(CDN) $3,128 (range 1,149-21,293) per patient. Conclusions: The management of serious cutaneous and hy- persensitivity ADRs due to AEDs is associated ...
Epiiepsia, 39(Suppl. 7):S27-S32, 1998 Lippincott Williams & Wilkins, Philadelphia 0 International League Against Epilepsy
Quantifying the Costs of Serious Adverse Drug Reactions to Antiepileptic Drugs *Raymond G. Schlienger, *Paul I. Oh, *Sandra R. Knowles, and *?Neil H. Shear Divisions of “Clinical Pharmacology and fDermatology, Department of Medicine and Pharmacology, Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario, Canada
Summary: Purpose: We assessed from an institutional perspective the direct costs of severe adverse cutaneous or hypersensitivity reactions due to antiepileptic drug (AED) therapy that led to hospitalization or prolonged hospital stay. Methods: Patients admitted for or developing severe AEDinduced cutaneous or hypersensitivity reactions while in hospital from January 1990 through June 1996 were identified by ICD-9 codes E936, E937, E693, E695.1, E995.1, and E995.2. Identified cases were analyzed retrospectively by chart review and were included in the analysis if a causal relationship was determined to be possible, probable, or definite. Clinical outcomes were abstracted and related direct costs of the adverse drug reactions (ADRs) calculated. Results: A total of 384 cases were identified by ICD-9 codes, of which 13 cases (mean age f SD 52.9 f 21.0 years) were
included for further analysis. Eight patients (62%) were admitted because of an ADR (median length of stay 9.5 days; range 4-43), five (38%) experienced an ADR during hospitalization (median duration of ADR episodes 8.5 days; range: 7-21 days). The median direct medical costs of the ADRs were Canadian (CDN) $3,128 (range 1,149-21,293) per patient. Conclusions: The management of serious cutaneous and hypersensitivity ADRs due to AEDs is associated with considerable direct medical costs. These figures should be considered along with drug acquisition costs and treatment of clinical successes and failures in the overall assessment of the economic impact of pharmacotherapy. Prospective collection of direct costs associated with ADRs in clinical trials would be of value. Key Words: Antiepileptic drugs-Adverse drug reactionsSkin-Hypersensitivity-Costs .
To accurately reflect the total management costs, pharmacoeconomic analyses should include the evaluation of costs related to negative outcomes of pharmacotherapy such as adverse drug reactions (ADRs). Like any type of illness, ADRs may require treatment ranging from minor symptomatic care to very expensive, intensive hospitalization or support for the victim for the rest of his or her life (1). In addition to direct medical costs attributable to an ADR (e.g., costs for diagnosis and treatment, physician fees, hospitalization), potential disability, loss of employment, or death are all associated with significant additional indirect, nonmedical costs. The antiepileptic drugs (AEDs) phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), and valproate (VPA) are effective for the treatment of partial and generalized tonic-clonic seizures (2).CBZ and VPA are also effective in the management of psychiatric diseases such as bipolar disorders (3,4). However, the therapeutic benefit of these AEDs may be limited by potentially severe
ADRs. The most common ADRs involve the central n&rvous system (e.g., somnolence, nystagmus, ataxia) and the skin (most often exanthematous rashes) (5,6). More severe drug-induced skin reactions, such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), may also develop (5). Such severe cutaneous reactions to AEDs are rare, occurring in less than 1% of patients treated (5,7-9). It has been estimated that one in 450 adult patients treated with CBZ requires admission to the hospital because of a cutaneous reaction (lo). A rash may also be a marker of a severe systemic reaction, the ‘‘AED hypersensitivity syndrome” (AHS), which is characterized by the triad of fever, skin rash, and single or multiorgan system involvement (e.g., hepatitis, blood dyscrasias, nephritis) (1 1). In a recent cohort study, the risk for this syndrome in first-time users of PHT or CBZ was estimated at 2.3-4.5/10,000 and 1-4.1/10,000 patients, respectively (12). However, up to 3 1% of patients receiving AED therapy may complain of one or more ADRs, as shown in a recent multicenter survey. More than half of these reactions were considered to be clinically significant, and hospital admission
Address correspondence and reprint requests to Dr. N. H. Shear at Division of Clinical Pharmacology, Room E-240, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5.
