Cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated alcohol-withdrawal syndrome ,Vikram K Reddy1, K Girish1, Pandit Lakshmi2, R Vijendra1, Ajay Kumar2, R Harsha1, : Indian Journal of Pharmacology

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Year : 2014 \| Volume : 46 \| Issue : 4 \| Page : 372--377

Cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated alcohol-withdrawal syndrome

Vikram K Reddy¹, K Girish¹, Pandit Lakshmi², R Vijendra¹, Ajay Kumar², R Harsha¹,
¹ Department of Pharmacology, Kempegowda Institute of Medical Sciences, Bangalore, Karnataka, India
² Department of Psychiatry, Kempegowda Institute of Medical Sciences, Bangalore, Karnataka, India

Correspondence Address:
R Vijendra
Department of Pharmacology, Kempegowda Institute of Medical Sciences, Bangalore, Karnataka
India

Abstract

Objectives: Benzodiazepines (BZDs) are the first-line drugs in alcohol-withdrawal syndrome (AWS). Baclofen, a gamma-aminobutyric acid _B (GABA _B ) agonist, controls withdrawal symptoms without causing significant adverse effects. The objective of this study was to compare the cost-effectiveness of baclofen and chlordiazepoxide in the management of uncomplicated AWS. Materials and Methods : This was a randomized, open label, standard controlled, parallel group study of cost-effectiveness analysis (CEA) of baclofen and chlordiazepoxide in 60 participants with uncomplicated AWS. Clinical efficacy was measured by the Clinical Institute Withdrawal Assessment for alcohol (CIWA-Ar) scores. Lorazepam was used as supplement medication if withdrawal symptoms could not be controlled effectively by the study drugs alone. Both direct and indirect medical costs were considered and the CEA was analyzed in both patient«SQ»s perspective and third-party perspective. Results : The average cost-effectiveness ratio (ACER) in patient«SQ»s perspective of baclofen and chlordiazepoxide was Rs. 5,308.61 and Rs. 2,951.95 per symptom-free day, respectively. The ACER in third-party perspective of baclofen and chlordiazepoxide was Rs. 895.01 and Rs. 476.29 per symptom-free day, respectively. Participants on chlordiazepoxide had more number of symptom-free days when compared with the baclofen group on analysis by Mann-Whitney test (U = 253.50, P = 0.03). Conclusion : Both study drugs provided relief of withdrawal symptoms. Chlordiazepoxide was more cost-effective than baclofen. Baclofen was relatively less effective and more expensive than chlordiazepoxide.

How to cite this article:
Reddy VK, Girish K, Lakshmi P, Vijendra R, Kumar A, Harsha R. Cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated alcohol-withdrawal syndrome .Indian J Pharmacol 2014;46:372-377

How to cite this URL:
Reddy VK, Girish K, Lakshmi P, Vijendra R, Kumar A, Harsha R. Cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated alcohol-withdrawal syndrome . Indian J Pharmacol [serial online] 2014 [cited 2023 May 29 ];46:372-377
Available from: https://www.ijp-online.com/text.asp?2014/46/4/372/135947

Full Text

Introduction

Alcohol is commonly abused worldwide. It is estimated that about 4% of all global diseases are the direct result of alcohol consumption. [1] An estimated 14 million people in India suffer from alcohol-related health disorders. [2] The incidence of alcohol dependence is estimated to be 10-15%, affecting all classes of the Indian society. [3] According to the World Health Organization (WHO) global alcohol report (2007-08), the annual adult per capita alcohol consumption in India increased from 0.4 to 0.6 liters from 2000 to 2007. The 12-month prevalence of alcohol-associated morbidity in India was 3.47% for men and 0.42% in women in 2004. [4]

