Original Research

Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top

METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top

METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top

METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

As the physician workforce diversifies,^1,2 the question of patients’ preferences for physicians by sex and race becomes increasingly important. Early investigations suggested that many patients, especially males, prefer same-sex physicians across a variety of clinical complaints,^3-5 but subsequent studies found these preferences to be more limited,^6-9 except for sex-specific health problems (eg, gynecologic examinations and sexual health issues).¹⁰

A more recent study examining patients’ actual selections of physicians in a large health maintenance organization showed that most patients of both sexes chose a male physician.¹¹ Whether these findings reflect actual patients’ preferences is debatable, however, because patients’ choices may have been influenced by the greater availability of male physicians on the panel.

Compared with sex, even less is known about preferences for physicians’ race, a topic that is complicated by patient and physician attributes such as language, religion, ethnicity, immigration status, acculturation, and multiracial identities. One recent survey on minority health care found that approximately one fourth of African American and Latino patients who had chosen same-race physicians reported explicitly considering the physician’s race or ethnicity in making their selection.¹²

In this study, we examined people’s choices when asked to select a male or female African American, Latino, or European American actor-portrayed “video doctor” to be their physician. Choices were examined at 2 time points: after viewing a brief introduction and after viewing the delivery of a brief health advice message. Our research questions were: After gaining a first impression, will patients choose a male of European descent regardless of their own sex and race? Will exposure to the video doctors’ deliveries of a brief health advice message alter these preferences? The video doctor methodology allowed us to offer participants a verisimilar experience of choosing a physician from a diverse panel and to avoid the limitations of availability and access inherent in real-life choices.

Methods

Video doctor filming and editing

We selected 6 actors of similar age (45 years) and attractiveness: 1 female and 1 male African American, Latino, and European American. We used the term Latino to represent a racial identity characterized by dark hair and a medium complexion. The fictitious surnames of the Latino and Latina video doctors also indicated their ethnicity.

When producing the video doctor presentations, we held constant the script, the setting (a doctor’s office), and the clothing. Two segments were produced for each video doctor: a brief introduction in which the doctor used a fictitious name assigned by the researchers to say, for example, “Hi, I’m Dr. Ann Johnson,” and a 45-second health advice message about eating 5 fruits and/or vegetables a day (chosen because of the neutral and universally relevant nature of this topic). The health message contained key elements known to enhance effectiveness of brief interventions.¹³ The actors’ deliveries of the message were standardized to include interpersonal elements associated with patient-centered health care and positive patient behavior change—for example, warmth, friendliness, empathy, and a nonjudgmental, respectful, and collaborative affect.^14,15 (A full description of our procedures is available in Appendix A at www.jfponline.com.)

To balance the video doctors with respect to any possible order effect, we created 18 video presentations showing the video doctors in different orders. We obtained the sequences by creating 6 x 6 Latin squares containing all 720 possible orders and then randomly selecting 3 Latin squares and using the 18 orders contained therein. By delivering 1 of the 18 orders to each group of 22 to 24 participants, we obtained nearly perfect balance in the ordering of the video doctors.

Participants

Individuals at a shopping mall in the San Francisco Bay Area aged >18 years and able to read and write English were invited to watch a short video and rate doctors for a healthcare research project. Four hundred people participated; 395 completed questionnaires. Participants were told that their responses were anonymous, and each questionnaire was marked only with the group number. Study procedures were approved by the Committee on Human Research at the University of California at San Francisco.

FIGURE
Video doctors

Study design and procedures

After viewing brief introductions of each video doctor (Figure), participants were asked: “If you were to choose 1 of these doctors to be your doctor, which would you pick?” They were then instructed to write the number of their choice on the questionnaire.

Participants then viewed the message from each video doctor about eating 5 fruits and vegetables a day. After each presentation, participants rated the video doctor by circling a number on 7-point scales, where a response of 7 indicated the following qualities: very professional, very knowledgeable, excellent communication skills, respectfulness, genuine/authentic, warm/friendly, and pleasant facial expressions.^14,15 Participants also rated each video doctor on a 7-point scale for how likely they would be to increase their fruit and vegetable consumption, how interested they might be in choosing this person as their doctor, and how comfortable they might be in talking with this person about personal health matters such as sexual, alcohol, and drug-using behaviors.

After viewing and rating all 6 video doctors, participants again viewed the 6 head shots together and answered the following question: “Now that you’ve heard each video doctor, which one would you pick to be your doctor?” To conclude, participants answered demographic questions, turned in their booklets, and received a $20 gift certificate.

Statistical analysis

Differences in the initial preferences for the sex and race of the video doctors by the sex and race of the participants were studied by using standard 2-way tables, with Fisher exact tests for 2 × 2 tables and χ² tests for larger tables. Multivariable analysis of sex preferences for the video doctor was done with logistic regression to test the effect of participants’ demographic variables. Matched pair analysis, with an exact version of the McNemar test, was used to assess whether participants’ tendency to choose a same-sex or a same-race video doctor changed from their initial to their final selection.

From each participant’s ratings of the video doctors, an assessment score was generated by averaging the 10 scaled ratings. The clustered assessment scores were analyzed with a normal linear mixed model analysis with a random effect to represent participant scoring tendency and fixed effects to account for the differential mean score for the preferred vs nonpreferred video doctors and differences in mean score depending on the order in which the video doctor was scored. All analyses were performed in Stata 6.0. (More detailed on the methods is found in Appendix A at www.jfponline.com.)

Results

Demographics

Participants were diverse in sex (61% female, 39% male), ethnicity (30% Asian American, 29% European American, 26% Latino, 8% African American, and 7% other), age (11% were 18 to 19 years old, 24% were 20 to 29, 18% were 30 to 39, 17% were 40 to 49, 13% were 50 to 59, 8% were 60 to 69, and 9% were 70 to 87), and education (9% had less than a high school education, 34% had a high school diploma or graduation equivalency diploma, 26% had some college, 22% were college graduates, and 9% had graduate degrees).

Initial preferences for video doctors

Initial sex preference. The strong preference for a female video doctor was significantly different from the 50% preference for each sex that would be expected in the absence of any sex preference (P<.0001). Most females (85%) and males (63%) selected a female video doctor (difference between males and females significant at P<.001; Table 1). The percentages of sex preference by race were not significantly different from one another (P=.36).

Multivariable logistic regression confirmed the relation between participants’ sex and the sex preference of the video doctor but showed no convincing evidence of differences in sex preference related to race (P=.73), age (P=.15), schooling (P=.23), marital status (P=.13), or employment status (P=.19).

Initial race preference. For their initial video doctor selection, 53% of participants chose a European American, 29% chose a Latino, and 18% chose an African American. This pattern of preference was significantly different from the 33.3% for each race that would be expected in the absence of a racial preference (P<.001; Table 2).

Video doctor racial preferences differed significantly by race of the participant (P<.0001), with a preference for the same race. A substantial number of participants, however, chose a different-race video doctor. Racial preferences were similar across male and female participants (P=.98).

TABLE 1
Initial and final video doctor selections by sex

TABLE 2
Initial and final video doctor selections by race

Final preferences for video doctors

Final sex preference. The preference for a female video doctor increased across female and male participants (P<.001; Table 1). The net shift among males from male to female video doctor was significant (P=.014). More female participants shifted from male to female (9%) than from female to male (4%), although the difference was not statistically significant (P=.10).

Final race preference. Forty-eight percent of African American participants, 56% of Latino participants, and 44% of European Americans chose a different-race video doctor. Among Asian and other-race participants, a sizable shift occurred so that only 43% selected a European American video doctor (Table 2).

Between the initial and final selections, 3% of African American participants shifted to a video doctor of a different race, whereas 7% shifted to an African American video doctor. Eleven percent of Latino participants shifted to a different-race video doctor, whereas 6% shifted to a Latino video doctor. Among European American participants, 22% shifted to a different-race video doctor, whereas 12% shifted to a European American video doctor. With the exception of African American participants, there was a significant net shift from same- to different-race choice (P=.036). Many Asian and other-race participants shifted from a European American video doctor to a non–European American video doctor (14% net).

Assessment scores

The 3 female video doctors, who were chosen by more participants than were the 3 male video doctors at the initial and final selections, also received higher mean assessment scores (Table 3). On particular items, the highest score was 6.001 (of a possible 7), received by the European American female for the question: “How professional is this doctor?” The lowest score was 3.590 received by the European American male for the question: “If this person were your doctor, how comfortable might you be in talking with this person about personal health matters?”

TABLE 3
Selection of video doctor by sex and race

Association of preferences and ratings. Analysis of the mean assessment scores showed a substantial rating tendency among participants, by which they tended to give all 6 video doctors relatively high or low scores. Our analysis indicated that 34.9% (95% confidence interval [CI], 30.4–39.5) of the variance in assessment scores is explained by rating tendency.

We also found that participants tended to increase their scores as they proceeded through the sequence of doctors. Compared with the first video doctor, the second through the sixth video doctors received increases in mean scores of 0.15 (P=.016), 0.16 (P=.011), 0.29 (P<.001), 0.43 (P<.001), and 0.60 (P<.001), respectively. These results showed the importance of using multiple presentation orders to balance the order effect.