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R. G. SCHLIENGER ET AL.
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was required in 8.3% of the patients with an AEDassociated ADR (6). Newer AEDs such as gabapentin (GBP), lamotrigine (LTG), vigabatrin (VGB), and felbamate (FBM) have been approved as add-on drugs in adults with partial seizures or secondarily generalized seizures ( 13,14). However, as with the older agents, severe ADRs, such as SJS or TEN with LTG or aplastic anemia and fatal liver reactions with FBM, have been reported (14). In a recent cost-minimization analysis from the United Kingdom comparing VGB, LTG, and GBP as add-on therapy in patients with partial seizures, ADRs were estimated to be responsible for 0.9-6.3% of the total direct costs of treatment in the first year of use (15). Studies determining the direct economic consequences associated with severe cutaneous or hypersensitivity reactions due to AEDs are lacking. In this study we evaluated the clinical outcomes of these reactions and their related direct costs from a hospital perspective.
METHODS Sunnybrook Health Science Centre (SHSC) is a 1,300bed teaching hospital, affiliated with the University of Toronto, Ontario, Canada, which provides primary and tertiary care. It serves a catchment area with an estimated population of approximately 235,OQO. At the time of our study the hospital had no burn unit and did not serve as a specific referral center for patients with SJS or TEN. Patients hospitalized from January 1990 through June 1996 with an ADR potentially associated with AED therapy, and patients who experienced such a reaction during their hospital stay, were identified by a medical records database search using ICD-9 codes E936 and E937 [drugs, medicinal and biologic substances causing adverse effects in therapeutic use including AEDs and anti-Parkinson drugs (E936) and sedatives and hypnotics (E937)] (16). To increase the number of potential cases, we also reviewed the hospital records for the ICD-9 codes E693 (dermatitis due to drugs), E695.1 (erythema multiforme, SJS, TEN), E995.1 (ADR unspecified), and E995.2 (allergy unspecified). Charts of patients identified by these codes were analyzed retrospectively. Patients were included who were identified as having been hospitalized for an AEDinduced cutaneous or hypersensitivity reaction in whom the causal relationship was assessed as either definite, probable, or possible. Patients identified as having an AED-induced reaction during their hospital stay were included if the ADR was classified either as a severe cutaneous reaction (defined as EM, SJS, or TEN) or as an AHS reaction (defined as rash with fever and single or multiple organ involvement), or if they experienced any cutaneous or hypersensitivity reaction leading to an estimated prolongation of their hospital stay of at least 3
days. The causal relationship had to be assessed as either definite, probable, or possible. Causality assessment was performed using a validated 10-item rating system for ADRs (17). The clinical details of the cases were abstracted (demographics, seizure history, associated conditions, drug exposure, details and time course of reaction) along with specific items representing hospital resource utilization (drugs, physician visits, laboratory tests, radiology). Costing of the entire admission was achieved through the hospital accounting system (Transition Systems Incorporated) with a breakdown of costs by department [nursing (including costs for nursing, hospital bed, and overhead costs), laboratory, and pharmacy (including drug costs and pharmacy operational costs)]. For patients admitted for an AED-induced ADR, the costs for the event were equated with the costs for their entire hospital stay. For patients who experienced an AED-induced ADR during hospitalization for another condition (e.g., neurosurgery for brain tumor), the costs associated with the reaction were derived as the proportion of the hospitalization attributable to the ADR over the total length of stay. Costs for nursing were estimated by dividing the total costs for nursing by the ratio between the length of the hospital stay and the length of the ADR episode. Costs for physicians (including specialist consultations and physician costs for patients with follow-up visits as outpatients), costs for laboratory tests, drugs, noninvasive and invasive procedures for the duration of the ADR were abstracted from the patient charts and from the accounting system. Costs were estimated in Canadian Dollars (CDN 8). Measures to adjust for inflation during the study period were not taken into account. Descriptive statistics were used to analyze the data.
