, and thiazolidinediones are not recommended in diabetic patients with symptoms of advanced heart failure. Little is known about patterns of use of these antihyperglycemic drugs in diabetic patients with heart failure.
Objective To determine the proportions of patients hospitalized with heart failure and concomitant diabetes treated with metformin or thiazolidinediones.
Design Serial cross-sectional measurements using data from retrospective medical record abstraction.
Setting Nongovernmental acute care hospitals in the United States.
Patients Two nationally representative samples of Medicare beneficiaries hospitalized with the primary diagnosis of heart failure and concomitant diabetes between April 1998 and March 1999 and between July 2000 and June 2001.
Main Outcome Measures The prescription of either metformin or a thiazolidinedione at hospital discharge.
Results In the 1998-1999 sample (n = 12 505), 7.1% of patients were discharged with a prescription for metformin, 7.2% with a prescription for a thiazolidinedione, and 13.5% with a prescription for either drug. In the 2000-2001 sample (n = 13 158), metformin use increased to 11.2%, thiazolidinedione use to 16.1%, and use of either drug to 24.4% (P<.001 for all comparisons). Similar increases were seen among patients of all age groups, all races, and both sexes.
Conclusions The use of metformin and thiazolidinediones is common and has increased rapidly in Medicare beneficiaries with diabetes and heart failure in direct contrast with explicit warnings against this practice by the Food and Drug Administration. Further studies to establish the safety and effectiveness of this practice are needed to ensure optimal care of patients with diabetes and heart failure.
INTRODUCTION
Although diabetes and heart failure commonly coexist, the treatment of diabetes in patients with both conditions is complicated because the popular oral insulin sensitizers are not recommended for treatment of patients with moderate-to-severe heart failure. According to the package insert, metformin is contraindicated in all patients with "heart failure requiring pharmacologic treatment" because of the increased risk of potentially lethal lactic acidosis.1 Thiazolidinediones are not recommended for patients with "New York Heart Association class III or IV status" because these agents expand intravascular volume and may exacerbate heart failure.2-3 Despite these strong admonitions, limited data suggest that metformin is often prescribed in patients with contraindications.4-6
Our objective was to determine the rates of prescription of these medications in a contemporary national sample of Medicare patients discharged after hospitalization for heart failure. Given the high prevalence of diabetes among populations with heart failure, this represents an unexplored area with significant potential implications for the safety of patients with both conditions.
METHODS
The National Heart Care Project
The National Heart Care Project is a Centers for Medicare & Medicaid Services initiative to improve the quality of care for Medicare beneficiaries hospitalized with heart failure. This project included the construction of 2 cross-sectional samples of Medicare fee-for-service beneficiaries hospitalized with a principal discharge diagnosis of heart failure (International Classification of Diseases, Ninth Revision, Clinical Modification codes 402.01, 402.11, 402.91, 404.01, 404.91, or 428). This method of case identification is considered specific for heart failure.7
The first sample was obtained between April 1998 and March 1999 and the second between July 2000 and June 2001. All identified discharges during a 6-month period within each of the sampling frames within each of the 50 states, Washington, DC, and Puerto Rico were sorted by age, sex, race, and treating hospital. In each state, up to 800 records were selected; a census of records was obtained in states with fewer than 800 eligible records. Records were reviewed in central clinical data abstraction centers for demographic characteristics, medical history, laboratory evaluations, and medications taken at admission and prescribed at discharge. Data quality was ensured through the use of trained reviewers, electronic abstraction instruments, and record reabstraction.
Study Sample
The initial samples included 39 477 records from 1998-1999 and 39 405 records from 2000-2001. Patients without valid social security numbers, those undergoing long-term hemodialysis, and those transferred to another hospital or who left against medical advice were excluded. Only patients with the diagnosis of diabetes in the hospital record were included. Patients younger than 65 years and those not surviving hospitalization were excluded. After applying these criteria, samples of 12 505 records from 1998-1999 and 13 158 records from 2000-2001 were analyzed.