Alcohol-withdrawal syndrome (AWS) is a distressing and sometimes life threatening for alcohol-dependent individuals. It is due to the abrupt cessation of alcohol consumption in habituated consumers, the symptoms of which can be mild, moderate, or severe. Mild to moderate symptoms are characterized by anxiety, depression, tremors, restlessness, insomnia, sweating, vivid dreams, diarrhea, tachycardia, and headache, which are mostly self-limiting. Medical intervention is necessitated only if symptoms persist. Severe withdrawal symptoms are characterized by seizures, hallucinations (auditory, visual, and tactile), agitation, tremulousness, and delirium tremens where prompt therapy is necessary to control the symptoms and prevent complications. [5] The worldwide incidence of AWS is estimated to be about two million per year, of which half a million have moderate to severe withdrawal symptoms necessitating pharmacological intervention. [6]

Benzodiazepines (BZDs) constitute the standard line of treatment for AWS-chlordiazepoxide, diazepam, and lorazepam being the principle BZDs employed. [7] Though many other drugs such as topiramate, carbamazepine, phenobarbitone, clomethiazole, clonidine, flumazenil, and nitrous oxide are being tried in AWS, none of them are as effective as BZDs in managing AWS. [8],[9],[10],[11]

Chlordiazepoxide, a prototype BZD, is one of the standard treatment option in AWS. Chlordiazepoxide is an allostearic modulator which sensitizes the gamma-aminobutyric acid A (GABA A ) receptors by binding with a specific area in the GABA A receptor-chloride channel complex and enhances GABAergic action. Some of the major limitations of chlordiazepoxide are prolonged sedation, increased potential for misuse, tolerance, dependence, withdrawal tendency, hepatotoxicity, and cognitive impairment. [12]

Baclofen, a GABA analogue and a gamma-aminobutyric acid B (GABA B ) agonist which is used to relive spasticity and muscle spasms, has been tried as an alternative to BZDs in the management of AWS. Baclofen acts by enhancing GABA action by binding to GABA B receptors. Studies have equated the efficacy and safety of baclofen with diazepam, a BZD, in the management of AWS. [13],[14] Baclofen also has anti-craving action and is less likely to produce sedation, dependence and is less likely to be abused. It is also safe in patients with hepatic dysfunction and can be continued as an anti-craving agent after the withdrawal symptoms subside. [15]

The utility of baclofen and chlordiazepoxide in AWS has specific advantages, with chlordiazepoxide being inexpensive, but baclofen having additional advantages such as having anti-craving action, less abuse and addiction potential, and being safe in hepatic dysfunction, which is very common in alcoholics. [16]

Currently, there are no studies available on usefulness of baclofen in AWS in Indian population; hence, the present study was taken up to compare the cost-effectiveness of baclofen with chlordiazepoxide in uncomplicated AWS.

Materials and Methods

Trial Design

This study was designed as a fixed dose, randomized, open label, standard controlled, parallel group study of cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated AWS. The study was registered retrospectively with Clinical Trial Registry, India (CTRI/2013/04/003588).

Materials and Place of Study

The study was conducted in the Department of Psychiatry, Kempegowda Institute of Medical Sciences and Research Center, Bangalore, between February and December 2012. The study included 60 participants who were diagnosed with uncomplicated AWS, randomized into two groups-baclofen and chlordiazepoxide in 1:1 ratio by using the randomization table.

Inclusion Criteria

Following patients were included in the study

Either gender aged between 18-65 yearsThose fulfilling Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; TR) criteria for AWS and or alcohol dependenceThose with a history of last alcohol intake within 24-48 hours preceding the initiation of therapyWilling to give written informed consent.

Exclusion Criteria

Following patients were excluded from the study

Patients with complicated AWS like delirium tremens and cognitive impairment (Wernicke-Korsak off syndrome)Patients with known psychiatric disordersThose with a history of multi-drug abuse (except nicotine)Those with advanced hepatic, renal, and cardiovascular diseasesPatients with known allergy to any of the study medications.

Methodology

After prior approval from the institutional ethics committee, 60 participants who met the inclusion and exclusion criteria were included in the study. A voluntary written informed consent was obtained from all the study participants and/or their legal representatives before their enrolment into the study, after explaining the study details to their satisfaction. This study was conducted according to the International Conference on Harmonisation-World Health Organization Good Clinical Practice (ICH-GCP) guidelines and the Modified Declaration of Helsinki.

