|Safety and cost of low-molecular-weight heparin as bridging anticoagulant therapy in subacute cerebral ischemia
|Kalafut M A, Gandhi R, Kidwell C S, Saver J L
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
The use of a subcutaneous injection of low molecular weight heparin (LMWH) as a bridging anticoagulant therapy for patients with acute and subacute cerebral ischaemia. Patients received enoxaparin (1 mg/kg twice daily), and warfarin was initiated on the same day as the start of LMWH therapy. If patients could be discharged, LMWH was continued at home or in a rehabilitation centre.
Economic study type
The study population comprised patients with cerebral ischaemia. The inclusion criteria considered the clinical diagnosis of transient ischaemic attack or cerebral infarction, and the wish of the attending neurologist to pursue a treatment plan of acute followed by chronic anticoagulation. Patients with a medical condition requiring treatment with IV-UFH were excluded, as were those with active bleeding or anaemia. Also excluded were patients who had undergone a major operation in the last 24 hours, those with uncontrolled hypertension (systolic blood pressure >220 mmHg or diastolic blood pressure >120 mmHg), those with renal, hepatic, respiratory, or cardiac failure, and those with hypersensitivity to heparin compounds. Other characteristics for exclusion were known or suspected infectious endocarditis, pregnancy and coma.
The setting was a hospital. The economic study was carried out in the USA.
Dates to which data relate
The effectiveness and resource use data were gathered from 1996 to 1997 for IV-UFH patients, and from 1997 to 1999 for LMWH patients. The price year was not explicitly reported.
Source of effectiveness data
The effectiveness evidence was derived from a single study.
Link between effectiveness and cost data
The costing was performed on the same sample of patients as that used in the effectiveness study, but it was unclear whether it was carried out prospectively or retrospectively.
Power calculations were not reported. LMWH patients were identified among consecutive eligible individuals who were treated at the study institution from 1997 to 1999, when LMWH was in use. Overall, 24 patients were identified. These had a mean age of 66 years (age range: 40 - 92) and 50% were female. A sample of 24 IV-UFH patients was identified among consecutive eligible individuals who were treated at the study institution from 1996 to 1997, when only IV-UFH was in use. These patients had a mean age of 69 years (age range: 29 - 90) and 54% were female. A total of 79% of patients in the LMWH group and 75% of patients in the IV-UFH group suffered from a stroke, while 21% (LMWH) and 25% (IV-UFH) suffered from a transient ischaemic attack.
This was a comparative study with historical control, which was carried out at the Los Angeles Stroke Unit of the University of California. It was unclear whether the LMWH patients were evaluated prospectively or retrospectively. The length of follow-up was not reported. No patient was lost to the follow-up assessment.
Analysis of effectiveness
All of the patients included in the initial study sample were accounted for in the analysis of the effectiveness. The outcome measures used were:
starting days for LMWH or IV-UFH and warfarin;
patterns of transition to warfarin and time to achievement of a therapeutic international normalised ratio (INR);
the incidence of adverse events;
the proportion of patients receiving physical and occupational therapy; and
the duration of physical and occupational therapy.
The study groups were comparable at baseline in terms of demographic and clinical characteristics. However, thrombolytic treatment (tissue plasminogen activator) was more common among LMWH patients than among IV-UFH patients (21% versus 0%; p=0.018).
IV-UFH was started on average on hospital day 1.3 (range: 0 -o 9), while warfarin was begun on hospital day 2.1 (range: 0 - 10). LMWH was started on average on day 2.2 (range: 0 - 9) and post-symptom onset day 4.9 (range: 0 - 30), while warfarin was begun on hospital day 2 (range: 0 - 9).
Warfarin was initiated with a 10-mg loading dose in 80% of IV-UFH patients and 67% of LMWH patients. Sixty-seven per cent of IV-UFH patients and 46% of LMWH patients received their 10-mg loading doses of warfarin on both their first and second days.