Medications
A complete list of admission and discharge medications was abstracted from the records. Patients prescribed insulin-sensitizing agents at discharge were categorized in nonexclusive groups, including treatment with (1) metformin (Glucophage and Glucophage XR; Bristol-Myers Squibb, New York, NY), (2) thiazolidinediones, or (3) either agent. The only thiazolidinedione available on the US market during the first sampling period was troglitazone (Rezulin; Parke-Davis, a division of Warner-Lambert Co, Morris Plains, NJ). Although the manufacturer withdrew this medication from the US market because of fatalities due to hepatic failure in March 2000, this was between the sampling periods. By the beginning of the second sampling period, both rosiglitazone (Avandia; GlaxoSmithKline, Research Triangle Park, NC, approved in May 1999) and pioglitazone hydrochloride (Actos; Takeda, Lincolnshire, Ill, approved in July 1999) were available for use in the United States.
Medication use was assessed in subgroups of patients by demographic characteristics and cardiovascular history. Because renal insufficiency (defined in the metformin package insert as a serum creatinine level of ≥1.5 mg/dL [≥133 µmol/L] in men or ≥1.4 mg/dL [≥124 µmol/L] in women) is also considered an absolute contraindication to metformin use,1 prescription patterns in patients with and without renal insufficiency using this definition were also assessed. The creatinine measurement closest to discharge was used to define renal insufficiency.
Other drug prescriptions at admission and discharge were also examined. To determine the proportion of new prescriptions for metformin and thiazolidinediones, admission use of both medications was assessed. Because metformin is contraindicated in patients with heart failure requiring drug therapy,1 patterns of prescription of drugs commonly used to treat heart failure were assessed. Because fluid retention with thiazolidinediones is more common in patients also treated with insulin,2-3 use of oral agents was also assessed according to concomitant insulin prescription at discharge.
Statistical Analysis
The proportions of patients treated with different classes of antihyperglycemic agents were calculated for both samples. To account for the National Heart Care Project sampling design and to estimate the national prevalence of medication use, probability weights, based on inverse sampling fraction for each state, were applied. Bivariate comparisons between treatment proportions between the 2 samples were calculated using the Wald  2 test for categorical variables. All statistical analyses were performed with SAS 8.2 statistical software (SAS Institute Inc, Cary, NC).
RESULTS
Metformin and Thiazolidinedione Prescription
The characteristics of the patients in the 2 samples are shown in Table 1. In 1998-1999, 7.1% of diabetic patients were treated with metformin at hospital discharge (Table 2). By 2000-2001, metformin was prescribed to 11.2% of diabetic patients, a relative increase of 61% (P<.001). Use in 2000-2001 increased significantly in patients of all age groups and other strata studied (Table 2). Although physicians prescribed metformin less frequently for patients with elevated serum creatinine levels, metformin was used in 4.4% of patients with renal insufficiency in 1998-1999; this increased to 6.7% by 2000-2001.
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Table 1. Clinical Characteristics of Diabetic Patients in the National Heart Care Project Baseline (1998-1999) and Remeasurement (2000-2001) Cohorts
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Table 2. Weighted Percentages of Diabetic Patients Treated With Metformin and/or Thiazolidinediones*
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Patterns of use of thiazolidinediones during 1998-1999 were similar to those of metformin. In the remeasurement sample, however, thiazolidinedione prescriptions increased to 16.1%, representing a relative increase of 124% (P<.001). By 2000-2001, the use of these agents increased significantly in all patient strata.
By 2000-2001, 24.4% of all patients and more than 20% of patients in nearly all strata were treated with either medication. Exceptions included patients older than 85 years (16.6% treated with either drug) and those with severe left ventricular systolic dysfunction (18.8%).
Admission Medications and Other Discharge Prescriptions
Most patients discharged with a prescription for metformin were taking this medication at admission (88% in 1998-1999 and 87% in 2000-2001, Table 3). At discharge, 98% of patients treated with metformin were also prescribed at least one drug commonly used for the treatment of heart failure. More than half of these patients treated were also discharged with a prescription for a sulfonylurea in both periods.