The participants were assigned either to the baclofen (n = 30) or to the chlordiazepoxide group (n = 30) based on the randomization table. They were clinically evaluated and baseline scores of Clinical Institute of Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar) were assessed. [17] Baseline investigations included complete hemogram, liver function tests (LFTs), ultrasonography (USG) abdomen, and any other as required. All participants received the study medications as inpatients for the entire study duration.

A 9-day-fixed-dose therapy was designed for the study. If the withdrawal symptoms did not subside completely by the end of the 9-day period, the same regimen was to be continued till the withdrawal symptoms abated. Both the treatment groups received the medications in the form of tablets (p.o.) with plenty of water.

Baclofen [Tab. Baclof 10 mg; Intas Pharmaceuticals Ltd.] was started at 30 mg per day in three divided doses after food (10 mg in the morning, afternoon, and at night) for first 3 days (day 1 to day 3), 20 mg per day in two divided doses (10 mg in the morning and at night) for next 3 days (day 4 to day 6), and 10 mg per day at night for the subsequent 3 days (day 7 to day 9)Chlordiazepoxide [Tab. Librium 25 mg; Valeant Pharmaceuticals Inc.] was started at 75 mg per day in three divided doses administered after food (25 mg in the morning, afternoon, and at night) for initial 3 days (day 1 to day 3), 50 mg per day in two divided doses (25 mg in the morning and at night) for next 3 days (day 4 to day 6), and 25 mg per day at night for the last 3 days (day 7 to day 9)Lorazepam (i.m.) [Inj. Lopez 2 mg; Intas Pharmaceuticals Ltd.] was supplemented whenever necessary; if the withdrawal symptoms did not improve with any of the study medication or if the participants had anxiety/tremors/irritability/insomnia during the study periodAll participants received vitamin supplements [Inj. Neurobion Forte 3 ml; Merck Ltd.] containing thiamine hydrochloride 100 mg, riboflavin sodium phosphate 5 mg, pyridoxine hydrochloride 100 mg, cyanocobalamin 1 mg, nicotinamide 100 mg, and D-panthenol 50 mg as intramuscular (IM) injection. Pantoprazole 40 mg [Tab. 3a-PAN 40 mg; 3a Pharmaceuticals.] was also administered daily before food for 5 days (continued if required).

Withdrawal symptoms were monitored and assessed daily by CIWA-Ar scores before the administration of morning dose.

Lorazepam/haloperidol was to be used as rescue medication if the participants did not respond to the study protocol or showed any signs of delirium or if the withdrawal symptoms persisted in spite of supplementation with IM lorazepam, the participants were taken out of the study and treated according to the standard guidelines.

Cost effectiveness analysis (CEA) was carried out using following cost measurements. Direct medical costs included study medication costs, admission charges, bed (hospitalization) charges, and cost of investigations and other medications. Direct non-medical costs such as transportation expenditure for both participants and their caretakers was calculated by using the local public bus transport (BMTC) fares for the year 2012 (Rs. 1.75/km). The travelling expenditure was calculated for turnaround, i.e. onward and outward journey (one time).

Indirect medical costs such as loss of wages were calculated by obtaining the participants' monthly income. Loss of leisure time and loss of wages of patients' caretaker/s (attendee/s) was standardized as per the Minimum Wage Rate and Variable Dearness Allowance (VDA) by Ministry of Labor and Employment, Government of India, 2012 (Rs. 198/day in Bangalore for semi-skilled and unskilled workers and Rs. 215/day for skilled workers). [18],[19]

Unit Costs

Cost of the study medications

Medications of the same brand were used for the entire duration of the study. The costs of all the study medications were calculated based on the retail selling price from the hospital pharmacy. All direct medical costs are mentioned in [Table 1].{Table 1}

The CEA was analyzed using two tools-average cost-effectiveness ratio (ACER) and incremental cost-effectiveness ratio (ICER). Medical costs were measured in monetary terms and clinical outcome in terms of symptom-free days (number of days with CIWA-Ar scores of ≤ 1). All adverse events and costs incurred in the management of them were considered for CEA analysis.

