Cost-effectiveness of venlafaxine for the treatment of major depression in hospitalized patients

CLINICAL THERAPEUTICSVVOL.

18, NO. 2, 1996

Cost-Effectiveness of Venlafaxine for the Ikeatment of Major Depression in Hospitalized Patients Robert G. Priest, MD St. Mary’s Hospital Medical School, London, United Kingdom

ABSTRACT The economic burden of depression is often underestimated, especially when both the direct and indirect costs of treating the disease are considered. The costs associated with antidepressant drug therapy are often the focus of efforts to reduce overall treatment costs, but in actuality they represent only 10% of the overall economic costs of depression. Thus, in analyses of the costs of depression, other factors-including hospitalization, physician costs, monitoring, and indirect costs associated with lost productivity and comorbidityare important. Economic assessments comparing different antidepressant classes have often found that newer antidepressants are more cost-effective than older, less expensive drugs because of improved tolerability or efficacy. Venlafaxine represents the newest class of antidepressants and offers potential pharmacologic benefits, including early onset of action, dose

0149-2918/96/$3.50

flexibility, broad range of activity, and improved tolerance. In one analysis that used the results from a study of 67 hospitalized depressed patients, venlafaxine was estimated to result in a cost savings of 11.3% versus fluoxetine. These findings support the concept that the overall costs of depression are more important than the drug costs in determining the cost-effectiveness of therapy.

INTRODUCTION Major unipolar depression is one of the most common psychiatric disorders and is characterized by a chronic, recurrent course with remission and relapse.’ The lifetime prevalence of depression has been estimated to be as high as 7% in women and 2.6% in men.* In 50% to 85% of patients who experience a first major depressive episode, a second episode of major depression will occur at some point during their lifetime.3

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The direct health care costs of depression in 1990 were estimated at $12.4 billion annually in the United States4 and &222 million in the United Kingdom.5 These figures include costs for hospitalization, physician charges, and drugs (Figure 1). However, these costs do not include indirect costs related to lost productivity, comorbidity, and decreases in health status and well-being. Results from the Medical Outcomes Study6 indicated that patients with depression experience impaired social and physical functioning. Stoudemire et al’ estimated that lost productivity from depression-related morbidity and mortality resulted in an additional $14 billion in indirect costs in the United States. Importantly, several analyses have found that drug costs account for only 10% of the total direct costs of treating major depression.4,7s8 Because of the large economic burden of major depression, small differences in efficacy between treatments or interven-

tions that produce small reductions in direct costs can have an important impact on overall costs. The objective of this paper is to discuss the components that are relevant in assessing the economic impact of major depression and to review the cost-effectiveness data for venlafaxine.

THE ECONOMICS OF DEPRESSION Several factors must be considered in the overall costs of treating depression.9 Direct costs of treatment include hospitalization, treatment costs, physician costs, monitoring, and outpatient costs. However, indirect costs, such as lost productivity, reduction in social and physical functioning, and increases in comorbidity, represent a larger proportion of the costs of depression. Analysis of the cost-effectiveness of treatment assesses the magnitude of treatment outcomes but is limited by assessment of a single outcome measure (Table

Outpatient Clinic 2.2%

. . . . . . . . . .

Social Services 9.6%

GP Home Visits

Community Psychiatric Nurses 3.9%

Figure 1. Percentage of direct costs of treatment failure in depressed patients from a population in the United Kingdom. GP = general practitioner. Data from Kind and Sorensen.8

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Table I. Definitions Method Cost-effectiveness

Cost-benefit

Cost-utility

of methods of pharmacoeconomic Objective

analysis.

Variables

Use

To measure size of

Clinical measure

Determination

treatment outcome

of outcome

of different therapies

To assess direct and

Monetary

indirect costs of treatment

of cost

units

Measurement

of relative value

of relative costs

and benefits of treatment

To evaluate treatment by

Outcome measured

Multidimensional

assessing total outcome

with health-related

of outcome

quality-of-life

I). Cost-benefit analysis evaluates the direct and indirect costs of treatment but is limited in that it only considers factors that can be assigned a cost. Thus many indirect costs of depression, such as psychosocial costs, are not included in the analysis. Costutility analysis includes several outcomes, including efficacy, tolerability, quality of life, and others, to determine the total cost of treatment. However, many of the measurement tools for assessing these variables are not standardized. Despite their limitations, each of these methods provides information on the economic impact of major depressive disorder.