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Table 3. Admission and Discharge Medications of Diabetic Patients Discharged With a Prescription for Metformin, a Thiazolidinedione, or Neither of the Insulin Sensitizers (Weighted Percentages)
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Similarly, more than 80% of patients discharged with a thiazolidimedione prescription were taking a medication in this class at admission. Although concomitant insulin use decreased between sampling frames, 41% of patients discharged with a thiazolidinedione prescription were also discharged with an insulin prescription in 2000-2001. In contrast, concomitant sulfonylurea prescription at discharge among these patients increased from 35% in 1998-1999 to 40% in 2000-2001.
COMMENT
In this study of nationally representative samples of hospitalized heart failure patients with diabetes, the use of antihyperglycemic agents not recommended in the package insert in this setting was widespread. This practice nearly doubled between 1998-1999 and 2000-2001, reflecting increasing popularity and familiarity with these agents by prescribing physicians. Use of these drugs in patient populations at particularly high risk for adverse events (ie, metformin with renal dysfunction or thiazolidinediones with insulin) also increased.
According to the prescribing information approved by the US Food and Drug Administration (FDA), metformin is contraindicated in patients with heart failure requiring drug therapy and thiazolidinediones are not recommended for patients with advanced heart failure.1-3 There are several possible explanations for the discordance between these recommendations and the findings of this study. First, some physicians may not be aware of the potential risks of prescribing these medications to patients with heart failure. Second, clinicians may believe that the importance of glucose control overrides the potential risks or that the risks in well-compensated heart failure are reduced. In the case of metformin, this perception may be in part attributable to the "black box" warning, which states that "patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk for lactic acidosis."1 Finally, physicians may believe that the risks of these drugs are overestimated. Ultimately, however, the assessment of drug safety should emerge from rigorous studies. Therefore, additional data are urgently needed to clarify the optimal approach to the treatment of diabetes in patients with heart failure.
The safety concerns surrounding metformin result from its association with life-threatening lactic acidosis. Although the risk of this complication is reportedly low in general populations (between 2 and 10 per 100 000 person-years of treatment), these precautions for metformin likely reflect reports of higher risks in patients with heart failure and renal insufficiency.8-13
A recent systematic review by the Cochrane Collaboration13 of 176 clinical studies with more than 35 000 patient-years of follow-up identified no cases of lactic acidosis. Although some of the studies in this review permitted the inclusion of patients with cardiovascular conditions and renal insufficiency, there was inadequate information to estimate the risk of lactic acidosis in these high-risk subgroups. The current recommendations for metformin use may stem not only from the uncertainty surrounding the risk of lactic acidosis in patients with heart failure but also from experience with phenformin hydrochloride, which was withdrawn from the market due to a relatively high risk of lactic acidosis.
The recognition of the potential hazards of fluid retention due to thiazolidinediones in patients with heart failure has increased over time. The original package insert for troglitazone included a statement that use in patients with advanced heart failure symptoms should be considered only if the perceived benefits of treatment outweighed the potential risks.14 The package inserts for rosiglitazone and pioglitazone were changed in 2000 to include a specific caution to avoid use in patients with class III and IV heart failure unless the benefit was judged to outweigh the risk.15 In response to postmarketing events, the FDA strengthened this precaution to a warning in April 2002.16
Because fluid retention with thiazolidinedione use is not accompanied by decreased left ventricular systolic performance,17 the clinical relevance of this phenomenon is not clear. A recent series from a single heart failure clinic found that although 17% of patients taking thiazolidinediones developed significant fluid retention after initiation of therapy, this was manifested as peripheral edema and usually resolved promptly with discontinuation of use of the drug.18
Both metformin and thiazolidinediones exert positive effects on cardiovascular risk factors.17, 19-20 Metformin also decreases the risk of macrovascular events in overweight patients with newly diagnosed diabetes.21 Despite these potential advantages, however, the FDA does not support the current patterns of use of insulin sensitizers in patients with diabetes and coexisting heart failure. Until further data clarify the safety and effectiveness of these medications in patients with heart failure, clinicians must practice contrary to explicit recommendations or use a more limited armamentarium in the treatment of diabetes in patients with heart failure.