After adjusting for the order effect and the respondent rating tendency, the mean assessment scores given to video doctors selected at the initial stage were an average of 0.7 points higher than scores given to the other video doctors (P<.001, 95% CI, 0.56–0.81). At the final selection, the chosen video doctor scored on average 1.04 units higher on the assessment scores than did the other video doctors (P<.001, 95% CI, 0.94–1.1). Thus, the selection made based on the video doctors’ images and brief introductions alone was significantly associated with the subsequent assessment, and the final selection of video doctor was even more strongly associated with the assessment.

Discussion

More participants preferred same-race physicians at the initial selection (66% of European Americans, 51% of Latinos, and 50% of African Americans). This effect was not as large as one might expect, however, because a substantial minority of subjects in each racial category selected a different-race video doctor at the initial selection and a majority of Latinos selected a different-race video doctor at the final selection.

After viewing the delivery of the prevention message, more in each group, except for African Americans, chose a video doctor of a different race. In addition, at final selection, 57% of Asian and other-race participants chose a non– European American video doctor. With regard to sex, most males and females chose a female video doctor at the initial selection, and even more did so at the final selection. These data suggested that many healthcare consumers are in concordance with the recent shift toward a more diverse population of physicians and that the white male physician may no longer be viewed as the stereotypical medical professional.

The qualities patients seek in a doctor

The assessment scores for the video doctors indicated that participants were choosing, both on first impressions and after further exposure, video doctors who they perceived to possess the qualities associated with patient-centered care.^21,22 Although the overall ranking of the 6 video doctors was unchanged from initial to final selection, after viewing the delivery of the prevention message, many participants altered their choices: more males and females chose a female video doctor; more European American and Latino participants shifted from same-race to different-race video doctors; and more Asian and other-race participants shifted from European American to non–European American video doctors.

These findings suggested that, even in brief meetings with physicians, patients respond to a combination of patient-centered qualities and that this combination may carry more weight than the physician’s sex and race. In other words, from the point of view of the public at large, physicians of both sexes and all races can possess the desired physician qualities, and people may be receptive to any physician who exhibits these qualities.

Preference for a female doctor

Our finding that men and women in our sample preferred a female video doctor contrasts with sex preference findings from previous studies,^3,6,8,10,11 although in general studies on sex preference of physicians have shown inconsistent findings. The female preference finding in our study may represent evolving positive attitudes toward and increasing familiarity with female physicians. From 1971 to 1991, the percentage of women first-year medical school students rose from 13.7% to 39.8%.¹⁴

The strong female preference also may represent sex stereotyping. Patients reported that they desire physicians who are sensitive to their needs and circumstances, deliver a warm and empathic style of care,¹⁵ invite participation in decision making,¹⁶ engage in emotionally focused talk, and provide health information within patients’ social, emotional, and cultural contexts.¹⁷ Other studies found that women, when compared with men, provide a style of care that approximates these patient-centered characteristics.^18-20

Our participants, many of whom preferred female video doctors even at first, may have strongly associated a patient-centered, empathic style with being female. The particular female actors we chose also may have been better able to exhibit, regardless of our efforts to standardize, the combination of professional and personal skills most desired in a doctor.

Racial preferences

The preference for a same-race video doctor may have several origins. People may feel more familiar and comfortable with race-concordant relationships in general and may believe that a physician of one’s own race can better attend to specific health concerns. Same-race preference also may arise from the desire to avoid a racially prejudiced physician. Racially concordant as opposed to discordant care has been associated with increased patient satisfaction and use of health care services and with higher ratings from patients regarding their level of participation during physician visits.^16,23

As indicated in our study and others, African Americans express a stronger preference than do individuals from other racial groups for receiving care from physicians of their own race.²³ To support patients in exercising their racial preferences, some health care professional organizations, such as the National Medical Association, have provided a toll-free number that patients can call to locate a local African American physician.

Limitations of the study

The study had several limitations. We may not have successfully held constant the actors’ personalities and acting abilities. Future video doctor studies about patients’ acceptance regarding physicians’ race and sex could address this drawback by including multiple video doctors in each sex and race category.

Because only English-speaking participants were included in the study, we do not know whether Latinos who spoke only Spanish would have chosen differently. Our study also used a convenience sample in a San Francisco Bay Area shopping mall, and our results may not be generalizable to other populations.

We were unable to study the same-race preferences of the Asian participants in our sample. Because more than 10% of physicians practicing in the United States are of Asian ancestry, patients’ receptivity to Asian physicians and Asian patients’ preference for a same-race physician would be important research topics. Diversity of language and culture among various Asian and other ethnicities also could be addressed with a well-designed video doctor study. The absence of an Asian video doctor, however, did allow us to examine the selections made by participants when no same-race video doctor was available.

Strengths of the study

A major strength of our study was that participants represented both sexes and a range of ages, races, and education levels. In addition, the video technology allowed participants to select a video doctor based on a verisimilar experience and without the constraints of availability and access found in real-life choices. All our study participants accepted the survey questions and responded to the video doctor as a “real” physician.

Video doctor technology does allow for holding constant certain variables such as age, appearance, message content, and style of delivery, an advantage that cannot be achieved in real encounters between patients and physicians.

Challenges for the future

Some of our most crucial health care challenges are providing access to quality care and equal career opportunities for those who seek to practice medicine. Our results supported the growing diversity of the population of physicians, and emphasized that many patients will choose physicians, regardless of their sex and race, who appear professional, competent, and caring. Medical schools need to continue the trend toward teaching patient-centered, empathic care and recruiting and retaining minority physicians to rectify current imbalances. In addition, practicing physicians can take note that providing quality care for patients of all cultural backgrounds may be an easier task than they think—the common language of compassion may transcend our differences.

Future studies could use video doctor technology to confirm our findings and to further investigate patients’ preferences and attitudes about various dimensions of the relationship between patient and physician. As the patient population and the physician workforce diversify, and as managed care organizations continue to strive to increase patient satisfaction and retention, information about patient preferences could inform the future of health care delivery.

Acknowledgments

We thank Scott Ludwig for his excellent casting of actors, directing, and video production; and Annabelle Ison for designing subject recruitment materials. We also thank our video doctors, the staff of Tanforan Park Shopping Center in San Bruno, CA, and the mall visitors who volunteered to participate in the study.

Corresponding author
Barbara Gerbert, PhD, University of California at San Francisco, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94117. E-mail: [email protected].

As the physician workforce diversifies,^1,2 the question of patients’ preferences for physicians by sex and race becomes increasingly important. Early investigations suggested that many patients, especially males, prefer same-sex physicians across a variety of clinical complaints,^3-5 but subsequent studies found these preferences to be more limited,^6-9 except for sex-specific health problems (eg, gynecologic examinations and sexual health issues).¹⁰

A more recent study examining patients’ actual selections of physicians in a large health maintenance organization showed that most patients of both sexes chose a male physician.¹¹ Whether these findings reflect actual patients’ preferences is debatable, however, because patients’ choices may have been influenced by the greater availability of male physicians on the panel.

Compared with sex, even less is known about preferences for physicians’ race, a topic that is complicated by patient and physician attributes such as language, religion, ethnicity, immigration status, acculturation, and multiracial identities. One recent survey on minority health care found that approximately one fourth of African American and Latino patients who had chosen same-race physicians reported explicitly considering the physician’s race or ethnicity in making their selection.¹²

In this study, we examined people’s choices when asked to select a male or female African American, Latino, or European American actor-portrayed “video doctor” to be their physician. Choices were examined at 2 time points: after viewing a brief introduction and after viewing the delivery of a brief health advice message. Our research questions were: After gaining a first impression, will patients choose a male of European descent regardless of their own sex and race? Will exposure to the video doctors’ deliveries of a brief health advice message alter these preferences? The video doctor methodology allowed us to offer participants a verisimilar experience of choosing a physician from a diverse panel and to avoid the limitations of availability and access inherent in real-life choices.

Methods

Video doctor filming and editing

We selected 6 actors of similar age (45 years) and attractiveness: 1 female and 1 male African American, Latino, and European American. We used the term Latino to represent a racial identity characterized by dark hair and a medium complexion. The fictitious surnames of the Latino and Latina video doctors also indicated their ethnicity.

When producing the video doctor presentations, we held constant the script, the setting (a doctor’s office), and the clothing. Two segments were produced for each video doctor: a brief introduction in which the doctor used a fictitious name assigned by the researchers to say, for example, “Hi, I’m Dr. Ann Johnson,” and a 45-second health advice message about eating 5 fruits and/or vegetables a day (chosen because of the neutral and universally relevant nature of this topic). The health message contained key elements known to enhance effectiveness of brief interventions.¹³ The actors’ deliveries of the message were standardized to include interpersonal elements associated with patient-centered health care and positive patient behavior change—for example, warmth, friendliness, empathy, and a nonjudgmental, respectful, and collaborative affect.^14,15 (A full description of our procedures is available in Appendix A at www.jfponline.com.)

To balance the video doctors with respect to any possible order effect, we created 18 video presentations showing the video doctors in different orders. We obtained the sequences by creating 6 x 6 Latin squares containing all 720 possible orders and then randomly selecting 3 Latin squares and using the 18 orders contained therein. By delivering 1 of the 18 orders to each group of 22 to 24 participants, we obtained nearly perfect balance in the ordering of the video doctors.

Participants

Individuals at a shopping mall in the San Francisco Bay Area aged >18 years and able to read and write English were invited to watch a short video and rate doctors for a healthcare research project. Four hundred people participated; 395 completed questionnaires. Participants were told that their responses were anonymous, and each questionnaire was marked only with the group number. Study procedures were approved by the Committee on Human Research at the University of California at San Francisco.