ASSESSMENT OF THE ECONOMIC BENEFITS OF ANTIDEPRESSANTS The costs of depression and the cost-effectiveness of treatment with imipramine or paroxetine were evaluated in the United Kingdom.5 A decision analysis was used to calculate the direct costs of treatment per patient and the costs per successfully treated patient. The expected costs per treated patient were estimated at g430 for paroxetine and &424 for imipramine. However, the costs per successfully treated pa-

assessment

units

tient were &824 for paroxetine and &lo24 for imipramine, which reflects the poorer tolerance and higher dropout rate with imipramine. Treatment failure resulted in a lower yearly cost with paroxetine. Importantly, drugs accounted for only 18% of the total direct treatment costs. Sclar et allo assessed health care expenditures for depression among patients in a health maintenance organization who were treated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine or one of three tricyclic antidepressants (TCAs; amitriptyline, nortriptyline, or desipramine). Health care expenditures for a l-year period were analyzed for 701 patients. The use of amitriptyline or desipramine was associated with a significant (P c 0.05) reduction in prescription costs compared with fluoxetine. However, all three TCAs were associated with significant (P c 0.05) increases in treatmentrelated costs, including costs of physician visits, laboratory tests, hospitalizations, and hospital services (Figure 2). In addition, patients receiving fluoxetine had a reduction in the number of months in which a prescription was not procured and a significantly higher rate of prescriptions

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Fluoxetine (n = 190)

EB

Amitriptyline (n = 211) Nortriptyline (n = 172) Desipramine (n = 128)

800 600

Figure 2. Depression-related expenditures among patients treated with different antidepressants in a health maintenance organization.*P < 0.05 versus fluoxetine. Data from Sclar et al.‘O obtained compared with patients prescribed a TCA. Thus, despite an increase in drug costs for fluoxetine, the direct costs of health care expenditures for treatment of depression were lower with fluoxetine. This finding could be attributed to an increase in costs associated with monitoring TCAs. Data from the California Medicaid program were used to assess the cost of antidepressant treatment failure among patients treated for depression.” Assessment of these data indicated that the costs of treating depression were increased by approximately $1000.00 in the first year, due to treatment failure. Of note, fewer than one third of patients received an adequate trial of the prescribed TCA, which probably was a major contributing factor to the incidence of treatment failure.

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Freemantle et al’* performed an analysis of the costs associated with suicide and the impact of TCAs, SSRIs, or other antidepressants such as maprotiline and trazodone on these costs in the United Ringdom. They estimated that switching from older TCAs to SSRIs as first-line agents could result in saving 300 to 450 lives per year. The annual cost per life-year gained associated with this switch was estimated at &19,000 to &173,000. Interestingly, the cost per life-year gained through the use of other antidepressants was estimated to be lower than with the SSRIs. Maintenance therapy with sertraline versus treatment of episodes of acute depression with dothiepin was examined in a costutility analysis. I3 Decision analysis was used to estimate the costs over a lifetime and the quality-adjusted life-years for each treatment. The incremental cost per qual-

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ity-adjusted life-year ranged from fi57 to &5260. Based on the economic analysis, the authors concluded that maintenance therapy with sertraline was justified in patients at high risk for recurrent depression.