RESULTS A total of 384 cases with either a single or a combination of several of the ICD-9 codes E936 or E937 (12.5%), E693 (46.6%). E695.1 (5.5%). E995.1 or E995.2 (24.2%), or a combination of E936/937 with one of the other codes ( 11.2%), were identified. In 82 cases (21%) the reaction was potentially associated with the use of an AED. Of these, 69 cases were excluded for the following reasons: no increase in the length of stay in patients who developed the reaction during hospitalization (48%); the reported ADR was neither a cutaneous nor a hypersensitivity reaction (46%); and no causal relationship with the AED (6%). We were therefore left with a sample of 13 cases with AED-associated severe cutaneous or hypersensitivity ADRs, highlighting the fact that these severe events occur infrequently. The mean age (+SD) of these patients was 52.9 years (+21.0 years); 62% were females. Eight patients (62%) were
S29
COSTS OF ADVERSE REACTIONS TO AEDS
hospitalized because of an AED-induced ADR; five (38%) experienced an AED-induced ADR during their hospital stay. None of the reactions was fatal. In seven patients the reaction was associated with PHT, in three with VPA, in two with CBZ, and in one with combined PHT and CBZ (Table 1). Nine patients were receiving long-term therapy with AEDs (two for bipolar disorders, seven for seizure disorders); four patients received shortterm prophylactic therapy. On average, ADR diagnosis and treatment provoked 54.4 laboratory tests (e.g., electrolytes, liver function tests, uredcreatinine), 1.7 specialist consultations, 0.5 noninvasive procedures (x-ray, CT scan), 0.2 invasive procedures (skin biopsy), and 3.7 drug treatments (number of drugs and different dosage forms of the same therapeutic class used for the treatment of the ADR) per case. The calculated total costs that resulted from AED-induced severe cutaneous or hypersensitivity ADRs during the study period of 78 months was CDN $71,518, of which CDN $44,426 (62%) was attributable to ADRs leading to hospitalization and CDN $27,092 (38%) to reactions that occurred during hospitalization. Hence, the mean costs for AEDinduced severe reactions at our institution during the study period were CDN $11,003 per year. The median length of stay for patients admitted for an ADR was 9.5 days. The median duration of ADR episodes in patients who experienced a reaction during hospitalization was 8.5 days. The median direct medical cost for severe cutaneous and hypersensitivity reactions to AEDs was CDN $3,128 (Table 2). The most important cost-driving component was the costs associated with nursing (including room charges and overhead costs), which were responsible for almost two-thirds of the total costs. A more detailed breakdown of costs is presented in Table 3.
DISCUSSION In two recent United States studies from 1993 and 1995, the direct costs of medication-related problems, such as ADRs and medication errors, at two universityaffiliated hospitals were estimated to be almost U.S. $1.1 million and U.S. $1.5 million per year, respectively (18,19). In another recent United States study in a 520bed teaching hospital, the additional hospital costs for patients with ADRs during hospitalization were estimated to be almost U.S. $3.2 million during the study period of 4 years (20). In the present study the total direct costs for severe cutaneous or hypersensitivity reactions caused by AEDs at our institution averaged CDN $11,003 (=US. $8,032) per year. This is a relatively small figure compared to the aforementioned studies, but we calculated only the costs related to severe ADRs of one specific therapeutic group, whereas in all of the above-mentioned evaluations the objective was to calculate the total costs associated with ADRs in general. We equated the direct medical costs for patients admitted because of an ADR with the costs for their entire hospital stay. In some of these patients this might have led to a overestimation of the costs related to the ADR because of costs associated with concurrent diseases and their drug therapies. However, because nursing and laboratory costs directly associated with the ADRs were the main cost factors, additional costs induced by therapies for other co-morbidities were regarded as minor. Calculation of costs for patients who experience a reaction during hospitalization is more difficult to estimate. It is often hard to assess if and how much a reaction really contributed to additional hospital days, especially when the underlying disease is severe. Therefore, our approach