FIGURE
Video doctors

Study design and procedures

After viewing brief introductions of each video doctor (Figure), participants were asked: “If you were to choose 1 of these doctors to be your doctor, which would you pick?” They were then instructed to write the number of their choice on the questionnaire.

Participants then viewed the message from each video doctor about eating 5 fruits and vegetables a day. After each presentation, participants rated the video doctor by circling a number on 7-point scales, where a response of 7 indicated the following qualities: very professional, very knowledgeable, excellent communication skills, respectfulness, genuine/authentic, warm/friendly, and pleasant facial expressions.^14,15 Participants also rated each video doctor on a 7-point scale for how likely they would be to increase their fruit and vegetable consumption, how interested they might be in choosing this person as their doctor, and how comfortable they might be in talking with this person about personal health matters such as sexual, alcohol, and drug-using behaviors.

After viewing and rating all 6 video doctors, participants again viewed the 6 head shots together and answered the following question: “Now that you’ve heard each video doctor, which one would you pick to be your doctor?” To conclude, participants answered demographic questions, turned in their booklets, and received a $20 gift certificate.

Statistical analysis

Differences in the initial preferences for the sex and race of the video doctors by the sex and race of the participants were studied by using standard 2-way tables, with Fisher exact tests for 2 × 2 tables and χ² tests for larger tables. Multivariable analysis of sex preferences for the video doctor was done with logistic regression to test the effect of participants’ demographic variables. Matched pair analysis, with an exact version of the McNemar test, was used to assess whether participants’ tendency to choose a same-sex or a same-race video doctor changed from their initial to their final selection.

From each participant’s ratings of the video doctors, an assessment score was generated by averaging the 10 scaled ratings. The clustered assessment scores were analyzed with a normal linear mixed model analysis with a random effect to represent participant scoring tendency and fixed effects to account for the differential mean score for the preferred vs nonpreferred video doctors and differences in mean score depending on the order in which the video doctor was scored. All analyses were performed in Stata 6.0. (More detailed on the methods is found in Appendix A at www.jfponline.com.)

Results

Demographics

Participants were diverse in sex (61% female, 39% male), ethnicity (30% Asian American, 29% European American, 26% Latino, 8% African American, and 7% other), age (11% were 18 to 19 years old, 24% were 20 to 29, 18% were 30 to 39, 17% were 40 to 49, 13% were 50 to 59, 8% were 60 to 69, and 9% were 70 to 87), and education (9% had less than a high school education, 34% had a high school diploma or graduation equivalency diploma, 26% had some college, 22% were college graduates, and 9% had graduate degrees).

Initial preferences for video doctors

Initial sex preference. The strong preference for a female video doctor was significantly different from the 50% preference for each sex that would be expected in the absence of any sex preference (P<.0001). Most females (85%) and males (63%) selected a female video doctor (difference between males and females significant at P<.001; Table 1). The percentages of sex preference by race were not significantly different from one another (P=.36).

Multivariable logistic regression confirmed the relation between participants’ sex and the sex preference of the video doctor but showed no convincing evidence of differences in sex preference related to race (P=.73), age (P=.15), schooling (P=.23), marital status (P=.13), or employment status (P=.19).

Initial race preference. For their initial video doctor selection, 53% of participants chose a European American, 29% chose a Latino, and 18% chose an African American. This pattern of preference was significantly different from the 33.3% for each race that would be expected in the absence of a racial preference (P<.001; Table 2).

Video doctor racial preferences differed significantly by race of the participant (P<.0001), with a preference for the same race. A substantial number of participants, however, chose a different-race video doctor. Racial preferences were similar across male and female participants (P=.98).

TABLE 1
Initial and final video doctor selections by sex

TABLE 2
Initial and final video doctor selections by race

Final preferences for video doctors

Final sex preference. The preference for a female video doctor increased across female and male participants (P<.001; Table 1). The net shift among males from male to female video doctor was significant (P=.014). More female participants shifted from male to female (9%) than from female to male (4%), although the difference was not statistically significant (P=.10).

Final race preference. Forty-eight percent of African American participants, 56% of Latino participants, and 44% of European Americans chose a different-race video doctor. Among Asian and other-race participants, a sizable shift occurred so that only 43% selected a European American video doctor (Table 2).

Between the initial and final selections, 3% of African American participants shifted to a video doctor of a different race, whereas 7% shifted to an African American video doctor. Eleven percent of Latino participants shifted to a different-race video doctor, whereas 6% shifted to a Latino video doctor. Among European American participants, 22% shifted to a different-race video doctor, whereas 12% shifted to a European American video doctor. With the exception of African American participants, there was a significant net shift from same- to different-race choice (P=.036). Many Asian and other-race participants shifted from a European American video doctor to a non–European American video doctor (14% net).

Assessment scores

The 3 female video doctors, who were chosen by more participants than were the 3 male video doctors at the initial and final selections, also received higher mean assessment scores (Table 3). On particular items, the highest score was 6.001 (of a possible 7), received by the European American female for the question: “How professional is this doctor?” The lowest score was 3.590 received by the European American male for the question: “If this person were your doctor, how comfortable might you be in talking with this person about personal health matters?”

TABLE 3
Selection of video doctor by sex and race

Association of preferences and ratings. Analysis of the mean assessment scores showed a substantial rating tendency among participants, by which they tended to give all 6 video doctors relatively high or low scores. Our analysis indicated that 34.9% (95% confidence interval [CI], 30.4–39.5) of the variance in assessment scores is explained by rating tendency.

We also found that participants tended to increase their scores as they proceeded through the sequence of doctors. Compared with the first video doctor, the second through the sixth video doctors received increases in mean scores of 0.15 (P=.016), 0.16 (P=.011), 0.29 (P<.001), 0.43 (P<.001), and 0.60 (P<.001), respectively. These results showed the importance of using multiple presentation orders to balance the order effect.

After adjusting for the order effect and the respondent rating tendency, the mean assessment scores given to video doctors selected at the initial stage were an average of 0.7 points higher than scores given to the other video doctors (P<.001, 95% CI, 0.56–0.81). At the final selection, the chosen video doctor scored on average 1.04 units higher on the assessment scores than did the other video doctors (P<.001, 95% CI, 0.94–1.1). Thus, the selection made based on the video doctors’ images and brief introductions alone was significantly associated with the subsequent assessment, and the final selection of video doctor was even more strongly associated with the assessment.

Discussion

More participants preferred same-race physicians at the initial selection (66% of European Americans, 51% of Latinos, and 50% of African Americans). This effect was not as large as one might expect, however, because a substantial minority of subjects in each racial category selected a different-race video doctor at the initial selection and a majority of Latinos selected a different-race video doctor at the final selection.

After viewing the delivery of the prevention message, more in each group, except for African Americans, chose a video doctor of a different race. In addition, at final selection, 57% of Asian and other-race participants chose a non– European American video doctor. With regard to sex, most males and females chose a female video doctor at the initial selection, and even more did so at the final selection. These data suggested that many healthcare consumers are in concordance with the recent shift toward a more diverse population of physicians and that the white male physician may no longer be viewed as the stereotypical medical professional.

The qualities patients seek in a doctor

The assessment scores for the video doctors indicated that participants were choosing, both on first impressions and after further exposure, video doctors who they perceived to possess the qualities associated with patient-centered care.^21,22 Although the overall ranking of the 6 video doctors was unchanged from initial to final selection, after viewing the delivery of the prevention message, many participants altered their choices: more males and females chose a female video doctor; more European American and Latino participants shifted from same-race to different-race video doctors; and more Asian and other-race participants shifted from European American to non–European American video doctors.

These findings suggested that, even in brief meetings with physicians, patients respond to a combination of patient-centered qualities and that this combination may carry more weight than the physician’s sex and race. In other words, from the point of view of the public at large, physicians of both sexes and all races can possess the desired physician qualities, and people may be receptive to any physician who exhibits these qualities.

Preference for a female doctor

Our finding that men and women in our sample preferred a female video doctor contrasts with sex preference findings from previous studies,^3,6,8,10,11 although in general studies on sex preference of physicians have shown inconsistent findings. The female preference finding in our study may represent evolving positive attitudes toward and increasing familiarity with female physicians. From 1971 to 1991, the percentage of women first-year medical school students rose from 13.7% to 39.8%.¹⁴

The strong female preference also may represent sex stereotyping. Patients reported that they desire physicians who are sensitive to their needs and circumstances, deliver a warm and empathic style of care,¹⁵ invite participation in decision making,¹⁶ engage in emotionally focused talk, and provide health information within patients’ social, emotional, and cultural contexts.¹⁷ Other studies found that women, when compared with men, provide a style of care that approximates these patient-centered characteristics.^18-20

Our participants, many of whom preferred female video doctors even at first, may have strongly associated a patient-centered, empathic style with being female. The particular female actors we chose also may have been better able to exhibit, regardless of our efforts to standardize, the combination of professional and personal skills most desired in a doctor.

Racial preferences

The preference for a same-race video doctor may have several origins. People may feel more familiar and comfortable with race-concordant relationships in general and may believe that a physician of one’s own race can better attend to specific health concerns. Same-race preference also may arise from the desire to avoid a racially prejudiced physician. Racially concordant as opposed to discordant care has been associated with increased patient satisfaction and use of health care services and with higher ratings from patients regarding their level of participation during physician visits.^16,23

As indicated in our study and others, African Americans express a stronger preference than do individuals from other racial groups for receiving care from physicians of their own race.²³ To support patients in exercising their racial preferences, some health care professional organizations, such as the National Medical Association, have provided a toll-free number that patients can call to locate a local African American physician.