PHARMACOECONOMIC CONSIDERATIONS WITH USE OF VENLAFAXINE IN MAJOR DEPRESSION

THE

As a consequence of its pharmacologic profile, venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI), demonstrates potential clinical benefits that may result in a more cost-effective treatment for major depressive disorder. Among these benefits are the potential for dose flexibility, which may allow treatment of a broad range of patients, early onset of antidepressant activity,14 and improved tolerability.15

Dose Flexibility of Venlafaxine The SSRIs are characterized by a flat dose-response effect that results in no additional efficacy with increased dosages.16 In addition, the dose flexibility of TCAs is often limited by safety or tolerability factors. In patients with major depression, however, several clinical studies have confirmed that higher doses of the SNRl venlafaxine can result in greater antidepressant efficacy and an earlier therapeutic response than other agents.‘7-20 An earlier response can be particularly beneficial in more severely depressed patients. The dose-response effects of venlafaxine have been examined in several publications.“**i*** Unlike SSRIs, venlafaxine exhibits evidence of an increasing therapeutic response with increasing doses. A randomized, double-masked, placebo-

controlled trial** was conducted in 323 depressed outpatients to evaluate the efftcacy of venlafaxine 75 mg/d, 150 to 225 mg/d, or 300 to 375 mg/d. A significant dose-response relationship was observed among the three venlafaxine groups, with a significantly greater response in the high-dose group as early as week 1. In a second, multicenter, doublemasked study, *l 312 outpatients with major depression were randomly assigned to either placebo or venlafaxine in dosages of 25 mg/d, 50 to 75 mg/d, or 150 to 200 mg/d administered twice daily for 6 weeks. Scores on the Hamilton Depression Scale (HAMD) and the Montgomery and Asberg Depression Rating Scale (MADRS) decreased over time in all three treatment groups. Trend analysis suggested that antidepressant efficacy was dose related over a range from 25 to 100 mg twice a day. A third, randomized, double-masked study” evaluated 3 14 outpatients with major depression who were randomly assigned to venlafaxine 37.5 mg twice daily or fluoxetine 20 mg once daily for up to 8 weeks. The dosage of venlafaxine could be increased to 75 mg twice daily after 2 weeks. Overall, a clinical response was attained in 72% of patients receiving venlafaxine and 60% of patients receiving fluoxetine (P = 0.023). However, among patients who increased their dose at 2 weeks, those taking venlafaxine showed significantly (P c 0.05) superior results on the HAMD from week 3 onward, which suggests a dose-response effect with venlafaxine.

Early Onset of Action Early onset of antidepressant activity has not been consistently demonstrated

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with any antidepressant.23v24 However, results from three clinical trialst4J8*25 suggest that venlafaxine exhibits an earlier onset of activity. In a randomized, double-masked trial of venlafaxine in 323 depressed outpatients,25 the dose was rapidly titrated upward from 75 mg/d to the target dose during the first week in the two high-dose groups. Patients had been randomized to placebo or one of three dose groups (venlafaxine 75 mg/d, 150 to 225 mg/d, or 300 to 375 mg/d). At week 1, a significantly (P I 0.05) greater response was observed in the high-dose group (300 to 375 mg/d), and at week 2, a significantly (P 5 0.05) greater response was observed in both the middle-dose group (150 to 225 mg/d) and the high-dose group compared with the placebo group. In another study, l4 93 hospitalized patients with major depression and melancholia were treated with venlafaxine, with the dose titrated to 375 mg/d. Significant differences from placebo were observed beginning at day 4 on the MADRS and at week 1 on the HAMD. In a study18 of 167 hospitalized patients with major depression and melancholia, venlafaxine (n = 85) was rapidly titrated to 375 mg/d over 5 days, then reduced to 150 mg/d, whereas imipramine (n = 82) was rapidly titrated to 200 mg/d over 5 days. Venlafaxine and imipramine were comparable with respect to the response on the HAMD total or MADRS total at 6 weeks. However, among the subset of patients who responded by week 6 on the HAMD, a significantly (P = 0.036) earlier response was observed with venlafaxine.