The CEA was analyzed by using ACER and ICER for both patient's perspective and third-party perspectives. [20],[21]

ACER was calculated from the following formula:

[INLINE:1]

The number of symptom-free days during the study period was analyzed as a measure of effectiveness of the study drugs.

ICER was calculated from the following formula:

[INLINE:2]

Additional drug costs (lorazepam and other drugs) in the management of AWS, which varied from person to person, were included in the common costs of the respective groups for both patient's and third-party perspective analysis.

Statistical Methods

Sample size calculation

This clinical study was conducted as an exploratory study. There were no studies conducted/published in India with regards to baclofen in the management of AWS at the time of conception and during conduct of our study. Therefore, the expected percentage response in baclofen was taken as 85% (based on study done by Addolorato et al.) and for chlordiazepoxide as 95% (based on study done by Kumar et al.). [13],[22] Based on the non-inferiority criteria set at an absolute value of 10%, setting alpha error at 5% and power of study at 80%, it was estimated that 54 subjects would be required for the study. With a withdrawal/non-evaluable subject rate of 10%, a total of 30 per group subjects were recruited leading to a total recruited sample size of 60 subjects.

Statistical Tests

Descriptive statistics included mean and standard deviation for demographic characteristics, ACER and ICER. Mann-Whitney (non-parametric) test was used for comparison of number of symptom-free days in baclofen and chlordiazepoxide study groups and to compare the cost difference in requirement of lorazepam supplementation in both the study groups (level of significance (P < 0.05, level of significance).

Results

A total of 65 participants were screened and 60 who met the inclusion and exclusion criteria were randomized into the study. [Figure 1] depicts the flow of study participants. All the participants (n = 60) completed the 9-day fixed dose study. None withdrew from the study and none required the therapy beyond 9 days.{Figure 1}

The average age of the study participants was 36.76 ± 8.81 and 40.03 ± 10.16 (mean ± SD) for baclofen and chlordiazepoxide groups, respectively. All the study participants were men. Eighty percent (n = 24) participants in baclofen group and 73.33% (n = 22) in chlordiazepoxide group were from urban areas.

The mean duration of alcohol consumption in the baclofen and chlordiazepoxide groups was 16.53 ± 8.24 and 17.93 ± 9.78 years, respectively, and 76.66% (n = 23) participants in baclofen group and 93.33% (n = 28) in chlordiazepoxide group were smokers.

Average Cost Effectiveness Ratio

The ACER of baclofen was 1.8 times more than the chlordiazepoxide group [Table 2] and [Table 3]. The mean costs from the patient's perspective in both study groups were nearly identical, but participants on chlordiazepoxide had 1.75 times more symptom-free days when compared to the baclofen group.{Table 2}{Table 3}

Incremental Cost-Effectiveness Ratio

The ICER from patient's perspective and from third-party perspective was negative (Rs. −116.45 and Rs. −70.07 per symptom-free day, respectively).

The difference in the mean costs (patient's perspective) and the number of symptom-free days in the baclofen group in comparison with chlordiazepoxide group when plotted on the cost-effectiveness plane fell in the fourth quadrant [Table 4] and [Figure 2].{Table 4}{Figure 2}

Requirement of Additional Lorazepam/Haloperidol Therapy In Study Groups

Lorazepam was used along with the study medications in 56.66% (n = 17) participants from the baclofen group and 30% (n = 9) of the participants in the chlordiazepoxide group.

Mann-Whitney test showed a significant difference between the baclofen and chlordiazepoxide groups in lorazepam utilization (U = 305.50, P = 0.018) [Figure 3].{Figure 3}

Haloperidol was not used as rescue medication in any of the participants.