Limitations of the study

The study had several limitations. We may not have successfully held constant the actors’ personalities and acting abilities. Future video doctor studies about patients’ acceptance regarding physicians’ race and sex could address this drawback by including multiple video doctors in each sex and race category.

Because only English-speaking participants were included in the study, we do not know whether Latinos who spoke only Spanish would have chosen differently. Our study also used a convenience sample in a San Francisco Bay Area shopping mall, and our results may not be generalizable to other populations.

We were unable to study the same-race preferences of the Asian participants in our sample. Because more than 10% of physicians practicing in the United States are of Asian ancestry, patients’ receptivity to Asian physicians and Asian patients’ preference for a same-race physician would be important research topics. Diversity of language and culture among various Asian and other ethnicities also could be addressed with a well-designed video doctor study. The absence of an Asian video doctor, however, did allow us to examine the selections made by participants when no same-race video doctor was available.

Strengths of the study

A major strength of our study was that participants represented both sexes and a range of ages, races, and education levels. In addition, the video technology allowed participants to select a video doctor based on a verisimilar experience and without the constraints of availability and access found in real-life choices. All our study participants accepted the survey questions and responded to the video doctor as a “real” physician.

Video doctor technology does allow for holding constant certain variables such as age, appearance, message content, and style of delivery, an advantage that cannot be achieved in real encounters between patients and physicians.

Challenges for the future

Some of our most crucial health care challenges are providing access to quality care and equal career opportunities for those who seek to practice medicine. Our results supported the growing diversity of the population of physicians, and emphasized that many patients will choose physicians, regardless of their sex and race, who appear professional, competent, and caring. Medical schools need to continue the trend toward teaching patient-centered, empathic care and recruiting and retaining minority physicians to rectify current imbalances. In addition, practicing physicians can take note that providing quality care for patients of all cultural backgrounds may be an easier task than they think—the common language of compassion may transcend our differences.

Future studies could use video doctor technology to confirm our findings and to further investigate patients’ preferences and attitudes about various dimensions of the relationship between patient and physician. As the patient population and the physician workforce diversify, and as managed care organizations continue to strive to increase patient satisfaction and retention, information about patient preferences could inform the future of health care delivery.

Acknowledgments

We thank Scott Ludwig for his excellent casting of actors, directing, and video production; and Annabelle Ison for designing subject recruitment materials. We also thank our video doctors, the staff of Tanforan Park Shopping Center in San Bruno, CA, and the mall visitors who volunteered to participate in the study.

Corresponding author
Barbara Gerbert, PhD, University of California at San Francisco, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94117. E-mail: [email protected].

As the physician workforce diversifies,^1,2 the question of patients’ preferences for physicians by sex and race becomes increasingly important. Early investigations suggested that many patients, especially males, prefer same-sex physicians across a variety of clinical complaints,^3-5 but subsequent studies found these preferences to be more limited,^6-9 except for sex-specific health problems (eg, gynecologic examinations and sexual health issues).¹⁰

A more recent study examining patients’ actual selections of physicians in a large health maintenance organization showed that most patients of both sexes chose a male physician.¹¹ Whether these findings reflect actual patients’ preferences is debatable, however, because patients’ choices may have been influenced by the greater availability of male physicians on the panel.

Compared with sex, even less is known about preferences for physicians’ race, a topic that is complicated by patient and physician attributes such as language, religion, ethnicity, immigration status, acculturation, and multiracial identities. One recent survey on minority health care found that approximately one fourth of African American and Latino patients who had chosen same-race physicians reported explicitly considering the physician’s race or ethnicity in making their selection.¹²

In this study, we examined people’s choices when asked to select a male or female African American, Latino, or European American actor-portrayed “video doctor” to be their physician. Choices were examined at 2 time points: after viewing a brief introduction and after viewing the delivery of a brief health advice message. Our research questions were: After gaining a first impression, will patients choose a male of European descent regardless of their own sex and race? Will exposure to the video doctors’ deliveries of a brief health advice message alter these preferences? The video doctor methodology allowed us to offer participants a verisimilar experience of choosing a physician from a diverse panel and to avoid the limitations of availability and access inherent in real-life choices.

Methods

Video doctor filming and editing

We selected 6 actors of similar age (45 years) and attractiveness: 1 female and 1 male African American, Latino, and European American. We used the term Latino to represent a racial identity characterized by dark hair and a medium complexion. The fictitious surnames of the Latino and Latina video doctors also indicated their ethnicity.

When producing the video doctor presentations, we held constant the script, the setting (a doctor’s office), and the clothing. Two segments were produced for each video doctor: a brief introduction in which the doctor used a fictitious name assigned by the researchers to say, for example, “Hi, I’m Dr. Ann Johnson,” and a 45-second health advice message about eating 5 fruits and/or vegetables a day (chosen because of the neutral and universally relevant nature of this topic). The health message contained key elements known to enhance effectiveness of brief interventions.¹³ The actors’ deliveries of the message were standardized to include interpersonal elements associated with patient-centered health care and positive patient behavior change—for example, warmth, friendliness, empathy, and a nonjudgmental, respectful, and collaborative affect.^14,15 (A full description of our procedures is available in Appendix A at www.jfponline.com.)

To balance the video doctors with respect to any possible order effect, we created 18 video presentations showing the video doctors in different orders. We obtained the sequences by creating 6 x 6 Latin squares containing all 720 possible orders and then randomly selecting 3 Latin squares and using the 18 orders contained therein. By delivering 1 of the 18 orders to each group of 22 to 24 participants, we obtained nearly perfect balance in the ordering of the video doctors.

Participants

Individuals at a shopping mall in the San Francisco Bay Area aged >18 years and able to read and write English were invited to watch a short video and rate doctors for a healthcare research project. Four hundred people participated; 395 completed questionnaires. Participants were told that their responses were anonymous, and each questionnaire was marked only with the group number. Study procedures were approved by the Committee on Human Research at the University of California at San Francisco.

FIGURE
Video doctors

Study design and procedures

After viewing brief introductions of each video doctor (Figure), participants were asked: “If you were to choose 1 of these doctors to be your doctor, which would you pick?” They were then instructed to write the number of their choice on the questionnaire.

Participants then viewed the message from each video doctor about eating 5 fruits and vegetables a day. After each presentation, participants rated the video doctor by circling a number on 7-point scales, where a response of 7 indicated the following qualities: very professional, very knowledgeable, excellent communication skills, respectfulness, genuine/authentic, warm/friendly, and pleasant facial expressions.^14,15 Participants also rated each video doctor on a 7-point scale for how likely they would be to increase their fruit and vegetable consumption, how interested they might be in choosing this person as their doctor, and how comfortable they might be in talking with this person about personal health matters such as sexual, alcohol, and drug-using behaviors.

After viewing and rating all 6 video doctors, participants again viewed the 6 head shots together and answered the following question: “Now that you’ve heard each video doctor, which one would you pick to be your doctor?” To conclude, participants answered demographic questions, turned in their booklets, and received a $20 gift certificate.

Statistical analysis

Differences in the initial preferences for the sex and race of the video doctors by the sex and race of the participants were studied by using standard 2-way tables, with Fisher exact tests for 2 × 2 tables and χ² tests for larger tables. Multivariable analysis of sex preferences for the video doctor was done with logistic regression to test the effect of participants’ demographic variables. Matched pair analysis, with an exact version of the McNemar test, was used to assess whether participants’ tendency to choose a same-sex or a same-race video doctor changed from their initial to their final selection.

From each participant’s ratings of the video doctors, an assessment score was generated by averaging the 10 scaled ratings. The clustered assessment scores were analyzed with a normal linear mixed model analysis with a random effect to represent participant scoring tendency and fixed effects to account for the differential mean score for the preferred vs nonpreferred video doctors and differences in mean score depending on the order in which the video doctor was scored. All analyses were performed in Stata 6.0. (More detailed on the methods is found in Appendix A at www.jfponline.com.)

Results

Demographics

Participants were diverse in sex (61% female, 39% male), ethnicity (30% Asian American, 29% European American, 26% Latino, 8% African American, and 7% other), age (11% were 18 to 19 years old, 24% were 20 to 29, 18% were 30 to 39, 17% were 40 to 49, 13% were 50 to 59, 8% were 60 to 69, and 9% were 70 to 87), and education (9% had less than a high school education, 34% had a high school diploma or graduation equivalency diploma, 26% had some college, 22% were college graduates, and 9% had graduate degrees).

Initial preferences for video doctors

Initial sex preference. The strong preference for a female video doctor was significantly different from the 50% preference for each sex that would be expected in the absence of any sex preference (P<.0001). Most females (85%) and males (63%) selected a female video doctor (difference between males and females significant at P<.001; Table 1). The percentages of sex preference by race were not significantly different from one another (P=.36).

Multivariable logistic regression confirmed the relation between participants’ sex and the sex preference of the video doctor but showed no convincing evidence of differences in sex preference related to race (P=.73), age (P=.15), schooling (P=.23), marital status (P=.13), or employment status (P=.19).

Initial race preference. For their initial video doctor selection, 53% of participants chose a European American, 29% chose a Latino, and 18% chose an African American. This pattern of preference was significantly different from the 33.3% for each race that would be expected in the absence of a racial preference (P<.001; Table 2).