Activity in a Broad Range of Patients When selecting antidepressant therapy, an important consideration

352

drug is the

drug’s spectrum of activity. There is evidence supporting the efficacy of SSRIs in patients with depression combined with anxiety or obsessional symptoms, patients with suicide ideation, and patients with severe depression.26 Several studies’7,19,27-30 suggest that SSRIs may be less effective in hospitalized patients, especially patients with melancholia, and possibly in the elderly. In contrast, venlafaxine appears to be effective in a broad range of patients with major depression, particularly in hospitalized patients with melancholia; this may be due, in part, to its dose flexibility.14,‘7,19,20*31TCAs, particularly clomipramine, generally are considered more effective than SSRIs in patients with severe depression and melancholia, whereas the monoamine oxidase inhibitors are considered more effective in patients with atypical depression.26

Safety/Tolerability of Venlafaxine A major part of the overall direct costs of treating depression is the cost of treatment failure.” In a meta-analysis of 42 randomized clinical trials, Montgomery et a132 observed that 14.9% of patients on SSRIs and 19% on TCAs discontinued therapy because of side effects, and that an additional 6% on SSRIs and 5.1% on TCAs discontinued them for lack of efficacy. Because of the risk of central nervous system and cardiovascular toxicity with TCAs, routine monitoring of plasma concentrations is required, especially in the elderly.9 Data on discontinuation rates with venlafaxine are available from randomized clinical trials.15 In short-term (~6 weeks) trials, discontinuation rates for adverse effects and for lack of efficacy with venlafaxine were comparable with rates for all

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Table II. Discontinuation rates from short-term (~6 weeks) and long-term (26 weeks) randomized, controlled clinical trials of venlafaxine and comparator antidepressants.i5 No. (%) of Patients Discontinuing Short-Term Trials Venlafaxine (n = 789) Adverse reaction Unsatisfactory response Patient request Other+

Long-Term Trials

Comparators (n = 591)

129 (16)

106 (18)

44 (6) 13 (2) 64 (8)

24 (4) 13 (2) 61 (10)

Venlafaxine (n = 292) 29 19 45 77

(lo)* (7)* (15) (26)

Comparators (n = 142) 25 17 28 33

(18) (12) (20) (23)

*Significantly different from comparators (P < 0.05). +Combines the following categories: failed to return, other medical event, other nonmedical event, and protocol violation.

comparators (Table II). In long-term trials (26 weeks), the discontinuation rates for adverse effects and unsatisfactory response with venlafaxine were significantly (P < 0.05) lower than with comparators. Another effect of antidepressants that has an impact on overall costs is lethality in overdose. One report3* estimated that when an overdose of a single antidepressant resulted in death from suicide in the United Kingdom, the older TCAs (amitriptyline and dothiepin) were responsible for more than 70% of these deaths. Among patients admitted to the hospital for TCA overdose, the average hospital stay in the United Kingdom was 6 days at a cost of more than $12,000.009 In contrast, SSRIs and venlafaxine have a wide therapeutic index; consequently, the occurrence of fatal overdose is extremely rare. lX3*

Pharmacoeconomic Venlafaxine

Assessment

of

Gross33 analyzed the potential cost savings per episode of major depressive dis-

order that would result from substituting venlafaxine for fluoxetine in hospitalized patients. Gross included both direct and indirect costs but excluded indirect costs associated with reduced suicide rates. Results from a separate analysis34 were used to establish data for venlafaxine and fluoxetine, respectively: average duration of a depressive episode (84 days for both), average length of hospitalization (16 days and 20.2 days), average duration of outpatient service (17 days and 11.75 days), number of general practitioner visits (2 and 3), and the number of lost workdays (33 to 51 and 31.95 to 52.05). Costs for treating relapses or recurrences were excluded. For this analysis, the daily doses were venlafaxine 150 mg/d and fluoxetine 40 mg/d. Based on results from a clinical study of 67 hospitalized patients comparing these two treatments,27 Gross assumed that venlafaxine was 20% more effective than fluoxetine and that its safety was comparable. Using these definitions and assumptions, venlafaxine was estimated to result in a savings of 11.3% ver-

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Table III. Comparison of the treatment costs for venlafaxine talized depressed patients in France.34 Type of Care Venlafaxine Inpatient care Outpatient care GP care Drugs Lost work Pluoxetine Inpatient care Outpatient care GP care Drugs Lost work

and fluoxetine

Unit

Quantity

Cost/Unit*

Days

16 17 2 84 33

1100 125 90 12.46 130.6

20.2

1100 125 90 12.60 130.6

Visits Visits 150 mg/d Days Days

Visits Visits 40 mg/d Days

11.75 3 84 31.95

in 67 hospi-

Total Cost* Total = 31,923 17,600 2125 180 1047 10,971 Total = 35,988 22,220 1469 270 1058 10,971