TABLE 1. Characteristics of 13 patients hospitalized or with prolonged hospital stay due to severe cutaneous or hypersensitivity ADRs induced by AEDs Patient
Age
Sex
Indication for AED
AED
1"
28
F
Prophylaxis after neurosurgery
Phenytoin
2"
38
F
Prophylaxis after neurosurgery
Carbamazepine
3
16
F
Bipolar disorder
Valproate
4 5" 6" 7" 8" 9 10" 11 12" 13
20 72 59 67 78 65 69 70 46 60
F M M F M M F F M M
Bipolar disorder Prophylaxis due to brain metastases Prophylaxis due to brain metastases Generalized seizures Seizures secondary to stroke Prophylaxis after neurosurgery Idiopathic seizure disorder Postoperative seizures Seizures secondary to brain metastases Seizures secondary to CNS lymphoma
Valproate Phenytoin Carbamazepine Phenytoin Valproate Phenytoin Phenytoidcarbamazepine Phenytoin Phenytoin Phenytoin
ADR AHS (rash, fever, facial edema, lymphadenopathy, hepatitis , increased WBC) AHS (erythema, fever, generalized lymphadenopathy, facial edema, anemia) AHS (exanthematous rash, fever, cholestatic hepatitis, facial edema) Cholestatic hepatitis EM Generalized rash Rash, fever, lethargy Rash A H S (rash, fever, increased AST) Hepatitis Rash SJS Rash
Hospitalized because of AED-induced ADR. AHS, antiepileptic drug hypersensitivity syndrome; ADR, adverse drug reaction: AST, aspartate aminotransferase: EM, erythema multiforme; SJS, Stevens-Johnson syndrome; WBC, white blood cell count: AED, antiepileptic drug. LI
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R. G. SCHLIENGER ET AL. TABLE 2. Length of stay, length of ADR episode during hospitalization, and total direct costs for patients admitted for an AED-induced ADR and patients who experienced an ADR during hospitalization
LOS (days) Mean f SD Median Range Duration of ADR episode during hospitalization (days) Mean f SD Median Range Total direct costs (CDN$)" Mean f SD Median Range
ADRs leading to hospitalization (n = 8)
ADRs during hospitalization (n = 5)
All ADRs (n = 13)
14.6 12.9 9.5 4-43
31.4f 18.8 25 16-60
21.1 16.9 16 4-60
14.6 r 12.9 9.5 4-43
10.4 f 6.0 8 7-2 1
13.0 f 10.7 8 443
5,553 f 6,638 2,780 1,149-21.293
5,419 f 4,147 3,806 2.693-12.687
5,501 5 5,607 3,128 1,149-2 1,293
aCosts are expressed in Canadian dollars (CDN $1.00 = U.S. $0.73 at 1996 exchange rates). LOS, length of stay; ADR, adverse drug reaction; AED, antiepileptic drug.
to calculate the nursing costs for patients experiencing an ADR during their stay by relating the length of the ADR episode to the overall length of stay may overestimate the actual costs. To precisely evaluate additional direct costs for an AED-induced ADR occurring during hospitalization, comparison with a sex-, age-, and diseasematched control group with no evidence of either an adverse drug event or a nosocomialinfection during hospitalization would have been informative, but this was
not feasible. In the study by Evans et al. (19), it was estimated that patients who experienced an ADR during hospitalization had their stay increased by 1.94 days compared to control patients, and ADRs accounted for additional costs of U.S. $1,939 in affected patients. Similar results were found by Classen and colleagues (20), in which the mean attributable excess hospital costs were found to be U.S. $2,013 with an excess length of stay of 1.74 days. For a subset of cases with severe ADRs, the
TABLE 3. Breakdown of costs for 13 patients with AED-induced ADRs leading to hospitalization or prolonged hospital stay
Type of costa Nursing, bed charges, overheads Mean f SD Median % total costs Physicians Mean & SD Median % total costs Lab test Mean f SD Median % total costs Noninvasive procedures Mean f SD Median % total costs Invasive procedures Mean f SD Median % total costs Pharmacy Mean f SD Median % total costs
ADR leading to hospitalization (n = 8)
ADR during hospitalization (n = 5)
All ADRs (n = 13)
3,064 f 3,127 1,953 55.1
4,496 2 3,085 3,393 83.0
3,615 2 3,066 2,733 65.7
486 f 336 358 8.8
344 f 248 259 6.4
431 f 302 331 7.8
1,149* 1,818 337 20.7
250 2 420 85 4.6
803 i 1.481 265 14.6
*
37 72 0 0.7
23 f 32 0 0.4
31 *59 0 0.6
11 f 3 0 0 0.2
17 i 38 0 0.3
13 f 32 0 0.2
807 f 1,367 416 14.5
Costs are expressed in Canadian dollars (CDN $1.00 AED, antiepileptic drug; ADR, adverse drug reaction.
a
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=
289 434 114 5.3 U.S. $0.73 at 1996 exchange rates).