In the IV-UFH group, 96% of patients completed transition to warfarin while on the acute hospital services, with one patient discharged to a rehabilitation service while on heparin. The mean interval from start of warfarin to achievement of a therapeutic INR was 3.3 days (range: 2 - 9; one patient never achieved a therapeutic INR before discharge). Ten patients had INRs of less than 2.0 on the day of heparin discontinuation. In 63% of patients, hospital stay was extended solely because of a need to complete the IV-UFH transition to oral warfarin, and the mean extended stay was 2.4 days (range: 1 - 4). Of the 169 total days of hospitalisation, 21% were only for transitional IV-UFH.
In the LMWH group, 15 received only LMWH as an injectable anticoagulant, while 9 patients received IV-UFH acutely before the treatment plan was formulated and LMWH and warfarin were begun. Fifty-four per cent of patients were discharged home while still receiving LMWH, 8% were discharged to rehabilitation on LMWH, and 38% completed transition to warfarin on the acute hospital service. The mean interval from the start of warfarin to achievement of a therapeutic INR was 4.4 days (range: 1 - 20). Twenty-nine per cent of patients had INRs of less than 2.0 on the day of LMWH discontinuation. Among the 15 patients who received LMWH as outpatients, the mean duration of enoxaparin therapy was 3.6 days (range: 1 - 15). Ninety-six per cent of patients initiated on LMWH bridging therapy completed transition to warfarin while still on LMWH; enoxaparin was discontinued in one patient who experienced worsening of neurological deficit.
The total number of adverse events was 3 in the LMWH group and 20 in the IV-UFH group, (p<0.01). The number of patients who experienced adverse events was 3 (12.5%) in the LMWH group and 9 (37.5%) in the IV-UFH group, (p<0.05). In particular, fewer patients had worsening of their neurological deficit, transiently or permanently, in the LMWH group compared with the IV-UFH group (2 versus 8; p=0.033).
The proportion of patients receiving physical and occupational therapy was 88% (started on average on hospital day 4.3) in the IV-UFH group and 58% (started on average on hospital day 4.2) in the LMWH group. The duration of physical and occupational therapy was 2.9 days (range: 1 - 10) in the IV-UFH group and 1.8 days (range: 1 - 6) in the LMWH group.
The effectiveness analysis showed that fewer adverse events were experienced in LMWH patients than in IV-UFH patients. Similarly, a shorter hospital stay was associated with LMWH therapy.
Measure of benefits used in the economic analysis
The health outcomes were left disaggregated and no summary benefit measure was used in the economic analysis. In effect, a cost-consequences analysis was carried out.
Discounting was not relevant since the costs were incurred during a short timeframe. The unit costs were presented, but information on the resource use data was less clear. The health services included in the economic evaluation were drugs, laboratory monitoring, hospital bed, and home nursing visits. The cost/resource boundary of the study was not reported. The costs were obtained from the hospital administration. The resource use data were derived from the sample of patients included in the clinical study. The price year was not reported. A further analysis estimated the costs that would have been incurred had a conservative strategy of a minimum of 5 days of IV-UFH or LMWH warfarin overlap been followed in all patients.
Statistical analysis of costs
The costs were treated deterministically.
The indirect costs were not considered in the economic evaluation.
Sensitivity analyses were not performed.
Estimated benefits used in the economic analysis
See the 'Effectiveness Results' section.
The total costs were $53,541 in the IV-UFH group and $51,136 in the LMWH group. In the IV-UFH group, hospital expenses accounted for 96.9% of all costs, laboratory monitoring accounted for 2.9% of costs, and heparin drug expenses accounted for 0.5% of costs. In the LMWH group, hospital expenses accounted for 86% of all costs, home nursing visits accounted for 2.9% of costs, and enoxaparin drug expenses accounted for 11% of costs.
In the hypothetical scenario where all patients in the LMWH group used IV-UFH, LMWH was associated with cost-savings of $865 per patients. Such savings were entirely accrued from the sub-set of patients discharged while still receiving LMWH. If a more conservative strategy of a minimum of 5 days of IV-UFH or LMWH warfarin overlap had been followed in all patients, then LMWH would have been associated with net savings of $1,654 per patient.