Video doctor racial preferences differed significantly by race of the participant (P<.0001), with a preference for the same race. A substantial number of participants, however, chose a different-race video doctor. Racial preferences were similar across male and female participants (P=.98).

TABLE 1
Initial and final video doctor selections by sex

TABLE 2
Initial and final video doctor selections by race

Final preferences for video doctors

Final sex preference. The preference for a female video doctor increased across female and male participants (P<.001; Table 1). The net shift among males from male to female video doctor was significant (P=.014). More female participants shifted from male to female (9%) than from female to male (4%), although the difference was not statistically significant (P=.10).

Final race preference. Forty-eight percent of African American participants, 56% of Latino participants, and 44% of European Americans chose a different-race video doctor. Among Asian and other-race participants, a sizable shift occurred so that only 43% selected a European American video doctor (Table 2).

Between the initial and final selections, 3% of African American participants shifted to a video doctor of a different race, whereas 7% shifted to an African American video doctor. Eleven percent of Latino participants shifted to a different-race video doctor, whereas 6% shifted to a Latino video doctor. Among European American participants, 22% shifted to a different-race video doctor, whereas 12% shifted to a European American video doctor. With the exception of African American participants, there was a significant net shift from same- to different-race choice (P=.036). Many Asian and other-race participants shifted from a European American video doctor to a non–European American video doctor (14% net).

Assessment scores

The 3 female video doctors, who were chosen by more participants than were the 3 male video doctors at the initial and final selections, also received higher mean assessment scores (Table 3). On particular items, the highest score was 6.001 (of a possible 7), received by the European American female for the question: “How professional is this doctor?” The lowest score was 3.590 received by the European American male for the question: “If this person were your doctor, how comfortable might you be in talking with this person about personal health matters?”

TABLE 3
Selection of video doctor by sex and race

Association of preferences and ratings. Analysis of the mean assessment scores showed a substantial rating tendency among participants, by which they tended to give all 6 video doctors relatively high or low scores. Our analysis indicated that 34.9% (95% confidence interval [CI], 30.4–39.5) of the variance in assessment scores is explained by rating tendency.

We also found that participants tended to increase their scores as they proceeded through the sequence of doctors. Compared with the first video doctor, the second through the sixth video doctors received increases in mean scores of 0.15 (P=.016), 0.16 (P=.011), 0.29 (P<.001), 0.43 (P<.001), and 0.60 (P<.001), respectively. These results showed the importance of using multiple presentation orders to balance the order effect.

After adjusting for the order effect and the respondent rating tendency, the mean assessment scores given to video doctors selected at the initial stage were an average of 0.7 points higher than scores given to the other video doctors (P<.001, 95% CI, 0.56–0.81). At the final selection, the chosen video doctor scored on average 1.04 units higher on the assessment scores than did the other video doctors (P<.001, 95% CI, 0.94–1.1). Thus, the selection made based on the video doctors’ images and brief introductions alone was significantly associated with the subsequent assessment, and the final selection of video doctor was even more strongly associated with the assessment.

Discussion

More participants preferred same-race physicians at the initial selection (66% of European Americans, 51% of Latinos, and 50% of African Americans). This effect was not as large as one might expect, however, because a substantial minority of subjects in each racial category selected a different-race video doctor at the initial selection and a majority of Latinos selected a different-race video doctor at the final selection.

After viewing the delivery of the prevention message, more in each group, except for African Americans, chose a video doctor of a different race. In addition, at final selection, 57% of Asian and other-race participants chose a non– European American video doctor. With regard to sex, most males and females chose a female video doctor at the initial selection, and even more did so at the final selection. These data suggested that many healthcare consumers are in concordance with the recent shift toward a more diverse population of physicians and that the white male physician may no longer be viewed as the stereotypical medical professional.

The qualities patients seek in a doctor

The assessment scores for the video doctors indicated that participants were choosing, both on first impressions and after further exposure, video doctors who they perceived to possess the qualities associated with patient-centered care.^21,22 Although the overall ranking of the 6 video doctors was unchanged from initial to final selection, after viewing the delivery of the prevention message, many participants altered their choices: more males and females chose a female video doctor; more European American and Latino participants shifted from same-race to different-race video doctors; and more Asian and other-race participants shifted from European American to non–European American video doctors.

These findings suggested that, even in brief meetings with physicians, patients respond to a combination of patient-centered qualities and that this combination may carry more weight than the physician’s sex and race. In other words, from the point of view of the public at large, physicians of both sexes and all races can possess the desired physician qualities, and people may be receptive to any physician who exhibits these qualities.

Preference for a female doctor

Our finding that men and women in our sample preferred a female video doctor contrasts with sex preference findings from previous studies,^3,6,8,10,11 although in general studies on sex preference of physicians have shown inconsistent findings. The female preference finding in our study may represent evolving positive attitudes toward and increasing familiarity with female physicians. From 1971 to 1991, the percentage of women first-year medical school students rose from 13.7% to 39.8%.¹⁴

The strong female preference also may represent sex stereotyping. Patients reported that they desire physicians who are sensitive to their needs and circumstances, deliver a warm and empathic style of care,¹⁵ invite participation in decision making,¹⁶ engage in emotionally focused talk, and provide health information within patients’ social, emotional, and cultural contexts.¹⁷ Other studies found that women, when compared with men, provide a style of care that approximates these patient-centered characteristics.^18-20

Our participants, many of whom preferred female video doctors even at first, may have strongly associated a patient-centered, empathic style with being female. The particular female actors we chose also may have been better able to exhibit, regardless of our efforts to standardize, the combination of professional and personal skills most desired in a doctor.

Racial preferences

The preference for a same-race video doctor may have several origins. People may feel more familiar and comfortable with race-concordant relationships in general and may believe that a physician of one’s own race can better attend to specific health concerns. Same-race preference also may arise from the desire to avoid a racially prejudiced physician. Racially concordant as opposed to discordant care has been associated with increased patient satisfaction and use of health care services and with higher ratings from patients regarding their level of participation during physician visits.^16,23

As indicated in our study and others, African Americans express a stronger preference than do individuals from other racial groups for receiving care from physicians of their own race.²³ To support patients in exercising their racial preferences, some health care professional organizations, such as the National Medical Association, have provided a toll-free number that patients can call to locate a local African American physician.

Limitations of the study

The study had several limitations. We may not have successfully held constant the actors’ personalities and acting abilities. Future video doctor studies about patients’ acceptance regarding physicians’ race and sex could address this drawback by including multiple video doctors in each sex and race category.

Because only English-speaking participants were included in the study, we do not know whether Latinos who spoke only Spanish would have chosen differently. Our study also used a convenience sample in a San Francisco Bay Area shopping mall, and our results may not be generalizable to other populations.

We were unable to study the same-race preferences of the Asian participants in our sample. Because more than 10% of physicians practicing in the United States are of Asian ancestry, patients’ receptivity to Asian physicians and Asian patients’ preference for a same-race physician would be important research topics. Diversity of language and culture among various Asian and other ethnicities also could be addressed with a well-designed video doctor study. The absence of an Asian video doctor, however, did allow us to examine the selections made by participants when no same-race video doctor was available.

Strengths of the study

A major strength of our study was that participants represented both sexes and a range of ages, races, and education levels. In addition, the video technology allowed participants to select a video doctor based on a verisimilar experience and without the constraints of availability and access found in real-life choices. All our study participants accepted the survey questions and responded to the video doctor as a “real” physician.

Video doctor technology does allow for holding constant certain variables such as age, appearance, message content, and style of delivery, an advantage that cannot be achieved in real encounters between patients and physicians.

Challenges for the future

Some of our most crucial health care challenges are providing access to quality care and equal career opportunities for those who seek to practice medicine. Our results supported the growing diversity of the population of physicians, and emphasized that many patients will choose physicians, regardless of their sex and race, who appear professional, competent, and caring. Medical schools need to continue the trend toward teaching patient-centered, empathic care and recruiting and retaining minority physicians to rectify current imbalances. In addition, practicing physicians can take note that providing quality care for patients of all cultural backgrounds may be an easier task than they think—the common language of compassion may transcend our differences.

Future studies could use video doctor technology to confirm our findings and to further investigate patients’ preferences and attitudes about various dimensions of the relationship between patient and physician. As the patient population and the physician workforce diversify, and as managed care organizations continue to strive to increase patient satisfaction and retention, information about patient preferences could inform the future of health care delivery.

Acknowledgments

We thank Scott Ludwig for his excellent casting of actors, directing, and video production; and Annabelle Ison for designing subject recruitment materials. We also thank our video doctors, the staff of Tanforan Park Shopping Center in San Bruno, CA, and the mall visitors who volunteered to participate in the study.

Corresponding author
Barbara Gerbert, PhD, University of California at San Francisco, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94117. E-mail: [email protected].

Two recent surveys of patients undergoing cardiac surgery reported that 75% (263 of 376) and 81% (224 of 246) of patients currently use some form of complementary medicine (including herbs, vitamins, supplements, megavitamins, prayer, relaxation, spiritual healing, massage, imagery, and lifestyle and diet modifications).^1,2

Many herbal medicinal products are promoted for hypercholesterolemia, including some of the top-selling supplements. It is therefore vital to establish both the efficacy of these herbal supplements in reducing serum cholesterol levels and their relative safety. This review is an attempt to systematically summarize the evidence from randomized clinical trials for the efficacy and safety of lipid-lowering herbal medicinal products.