National guidelines do not focus extensively on the treatment of diabetes in heart failure patients. The guidelines for diabetes treatment by the American Diabetes Association mention that both metformin and thiazolidinediones are not recommended in many patients with heart failure.22 The American College of Cardiology/American Heart Association guidelines for the treatment of heart failure mention that thiazolidinediones should be "used with caution" in patients with heart failure but do not note the metformin contraindication.23 Future guidelines should provide more explicit guidance in defining the safe treatment of diabetes in patients with heart failure. Greater clinical safety data would provide a stronger basis for such recommendations.
Because all patients in this study were hospitalized, we cannot characterize patterns of prescription of insulin sensitizers in a broader range of patients with heart failure and diabetes. Patients hospitalized with heart failure, however, are likely at higher risk for complications from these medications than are ambulatory patients.
Because New York Heart Association classification is not recorded consistently and reliably in hospital records, it is not possible to determine the clinician's assessment of the patient's functional status, which is relevant to the use of thiazolidinediones. However, patients with New York Heart Association class I or II symptoms are unlikely to be hospitalized for heart failure.
In conclusion, this study demonstrates that elderly, diabetic patients hospitalized with heart failure are commonly treated with antihyperglycemic drugs that are not recommended for patients with moderate-to-severe heart failure. There is a need for all parties interested in safe diabetes treatment to increase awareness of the recommended approach to diabetes in patients with heart failure. Further studies are needed to establish whether these drugs can be used safely and effectively in patients with heart failure. Other important questions for future study include whether patients with heart failure and normal systolic function are at the same risk for adverse events as those with reduced systolic function and whether the optimization of heart failure therapy may allow the safe use of these agents in some patient groups.
AUTHOR INFORMATION
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Corresponding Author and Reprints: Harlan M. Krumholz, MD, Yale University School of Medicine, 333 Cedar St, Room I-456 SHM, PO Box 208088, New Haven, CT 06520-8088 (e-mail: harlan.krumholz{at}yale.edu).
Author Contributions: Study concept and design: Masoudi, Inzucchi, Setaro, Foody, Krumholz.
Acquisition of data: Masoudi, Havranek, Krumholz.
Analysis and interpretation of data: Masoudi, Wang, Inzucchi, Setaro, Krumholz.
Drafting of the manuscript: Masoudi, Setaro.
Critical revision of the manuscript for important intellectual content: Wang, Inzucchi, Setaro, Havranek, Foody, Krumholz.
Statistical expertise: Masoudi, Wang, Setaro, Foody.
Obtained funding: Masoudi.
Administrative, technical, or material support: Setaro, Havranek, Krumholz.
Study supervision: Inzucchi, Krumholz.
Funding/Support: Dr Masoudi is supported by NIH Research Career Award K08-AG01011. The analyses on which this publication is based were performed under contract 500-02-CO 01 entitled "Utilization and Quality Control Peer Review Organization for the State of Colorado" sponsored by the Centers for Medicare and Medicaid Services, Department of Health and Human Services.
Disclaimer: The content of the publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The authors assume full responsibility for the accuracy and completeness of the ideas presented. This article is a direct result of the Health Care Quality Improvement Program initiated by the Centers for Medicare and Medicaid Services, which has encouraged indentification of quality improvement projects from analysis of patterns of care, and therefore required no special funding on the part of this contractor.
Author Affiliations: Division of Cardiology, Department of Medicine, Denver Health Medical Center (Drs Masoudi and Havranek), and Divisions of Cardiology (Drs Masoudi and Havranek) and Geriatric Medicine (Dr Masoudi), Department of Medicine, University of Colorado Health Sciences Center, Denver; Colorado Foundation for Medical Care, Aurora (Drs Masoudi, Havranek, and Krumholz); Sections of Cardiovascular Medicine (Drs Setaro, Foody, and Krumholz and Mr Wang) and Endocrinology (Dr Inzucchi), Department of Medicine, and Section of Health Policy and Administration, Department of Epidemiology and Public Health (Dr Krumholz), Yale University School of Medicine, and Center for Outcomes Research and Evaluation, Yale-New Haven Hospital (Dr Krumholz), New Haven, Conn.
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