Symptom-Free Days in Both Study Groups

The mean number of symptom-free days was 2.8 days and 1.6 days in the chlordiazepoxide group and the baclofen group, respectively. Mann-Whitney test showed a significant difference between both the groups in symptom-free days (U = 253.50, P = 0.03). The 95% confidence interval for chlordiazepoxide group and baclofen group were 2.25-3.41 and 1.04-2.15, respectively [Figure 4].{Figure 4}

Adverse Drug Events

All the adverse events were reported to the pharmacovigilance unit of the institution in Central Drugs Standard Control Organization (CDSCO) reporting form. There were no serious adverse events reported during the study period. All reported adverse events were mild and self-limiting in nature and did not warrant discontinuation from the study. The adverse events in the baclofen group (n = 18) included insomnia (n = 9), backache (n = 4), loose stools (n = 2), and reddish discoloration of urine (n = 3). Adverse events reported in the chlordiazepoxide group (n = 10) included insomnia (n = 4), loose stools (n = 3), reddish discoloration of urine (n = 2), and fever (n = 1).

Discussion

The cost difference between chlordiazepoxide and baclofen groups in the management of AWS is marginal, treatment with chlordiazepoxide being inexpensive. Baclofen group had higher common costs as per unit cost of baclofen was Rs 8.25 while that of the chlordiazepoxide group was Rs 3.75. The costs of all the study medications remained the same throughout the study period and hence no discounting was necessary.

Average Cost Effectiveness Ratio

From the patient's perspective, the mean number of symptom-free days in the baclofen group was 1.6 days and that of chlordiazepoxide group was 2.8 days. The cost incurred for a symptom-free day in the baclofen group was Rs. 5,308.61 and that of chlordiazepoxide group was Rs. 2,951.95. Chlordiazepoxide therefore provided more symptom-free days with relatively less cost when compared to baclofen.

By third-party perspective, baclofen group required an expenditure of Rs. 895.01 for a symptom-free day and the chlordiazepoxide group required Rs. 476.29 [Table 3].

Incremental Cost Effectiveness Ratio

The plotting of differences of the mean costs and number of symptom-free days from the patient's perspective showed the cost-effectiveness plane in the top left quadrant (fourth quadrant). When any new intervention is compared with the standard intervention, a plot in the fourth quadrant indicates that the standard intervention dominates the new intervention with lesser costs and higher effectiveness. [23] The present study therefore indicates that the chlordiazepoxide (standard) group with lesser costs and higher effectiveness dominated over the baclofen (new intervention) group with higher costs and less effectiveness [Figure 2].

Lorazepam was used as an additional agent to control withdrawal symptoms when the study drug alone could not control the AWS adequately. The use of lorazepam was an additional cost whenever it was needed to be used. Chlordiazepoxide group required less lorazepam (n = 9) when compared to the baclofen group (n = 17), also indicating that chlordiazepoxide was more effective than baclofen in controlling symptoms of AWS (P = 0.018, P < 0.05) [Figure 3].

Since all adverse events reported from the chlordiazepoxide (n = 10) and baclofen (n = 18) groups were mild, self-limiting, and did not require any intervention, no additional costs were required for the management for these adverse events.

Conclusion

Both the study drugs provided excellent relief of withdrawal symptoms. Both ACER and ICER indicate that chlordiazepoxide is a cost-effective option over baclofen in both patients' and third-party perspectives in the management of uncomplicated AWS. Baclofen was relatively less effective and more expensive than chlordiazepoxide.

This was an open-labelled exploratory study conducted on a small sample size. Further studies can help extrapolate the findings of this study.