Methods

Identification of clinical trials

To identify clinical trials involving herbal medicinal products with hypocholesterolemic properties, we conducted systematic literature searches in the following electronic databases (all from their inception to May 2001): MEDLINE (via PubMed), EMBASE, CINAHL, AMED (Alternative and Allied Medicine Database, British Library Medical Information Centre), the Cochrane Library (Issue 2, 2001), and CISCOM (Research Council for Complementary Medicine, London, UK). The search strategy is summarized in Appendix A (available online at http://www.jfponline.com).

Further relevant papers were located by hand-searching the reference lists of all papers and departmental files. In addition, experts in the field and manufacturers were contacted to provide published and unpublished material.

Inclusion and exclusion criteria

Only randomized clinical trials investigating serum cholesterol reduction of monopreparations of herbal medicinal products administered as supplements were included. These could be placebo-controlled or equivalent trials. All retrieved data including uncontrolled trials, case reports, and preclinical and observational studies were reviewed for safety data. No language restrictions were imposed.

Data extraction and quality assessment

All articles were read in full. Data relating to sample size, study design, intervention and control, treatment duration, primary outcome measures, and results were extracted by the first author and validated by the second. The methodological quality of each trial was assessed using the Jadad scoring system,³ which ranges from 0 (poorest) to 5 (highest). A score of 3 or above indicates reasonable methodological quality.

Results

We identified 11 herbal medicinal products investigated for hypocholesterolemic properties in randomized clinical trials: guggul (Commiphora mukul), artichoke (Cynara scolymus), garlic (Allium sativum), fenugreek (Trigonella foenum- graecum), red yeast (Monascus purpureus) rice, Asian ginseng (Panax ginseng), yarrow (Achillea wilhelmsii), eggplant (Solanum melongena), holy basil (Ocimum sanctum), milk thistle (Silybum marianum), and arjun (Terminalia arjuna).

The efficacy and safety of garlic has been reviewed extensively elsewhere4–6 and is therefore not discussed in this paper. Details of all identified studies are shown in Tables 1–5 (and Table W1, available online at http://www.jfponline.com). Guggul, fenugreek, red yeast rice, and artichoke have been studied most extensively; randomized clinical trials of these herbal medicinal products with a Jadad score of 3 or above are discussed in more depth in Appendix B (available online at http://www.jfponline.com). Table 6 summarizes the adverse events experienced by subjects within these clinical trials and potential herb-drug interactions identified from systematic reviews.

Guggul (Commiphora mukul)

Six randomized clinical trials of guggul, involving 388 patients with different diagnoses, were identified.^7-12 Five were conducted in India and 1 in the United States; 4 were placebo-controlled; and 1 compared guggul with 2 reference compounds. The results suggest reductions in total serum cholesterol from 10% to 27% compared with baseline levels (Tables 1 and W1).

High-density lipoprotein (HDL) cholesterol levels were measured in 3 of the studies.^{7- 9} A significant increase was seen after 8 weeks of treatment in 1 study⁹; in the others, no significant differences were seen.^7,8 A statistically significant decrease in lipid peroxide levels was reported in 1 study, with no corresponding change in the placebo-treated group.⁷

Several mild adverse events were reported during these trials, including rash, nausea, vomiting, eructation, hiccup, headache, loose stools, restlessness, and apprehension, although information regarding adverse events experienced during placebo administration was not always provided. A potential drug interaction with propranolol and diltiazem was investigated in a randomized crossover trial of 17 healthy volunteers, in which guggul was found to significantly reduce the peak plasma concentration of both drugs.¹³

Fenugreek (Trigonella foenum-graecum)

Fenugreek seeds. Five randomized clinical trials were identified, involving 140 patients; all but 1 trial was conducted in India.^14-17 Although the methodological quality of the studies was considered generally poor in 4 of the trials, statistically significant reductions in total serum cholesterol of between 15% and 33% compared with baseline were demonstrated (Table 2).

Fenugreek leaves. In a single-blind study of 20 healthy male volunteers, Abdel-Barry and colleagues found a nonsignificant decrease of 9% in total serum cholesterol after a single dose of an aqueous extract made from fenugreek leaves (40 mg/kg) compared with a reduction of 2.8% after dilute coffee extract (placebo) (Table 2). ¹⁸

Within all the identified studies of fenugreek, patients reported mild gastrointestinal symptoms such as increased flatulence, nausea, fullness, and diarrhea during fenugreek treatment, but none was severe enough to necessitate withdrawal from the study. A 14% reduction in serum potassium was noted in healthy volunteers after a single dose of an aqueous extract of fenugreek leaves. ¹⁸

Red yeast rice

Red yeast rice is produced by solid-state fermentation of washed and cooked rice using the fungus Monascus purpureus. It has been used in Asia as a food preservative and colorant and for its medicinal properties since the Tang Dynasty (ad 800). It is available in capsules that contain a pulverized powder of fermented rice and yeast.

Four randomized clinical trials of the lipid-lowering effects of red yeast rice conducted in patients (n=695) with hyperlipidemia were identified (Table 3).^19-22 In all studies, statistically significant reductions (16% to 31%) in total serum cholesterol compared with placebo or control or baseline were seen.

Adverse events experienced in clinical trials included stomachache, heartburn, dizziness, and flatulence. No changes in liver function tests were demonstrated. There was 1 case report of a 26-year-old man who used red yeast rice in preparing sausages and developed anaphylaxis due to immediate sensitivity to M purpureus.²³ Whether this is relevant to the oral administration of red yeast rice capsules is not clear.

Artichoke (Cynara scolymus)

The choleretic effect of the leaf extract of artichoke has been studied widely, but only 2 randomized clinical trials of its hypocholesterolemic effects, involving 187 patients, were identified (Table 4).^24,25 One trial (n=44 healthy volunteers), published in abstract form only, found no significant difference in lipid levels compared with placebo, although post hoc subanalyses revealed some reductions in total serum cholesterol in patients with baseline levels above 5.4 mmol/L; these results should be interpreted with some caution. Reductions in total cholesterol of 18.5% and 8.6% were reported in the other, larger trial after artichoke and placebo treatments, respectively.

No adverse events were reported during either study. Three post-marketing surveillance studies were located: one included 417 patients and reported excellent tolerability in 95%; in the second (203 patients) no adverse reactions were reported; and the third (553 patients) described mild adverse events in 1.3% of patients (flatulence, hunger, and weakness).²⁴-²⁸

Discussion

Many different herbal medicinal products have been identified with potential lipid-lowering properties (Table 5), but the evidence for each herb is limited. The largest amount of published literature exists for guggul, fenugreek, red yeast rice, and artichoke, with reductions in total serum cholesterol ranging from 10% to 33%.

Although HDL and low-density lipoprotein (LDL) cholesterol were not measured in all the studies, increases in HDL and decreases in LDL levels were seen with guggul, red yeast rice, and yarrow, and decreases in LDL levels were seen in studies of fenugreek, arjun, and artichoke.

Safety

Few adverse events or drug interactions were reported in clinical trials of any of the 11 herbs identified. Many are used extensively in traditional medicine and culinary practices around the world, which supports their relative safety.

However, the long-term safety for use as herbal medicinal products has not been established. Long-term exposure of large numbers of patients within a formal setting would be necessary to determine safety, although difficulties associated with all herbal medicinal products exist, such as the inability to identify active ingredients and the potential for adulteration and misbranded products. No direct or indirect evidence exists for herb-drug interactions for fenugreek, guggul, Asian ginseng, and milk thistle (Table 6).

Study limitations

Although differences in study design, methodological quality, statistical methods, and subject populations create problems with interpretation of these figures, they appear to compare favorably with studies of garlic; the most recent meta-analysis suggested an average effect size of 4% to 6%.⁶ Studies of conventional therapeutic options for hypercholesterolemia (eg, statins) have demonstrated reductions of 20% to 30% in serum cholesterol.²⁹

Several shortcomings of the review need to be addressed. First, although attempts were made to obtain data from unpublished trials by contacting authors and manufacturers, none were located. There is evidence to suggest that studies with significant positive results are more likely to be published,³⁰ and this may be more pronounced with unfamiliar herbal therapies.

Second, because much of this research has been conducted in India and China, our extensive search strategy may not have located all the published material.

Third, there were several weaknesses with the original trials; of the 25 randomized clinical trials of herbal medicinal products for serum cholesterol reduction identified, only 12 scored 3 or more points on the Jadad scale. The most frequent methodological flaws were conduct of single-blind or open studies and incomplete reporting of methods of randomization, blinding, and subject withdrawals.

Conclusions

Evidence suggests that physicians do not ask their patients about complementary and alternative therapies and that patients are reticent to discuss these treatments with their physicians.^{31- 34} Surveys indicate widespread use of complementary and alternative therapies among patients undergoing cardiac surgery.^1,2 Although no equivalent surveys have been conducted for patients with hypercholesterolemia, in light of the relatively large number of herbal medicinal products with potential lipid-lowering properties available, it seems prudent for physicians to explore this area in their clinical decision-making process.

In conclusion, although 11 herbal medicinal products were identified with potential hypo-cholesterolemic activity, the evidence supporting individual plants is limited. In addition to lowering cholesterol, several of the herbs may exert beneficial effects in cardiovascular disease by elevating HDL levels and inhibiting lipid oxidation. The safety profiles of the products in question seems to be encouraging. Further research is therefore warranted to establish the therapeutic value of these herbs in the treatment of hypercholesterolemia.