Synthesis of costs and benefits
A synthesis of the costs and benefits was not relevant since a cost-consequences analysis was performed.
Low molecular weight heparin (LMWH) was an effective, safe and efficient alternative to conventional intravenous unfractionated heparin (IV-UFH) for bridging anticoagulation therapy to warfarin in patients with acute and subacute cerebral ischaemia.
CRD COMMENTARY - Selection of comparators
The selection of the comparator (IV-UFH) was appropriate as it reflected the conventional approach for bridging patients from heparin to oral warfarin. Enoxaparin was selected as a possible LMWH. You should decide whether IV-UFH is a valid comparator in your own setting.
Validity of estimate of measure of effectiveness
The effectiveness evidence came from a comparative study with a historical control. It was unclear whether patients in the intervention group were recruited prospectively, or had been identified retrospectively. The two groups of patients were evaluated in two different periods of time and the impact of time-related bias was not investigated, although the authors noted that differences in treatment groups could have been due to temporal changes in stroke care occurring between the two study periods. The study groups were quite comparable at baseline. Details of the length of follow-up were not provided. No evidence about the appropriateness of the sample size was provided. In fact, the study sample was quite small, which was consistent with the pilot nature of the study. The evidence came from a single centre and the authors did comment on how representative the study sample was.
Validity of estimate of measure of benefit
No summary benefit measure was used in the analysis because a cost-consequences analysis was conducted. Please refer to the comments above in the 'Validity of estimate of measure of effectiveness' field.
Validity of estimate of costs
The authors did not state explicitly which perspective was adopted in the study. It was noted that some payers could not reimburse outpatient enoxaparin. Only the direct costs were included in the analysis and the unit costs were presented. However, limited information on resource consumption was provided. A hypothetical cost scenario was considered. The price year was not reported, which makes reflation exercises in other settings difficult. The costs were treated deterministically and economic estimates were specific to the study setting. No sensitivity analyses were performed.
The authors did not make extensive comparisons of their findings with those from other studies. The issue of the generalisability of the study results to other settings was not addressed and sensitivity analyses were not carried out. This reduces the external validity of the analysis. The study referred to patients with acute and subacute cerebral ischaemia and this was reflected in the authors' conclusions. The authors noted that a possible limitation to the validity of the study was the different techniques used to monitor adverse events in the LMWH and IV-UFH groups.
Implications of the study
The study results suggested that using LMWH for bridging anticoagulation therapy to warfarin in patients with cerebral ischaemia was feasible, potentially safer, and cheaper than IV-UFH. A prospective, randomised, clinical trial should be undertaken to corroborate the findings of the current analysis in populations of patients with stroke sub-types for which there was clear evidence that long-term anticoagulation was achieved.
Source of funding
Supported in part by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (grant K24 NS 02092-01), and by a fellowship grant from the American Heart Association.
Kalafut M A, Gandhi R, Kidwell C S, Saver J L. Safety and cost of low-molecular-weight heparin as bridging anticoagulant therapy in subacute cerebral ischemia. Stroke 2000; 31(11): 2563-2568
Other publications of related interest
Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Archives of Internal Medicine 2000;160:181-8.
Levine M, Gent M, Hirsh J, et al. A comparison of low-molecularweight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. New England Journal of Medicine 1996;334:677-81.
Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecularweight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. New England Journal of Medicine 1992;326:975-82.
Subject indexing assigned by NLM
Adult; Aged; Ambulatory Care; Anticoagulants /administration & Brain Ischemia /drug therapy; Drug Administration Schedule; Drug Therapy, Combination; Enoxaparin /administration & Female; Humans; Male; Middle Aged; Treatment Outcome; Warfarin /administration & dosage /therapeutic use; dosage /therapeutic use; dosage /therapeutic use
Date bibliographic record published
Date abstract record published