References

1	Room R, Babor T, Rehm J. Alcohol and public health. Lancet 2005;365:519-30.
2	Prasad R. Alcohol use on the rise in India. Lancet 2009;373:17-8.
3	Ranganathan TT. Alcohol Related Harm in India: A fact sheet. [Internet]. Available from: http://www.addictionindia.org/images-ttkh/alcohol-related-harm-in-india-a-fact-sheet.pdf [Last accessed on 2013 Jun 09].
4	Global Status Report on Alcohol and Health 2011. India-Socioeconomic context [Internet]; 2011. P 222. Available from: http://www.who.int/substance_abuse/publications/global_alcohol_report/msbgsrsear.pdf [Last accessed on 2013 Jun 09].
5	Hartsell Z, Drost J, Wilkens JA, Budavari AI. Managing alcohol withdrawal in hospitalized patients. JAAPA 2007;20:20-5.
6	Bayard M, McIntyre J, Hill KR, Woodside J Jr. Alcohol withdrawal syndrome. Am Fam Physician 2004;69:1443-50.
7	Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome, Cochrane Database of Systemic Reviews [Internet] 2011. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008537.pub2/pdf [Last accessed on 2013 Jun 09].
8	Mayo-Smith MF. Pharmacological management of alcohol withdrawal: A meta-analysis and evidence-based practice guideline: American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA 1997;278:144-51.
9	Williams D, Mcbride AJ. The drug treatment of alcohol withdrawal symptoms: A systemic review. Alcohol Alcohol 1998;33:103-15.
10	Ait-Daoud N, Malcolm RJ Jr, Johnson BA. An overview of medications for the treatment of alcohol withdrawal and alcohol dependence with an emphasis on the use of older and newer anticonvulsants. Addict Behav 2006;31:1628-49.
11	Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health Res World 1998;22:38-43.
12	Longo LP, Johnson B. Addiction: Part I. Benzodiazepines-side effects, abuse risk and alternatives. Am Fam Physician 2000;61:2121-8.
13	Addolorato G, Leggio L, Abenavoli L, Agabio R, Caputo F, Capristo E, et al. Baclofen in the treatment of alcohol withdrawal syndrome: A comparative study vs. diazepam. Am J Med 2006;119:276.e13-8.
14	Liu J, Wang L. Baclofen for alcohol withdrawal. Cochrane Database of Systematic Reviews [Internet] 2011. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008502/pdf [Last accessed on 2013 Jun 09].
15	Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, et al. Baclofen efficacy in reducing alcohol craving and intake: A preliminary double-blind randomized controlled study. Alcohol Alcohol 2002;37:504-8.
16	Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: Randomized, double-blind controlled study. Lancet 2007;370:1915-22.
17	Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: The revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar). Br J Addict 1989;84:1353-7.
18	Chattopadhyay S. Cost of Illness of Diabetes Mellitus in Thailand. Economist, National Institute of Cholera and Enteric Diseases, Kolkata, India. The Asian Scholar [Internet] 2011:1-19. Available from: http://www.asianscholarship.org/asf/ejourn/articles/Chattopadhyay.pdf [Last accessed on 2013 Jun 09].
19	Minimum Wage Rate and Variable Dearness Allowance (VDA) by Ministry of Labour and Employment. Government of India [Internet] 2012. Available from: http://labour.nic.in/main/MinWages12-13.pdf [Last accessed on 2013 Jun 09].
20	Contreras-Hernández I, Mould-Quevedo JF, Torres-González R, Goycochea-Robles MV, Pacheco-Domínguez RL, Sánchez-García S, et al. Cost-effectiveness analysis for joint pain treatment in patients with osteoarthritis treated at the Instituto Mexicano del Seguro Social (IMSS): Comparison of nonsteroidal anti-inflammatory drugs (NSAIDs) vs. cyclooxygenase-2 selective inhibitors. Cost Effect Res Allocat 2008;6:21.
21	Edejer TT, Baltussen R, Adam T, Hutubessy R, Acharya A, Evans DB, et al. World Health Organization Guide To Cost-Effective Analysis [Internet] 2003. Available from: http://www.who.int/choice/publications/p_2003_generalised_cea.pdf [Last accessed on 2013 Jun 09].
22	Kumar CN, Andrade C, Murthy P. A randomized, double-blind comparison of lorazepam and chlordiazepoxide in patients with uncomplicated alcohol withdrawal. J Stud Alcohol Drugs 2009;70:467-74.
23	Drummond MF, Sculpher MJ, Torrance GW, O`Brien BJ, Stoddart GL. Methods for the economic evaluation of health care programmes. 3 ^rd ed. New York: Oxford university press; 2005. Ch 8, Economic evaluation using patient-level data. p. 254-8.