Acknowledgments

The authors thank Jongbae Park, Barbara Wider, and Francesca Borelli, Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, for translation of papers from Chinese, Italian, and French, to and Esther Prati, Pharmaton, Lugano, for assistance with locating relevant articles. JTC received a research fellowship from Pharmaton SA, Lugano, Switzerland.

Two recent surveys of patients undergoing cardiac surgery reported that 75% (263 of 376) and 81% (224 of 246) of patients currently use some form of complementary medicine (including herbs, vitamins, supplements, megavitamins, prayer, relaxation, spiritual healing, massage, imagery, and lifestyle and diet modifications).^1,2

Many herbal medicinal products are promoted for hypercholesterolemia, including some of the top-selling supplements. It is therefore vital to establish both the efficacy of these herbal supplements in reducing serum cholesterol levels and their relative safety. This review is an attempt to systematically summarize the evidence from randomized clinical trials for the efficacy and safety of lipid-lowering herbal medicinal products.

Methods

Identification of clinical trials

To identify clinical trials involving herbal medicinal products with hypocholesterolemic properties, we conducted systematic literature searches in the following electronic databases (all from their inception to May 2001): MEDLINE (via PubMed), EMBASE, CINAHL, AMED (Alternative and Allied Medicine Database, British Library Medical Information Centre), the Cochrane Library (Issue 2, 2001), and CISCOM (Research Council for Complementary Medicine, London, UK). The search strategy is summarized in Appendix A (available online at http://www.jfponline.com).

Further relevant papers were located by hand-searching the reference lists of all papers and departmental files. In addition, experts in the field and manufacturers were contacted to provide published and unpublished material.

Inclusion and exclusion criteria

Only randomized clinical trials investigating serum cholesterol reduction of monopreparations of herbal medicinal products administered as supplements were included. These could be placebo-controlled or equivalent trials. All retrieved data including uncontrolled trials, case reports, and preclinical and observational studies were reviewed for safety data. No language restrictions were imposed.

Data extraction and quality assessment

All articles were read in full. Data relating to sample size, study design, intervention and control, treatment duration, primary outcome measures, and results were extracted by the first author and validated by the second. The methodological quality of each trial was assessed using the Jadad scoring system,³ which ranges from 0 (poorest) to 5 (highest). A score of 3 or above indicates reasonable methodological quality.

Results

We identified 11 herbal medicinal products investigated for hypocholesterolemic properties in randomized clinical trials: guggul (Commiphora mukul), artichoke (Cynara scolymus), garlic (Allium sativum), fenugreek (Trigonella foenum- graecum), red yeast (Monascus purpureus) rice, Asian ginseng (Panax ginseng), yarrow (Achillea wilhelmsii), eggplant (Solanum melongena), holy basil (Ocimum sanctum), milk thistle (Silybum marianum), and arjun (Terminalia arjuna).

The efficacy and safety of garlic has been reviewed extensively elsewhere4–6 and is therefore not discussed in this paper. Details of all identified studies are shown in Tables 1–5 (and Table W1, available online at http://www.jfponline.com). Guggul, fenugreek, red yeast rice, and artichoke have been studied most extensively; randomized clinical trials of these herbal medicinal products with a Jadad score of 3 or above are discussed in more depth in Appendix B (available online at http://www.jfponline.com). Table 6 summarizes the adverse events experienced by subjects within these clinical trials and potential herb-drug interactions identified from systematic reviews.

Guggul (Commiphora mukul)

Six randomized clinical trials of guggul, involving 388 patients with different diagnoses, were identified.^7-12 Five were conducted in India and 1 in the United States; 4 were placebo-controlled; and 1 compared guggul with 2 reference compounds. The results suggest reductions in total serum cholesterol from 10% to 27% compared with baseline levels (Tables 1 and W1).

High-density lipoprotein (HDL) cholesterol levels were measured in 3 of the studies.^{7- 9} A significant increase was seen after 8 weeks of treatment in 1 study⁹; in the others, no significant differences were seen.^7,8 A statistically significant decrease in lipid peroxide levels was reported in 1 study, with no corresponding change in the placebo-treated group.⁷

Several mild adverse events were reported during these trials, including rash, nausea, vomiting, eructation, hiccup, headache, loose stools, restlessness, and apprehension, although information regarding adverse events experienced during placebo administration was not always provided. A potential drug interaction with propranolol and diltiazem was investigated in a randomized crossover trial of 17 healthy volunteers, in which guggul was found to significantly reduce the peak plasma concentration of both drugs.¹³

Fenugreek (Trigonella foenum-graecum)

Fenugreek seeds. Five randomized clinical trials were identified, involving 140 patients; all but 1 trial was conducted in India.^14-17 Although the methodological quality of the studies was considered generally poor in 4 of the trials, statistically significant reductions in total serum cholesterol of between 15% and 33% compared with baseline were demonstrated (Table 2).

Fenugreek leaves. In a single-blind study of 20 healthy male volunteers, Abdel-Barry and colleagues found a nonsignificant decrease of 9% in total serum cholesterol after a single dose of an aqueous extract made from fenugreek leaves (40 mg/kg) compared with a reduction of 2.8% after dilute coffee extract (placebo) (Table 2). ¹⁸

Within all the identified studies of fenugreek, patients reported mild gastrointestinal symptoms such as increased flatulence, nausea, fullness, and diarrhea during fenugreek treatment, but none was severe enough to necessitate withdrawal from the study. A 14% reduction in serum potassium was noted in healthy volunteers after a single dose of an aqueous extract of fenugreek leaves. ¹⁸

Red yeast rice

Red yeast rice is produced by solid-state fermentation of washed and cooked rice using the fungus Monascus purpureus. It has been used in Asia as a food preservative and colorant and for its medicinal properties since the Tang Dynasty (ad 800). It is available in capsules that contain a pulverized powder of fermented rice and yeast.

Four randomized clinical trials of the lipid-lowering effects of red yeast rice conducted in patients (n=695) with hyperlipidemia were identified (Table 3).^19-22 In all studies, statistically significant reductions (16% to 31%) in total serum cholesterol compared with placebo or control or baseline were seen.

Adverse events experienced in clinical trials included stomachache, heartburn, dizziness, and flatulence. No changes in liver function tests were demonstrated. There was 1 case report of a 26-year-old man who used red yeast rice in preparing sausages and developed anaphylaxis due to immediate sensitivity to M purpureus.²³ Whether this is relevant to the oral administration of red yeast rice capsules is not clear.

Artichoke (Cynara scolymus)

The choleretic effect of the leaf extract of artichoke has been studied widely, but only 2 randomized clinical trials of its hypocholesterolemic effects, involving 187 patients, were identified (Table 4).^24,25 One trial (n=44 healthy volunteers), published in abstract form only, found no significant difference in lipid levels compared with placebo, although post hoc subanalyses revealed some reductions in total serum cholesterol in patients with baseline levels above 5.4 mmol/L; these results should be interpreted with some caution. Reductions in total cholesterol of 18.5% and 8.6% were reported in the other, larger trial after artichoke and placebo treatments, respectively.

No adverse events were reported during either study. Three post-marketing surveillance studies were located: one included 417 patients and reported excellent tolerability in 95%; in the second (203 patients) no adverse reactions were reported; and the third (553 patients) described mild adverse events in 1.3% of patients (flatulence, hunger, and weakness).²⁴-²⁸

Discussion

Many different herbal medicinal products have been identified with potential lipid-lowering properties (Table 5), but the evidence for each herb is limited. The largest amount of published literature exists for guggul, fenugreek, red yeast rice, and artichoke, with reductions in total serum cholesterol ranging from 10% to 33%.

Although HDL and low-density lipoprotein (LDL) cholesterol were not measured in all the studies, increases in HDL and decreases in LDL levels were seen with guggul, red yeast rice, and yarrow, and decreases in LDL levels were seen in studies of fenugreek, arjun, and artichoke.

Safety

Few adverse events or drug interactions were reported in clinical trials of any of the 11 herbs identified. Many are used extensively in traditional medicine and culinary practices around the world, which supports their relative safety.

However, the long-term safety for use as herbal medicinal products has not been established. Long-term exposure of large numbers of patients within a formal setting would be necessary to determine safety, although difficulties associated with all herbal medicinal products exist, such as the inability to identify active ingredients and the potential for adulteration and misbranded products. No direct or indirect evidence exists for herb-drug interactions for fenugreek, guggul, Asian ginseng, and milk thistle (Table 6).

Study limitations

Although differences in study design, methodological quality, statistical methods, and subject populations create problems with interpretation of these figures, they appear to compare favorably with studies of garlic; the most recent meta-analysis suggested an average effect size of 4% to 6%.⁶ Studies of conventional therapeutic options for hypercholesterolemia (eg, statins) have demonstrated reductions of 20% to 30% in serum cholesterol.²⁹

Several shortcomings of the review need to be addressed. First, although attempts were made to obtain data from unpublished trials by contacting authors and manufacturers, none were located. There is evidence to suggest that studies with significant positive results are more likely to be published,³⁰ and this may be more pronounced with unfamiliar herbal therapies.

Second, because much of this research has been conducted in India and China, our extensive search strategy may not have located all the published material.