GP = general practitioner. *Costs are expressed in French francs.

sus fluoxetine (Table III). One limitation of this analysis is the use of a fluoxetine dose (40 mg/d) that is higher than the usual dose. However, even if the dosage is adjusted, venlafaxine still results in a 10% savings over fluoxetine. The cost-effectiveness of venlafaxine versus SSRIs, TCAs, and heterocyclic antidepressants (HCAs) in major depressive disorder was evaluated using a pharmacoeconomic model.35 Decision analysis was used to calculate outcome probabilities on data assembled from a meta-analysis of clinical trials. Clinical success was defined as a 50% or greater reduction from baseline in the HAMD score. Drug costs were determined from data obtained from health maintenance organizations. Other direct costs included medical care, laboratory tests, adverse-effect management, hospitalization, and complications. An aggregate of the costs for treatment success

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and failure was used to compile total costs of treatment. In hospitalized patients, venlafaxine was more cost-effective than SSRIs and TCAs. In outpatients, generic HCAs were the most cost-effective option (Figure 3). However, none of these differences were statistically significant. A quality-of-life questionnaire was used to evaluate patient feelings, functioning, relationships, and other aspects of quality of life from three randomized, doublemasked trials of venlafaxine and imipramine or trazodone.36,37 The questionnaire assessed general life functioning, particularly well-being, life satisfaction, and ability to cope, and was highly correlated with physician rating scales on quality of life. Correlations of the quality-of-life questionnaire with measures of depression (HAMD, MADRS, and Clinical Global Impression Scale) showed that quality-oflife variables are distinct from variables

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Ia

Inpatient Outpatient

1.08

HCAs

. Venlafaxine

SSRls

I

.

nF

TCAs

’

Figure 3. Comparison of the costs of inpatient and outpatient care for depressed patients treated with venlafaxine or other antidepressants. Values represent cost ratio, which equals the total cost divided by the number of symptom-free days. HCA = heterocyclic antidepressants; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants. Data from Einarson et al.35 of depression. Pooled results from the three studies showed significant improvement in quality-of-life measures with venlafaxine compared with placebo (P = 0.001) and with imipramine or trazodone (P = 0.049; Figure 4).36

CONCLUSIONS The cost-effectiveness of antidepressant treatment is increasing in importance as government and private health care purchasers assume a greater decision-making role in the utilization of health care resources. A simplified approach is to make decisions solely on the basis of costs of

treatment, that is, drug acquisition costs. However, drug costs represent only a small portion of the overall treatment costs. A more enlightened approach is to consider other relevant factors contributing to the cost of treating depression, including response rates and long-term efficacy, safety and tolerability, and discontinuation rates. When considering these additional factors, acquisition costs may represent a minor portion of overall costs. Thus antidepressants such as venlafaxine, which may demonstrate benefits in terms of an early onset of action, activity in a broad range of patients, long-term efficacy, and safety and tolerability superior to TCAs, may of-

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CLINICAL THERAPEUTICS”

la

Placebo Active Comparator

I!@!

(I and T)

Venlafaxine

301

302

303

Figure 4. Comparison of quality-of-life (QOL) scores with venlafaxine, imipramine (I), and trazodone (T) from a pooled analysis of three double-masked, randomized trials (protocols 301,302, and 303) in depressed outpatients. Data from Rudolph et a1.36 *P = 0.049 versus comparator; +P = 0.001 versus placebo.

fer optimal cost-effective therapy for major depressive disorder. Pharmacoeconomic analyses done with venlafaxine suggest a reduction in the overall costs associated with treating depression compared with other antidepressants.

Address correspondence to: Robert G. Priest, MD, Academic Department of Psychiatry, St. Mary’s Hospital Medical School, Paterson Wing Building, 20 South Wharf Road, London, W2 IPD, United Kingdom.

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