608 f 1,105 211 11.1
COSTS OF ADVERSE REACTIONS TO AEDS
attributable length of stay was 3.6 days and the costs of hospitalization averaged U.S. $3,634. This cost of severe ADRs is close to the findings of our study, although we focused only on severe reactions to AEDs. In the same study by Classen and colleagues (20), the excess costs associated with each individual type of ADR, based on the major symptoms, were evaluated. For example fever, itching, or rash-symptoms we frequently observed in our patients with AED-induced reactions-were associated with estimated additional costs of U.S. $9,022, U.S. $677, and U.S. $1,868, respectively. The attributable length of stay for these reactions was 5.5, 0.7, and 1.4 days, respectively (20). Although severe cutaneous or hypersensitivity reactions associated with AEDs are rare and the individual costs associated with such reactions, as found in our study, are far from negligible, the impact on the overall therapy costs (including costs associated with ADRs) for patients receiving long-term AED treatment are probably minor. On the other hand, in 31% of our patients the AED therapy was used as a short-term prophylaxis after neurosurgery or cranial radiation. In this subgroup of patients, the high costs associated with severe AEDinduced ADRs may indeed have a major effect on the overall therapy costs. Severe reactions to AEDs are rare. In general, however, ADRs during AED therapy are not uncommon. In addition to potentially increasing the morbidity and therefore also influencing the quality of life, minor or moderate reactions also may give rise to additional costs (e.g., costs for diagnosis of the adverse event, additional drug therapy, therapeutic drug monitoring after switching to another AED), and hence would have an impact on the overall therapy costs. The finding that the ADRs analyzed in our study were, without exception, associated with older AEDs probably reflects the fact that some of the newer drugs were not marketed throughout our study period, and therefore their usage frequency was low compared to that of older AEDs. With the increasing use of newer drugs, the ADR pattern found in our study would probably change. LTG, for example, is associated with the AHS and with severe cutaneous adverse reactions (2 1-25). However, as yet there are no data regarding costs associated with such reactions for this newer AED. As suggested in a recent editorial by Dukes (26), any monetary measure of the adverse effects of drugs is to some extent artificial and incomplete. Our study has some limitations as well. The economic techniques used to identify the overall costs of illness involve determining the direct and indirect costs borne by the community. The direct costs of ADRs consist of the cost of treatment, hospitalization, avoidance (i.e., action taken to prevent ADRs), and detection (i.e., action taken to diagnose ADRs). Avoidance of costs is often omitted from calcu-
S31
lations because such costs are likely to be small in proportion to the other items (1). Because there is no general therapy to counteract and avoid some potential AEDinduced ADRs (in contrast to potassium supplements for patients being treated with thiazide diuretics or hematologic growth factors to prevent chemotherapy-induced neutropenia), costs for avoidance of ADRs were not included in our evaluation. The ADR-related costs we found in this study are specific to our institution, and therefore extrapolation of the results to other settings may be inaccurate. Our results nevertheless give an estimate of the type of resources consumed and the magnitude of the direct medical costs associated with the types of reactions analyzed in our study. We included only costs for patients hospitalized because of a severe cutaneous or hypersensitivity ADR or who experienced such an ADR during their hospital stay at our institution. We did not include the costs of the referring physician and preliminary evaluation because of the difficulty of obtaining such data in a retrospective review. Because serious hypersensitivity or cutaneous ADRs usually result in hospitalization, we believe that the contribution of such outpatient physician visits to the costs of serious reactions would be only minimal. Furthermore, we calculated only the direct costs and did not include indirect costs, such as the days lost from work and the implied temporary or permanent loss of productivity or the loss of the salaries of affected patients. These components would have greatly increased the cost impact. In conclusion, our study shows that the management of serious cutaneous or hypersensitivity ADRs to AEDs is related to considerable direct medical costs. These figures should be considered, along with the costs associated with drug acquisition, delivery, and treatment of all clinical successes and failures, in the overall assessment of the economic impact of a pharmacotherapy. Prospective collection of ADR-associated direct costs in clinical trials would be of value. Acknowledgments: This study was supported in part by Ciba-Geigy Canada, Ltd. Raymond G. Schlienger was supported by a grant from the Swiss National Science Foundation. Presented in part at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 5, 1997, San Diego, CA.
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