Third, there were several weaknesses with the original trials; of the 25 randomized clinical trials of herbal medicinal products for serum cholesterol reduction identified, only 12 scored 3 or more points on the Jadad scale. The most frequent methodological flaws were conduct of single-blind or open studies and incomplete reporting of methods of randomization, blinding, and subject withdrawals.

Conclusions

Evidence suggests that physicians do not ask their patients about complementary and alternative therapies and that patients are reticent to discuss these treatments with their physicians.^{31- 34} Surveys indicate widespread use of complementary and alternative therapies among patients undergoing cardiac surgery.^1,2 Although no equivalent surveys have been conducted for patients with hypercholesterolemia, in light of the relatively large number of herbal medicinal products with potential lipid-lowering properties available, it seems prudent for physicians to explore this area in their clinical decision-making process.

In conclusion, although 11 herbal medicinal products were identified with potential hypo-cholesterolemic activity, the evidence supporting individual plants is limited. In addition to lowering cholesterol, several of the herbs may exert beneficial effects in cardiovascular disease by elevating HDL levels and inhibiting lipid oxidation. The safety profiles of the products in question seems to be encouraging. Further research is therefore warranted to establish the therapeutic value of these herbs in the treatment of hypercholesterolemia.

Acknowledgments

The authors thank Jongbae Park, Barbara Wider, and Francesca Borelli, Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, for translation of papers from Chinese, Italian, and French, to and Esther Prati, Pharmaton, Lugano, for assistance with locating relevant articles. JTC received a research fellowship from Pharmaton SA, Lugano, Switzerland.

Two recent surveys of patients undergoing cardiac surgery reported that 75% (263 of 376) and 81% (224 of 246) of patients currently use some form of complementary medicine (including herbs, vitamins, supplements, megavitamins, prayer, relaxation, spiritual healing, massage, imagery, and lifestyle and diet modifications).^1,2

Many herbal medicinal products are promoted for hypercholesterolemia, including some of the top-selling supplements. It is therefore vital to establish both the efficacy of these herbal supplements in reducing serum cholesterol levels and their relative safety. This review is an attempt to systematically summarize the evidence from randomized clinical trials for the efficacy and safety of lipid-lowering herbal medicinal products.

Methods

Identification of clinical trials

To identify clinical trials involving herbal medicinal products with hypocholesterolemic properties, we conducted systematic literature searches in the following electronic databases (all from their inception to May 2001): MEDLINE (via PubMed), EMBASE, CINAHL, AMED (Alternative and Allied Medicine Database, British Library Medical Information Centre), the Cochrane Library (Issue 2, 2001), and CISCOM (Research Council for Complementary Medicine, London, UK). The search strategy is summarized in Appendix A (available online at http://www.jfponline.com).

Further relevant papers were located by hand-searching the reference lists of all papers and departmental files. In addition, experts in the field and manufacturers were contacted to provide published and unpublished material.

Inclusion and exclusion criteria

Only randomized clinical trials investigating serum cholesterol reduction of monopreparations of herbal medicinal products administered as supplements were included. These could be placebo-controlled or equivalent trials. All retrieved data including uncontrolled trials, case reports, and preclinical and observational studies were reviewed for safety data. No language restrictions were imposed.

Data extraction and quality assessment

All articles were read in full. Data relating to sample size, study design, intervention and control, treatment duration, primary outcome measures, and results were extracted by the first author and validated by the second. The methodological quality of each trial was assessed using the Jadad scoring system,³ which ranges from 0 (poorest) to 5 (highest). A score of 3 or above indicates reasonable methodological quality.

Results

We identified 11 herbal medicinal products investigated for hypocholesterolemic properties in randomized clinical trials: guggul (Commiphora mukul), artichoke (Cynara scolymus), garlic (Allium sativum), fenugreek (Trigonella foenum- graecum), red yeast (Monascus purpureus) rice, Asian ginseng (Panax ginseng), yarrow (Achillea wilhelmsii), eggplant (Solanum melongena), holy basil (Ocimum sanctum), milk thistle (Silybum marianum), and arjun (Terminalia arjuna).

The efficacy and safety of garlic has been reviewed extensively elsewhere4–6 and is therefore not discussed in this paper. Details of all identified studies are shown in Tables 1–5 (and Table W1, available online at http://www.jfponline.com). Guggul, fenugreek, red yeast rice, and artichoke have been studied most extensively; randomized clinical trials of these herbal medicinal products with a Jadad score of 3 or above are discussed in more depth in Appendix B (available online at http://www.jfponline.com). Table 6 summarizes the adverse events experienced by subjects within these clinical trials and potential herb-drug interactions identified from systematic reviews.

Guggul (Commiphora mukul)

Six randomized clinical trials of guggul, involving 388 patients with different diagnoses, were identified.^7-12 Five were conducted in India and 1 in the United States; 4 were placebo-controlled; and 1 compared guggul with 2 reference compounds. The results suggest reductions in total serum cholesterol from 10% to 27% compared with baseline levels (Tables 1 and W1).

High-density lipoprotein (HDL) cholesterol levels were measured in 3 of the studies.^{7- 9} A significant increase was seen after 8 weeks of treatment in 1 study⁹; in the others, no significant differences were seen.^7,8 A statistically significant decrease in lipid peroxide levels was reported in 1 study, with no corresponding change in the placebo-treated group.⁷

Several mild adverse events were reported during these trials, including rash, nausea, vomiting, eructation, hiccup, headache, loose stools, restlessness, and apprehension, although information regarding adverse events experienced during placebo administration was not always provided. A potential drug interaction with propranolol and diltiazem was investigated in a randomized crossover trial of 17 healthy volunteers, in which guggul was found to significantly reduce the peak plasma concentration of both drugs.¹³

Fenugreek (Trigonella foenum-graecum)

Fenugreek seeds. Five randomized clinical trials were identified, involving 140 patients; all but 1 trial was conducted in India.^14-17 Although the methodological quality of the studies was considered generally poor in 4 of the trials, statistically significant reductions in total serum cholesterol of between 15% and 33% compared with baseline were demonstrated (Table 2).

Fenugreek leaves. In a single-blind study of 20 healthy male volunteers, Abdel-Barry and colleagues found a nonsignificant decrease of 9% in total serum cholesterol after a single dose of an aqueous extract made from fenugreek leaves (40 mg/kg) compared with a reduction of 2.8% after dilute coffee extract (placebo) (Table 2). ¹⁸

Within all the identified studies of fenugreek, patients reported mild gastrointestinal symptoms such as increased flatulence, nausea, fullness, and diarrhea during fenugreek treatment, but none was severe enough to necessitate withdrawal from the study. A 14% reduction in serum potassium was noted in healthy volunteers after a single dose of an aqueous extract of fenugreek leaves. ¹⁸

Red yeast rice

Red yeast rice is produced by solid-state fermentation of washed and cooked rice using the fungus Monascus purpureus. It has been used in Asia as a food preservative and colorant and for its medicinal properties since the Tang Dynasty (ad 800). It is available in capsules that contain a pulverized powder of fermented rice and yeast.

Four randomized clinical trials of the lipid-lowering effects of red yeast rice conducted in patients (n=695) with hyperlipidemia were identified (Table 3).^19-22 In all studies, statistically significant reductions (16% to 31%) in total serum cholesterol compared with placebo or control or baseline were seen.

Adverse events experienced in clinical trials included stomachache, heartburn, dizziness, and flatulence. No changes in liver function tests were demonstrated. There was 1 case report of a 26-year-old man who used red yeast rice in preparing sausages and developed anaphylaxis due to immediate sensitivity to M purpureus.²³ Whether this is relevant to the oral administration of red yeast rice capsules is not clear.

Artichoke (Cynara scolymus)

The choleretic effect of the leaf extract of artichoke has been studied widely, but only 2 randomized clinical trials of its hypocholesterolemic effects, involving 187 patients, were identified (Table 4).^24,25 One trial (n=44 healthy volunteers), published in abstract form only, found no significant difference in lipid levels compared with placebo, although post hoc subanalyses revealed some reductions in total serum cholesterol in patients with baseline levels above 5.4 mmol/L; these results should be interpreted with some caution. Reductions in total cholesterol of 18.5% and 8.6% were reported in the other, larger trial after artichoke and placebo treatments, respectively.

No adverse events were reported during either study. Three post-marketing surveillance studies were located: one included 417 patients and reported excellent tolerability in 95%; in the second (203 patients) no adverse reactions were reported; and the third (553 patients) described mild adverse events in 1.3% of patients (flatulence, hunger, and weakness).²⁴-²⁸

Discussion

Many different herbal medicinal products have been identified with potential lipid-lowering properties (Table 5), but the evidence for each herb is limited. The largest amount of published literature exists for guggul, fenugreek, red yeast rice, and artichoke, with reductions in total serum cholesterol ranging from 10% to 33%.

Although HDL and low-density lipoprotein (LDL) cholesterol were not measured in all the studies, increases in HDL and decreases in LDL levels were seen with guggul, red yeast rice, and yarrow, and decreases in LDL levels were seen in studies of fenugreek, arjun, and artichoke.

Safety

Few adverse events or drug interactions were reported in clinical trials of any of the 11 herbs identified. Many are used extensively in traditional medicine and culinary practices around the world, which supports their relative safety.

However, the long-term safety for use as herbal medicinal products has not been established. Long-term exposure of large numbers of patients within a formal setting would be necessary to determine safety, although difficulties associated with all herbal medicinal products exist, such as the inability to identify active ingredients and the potential for adulteration and misbranded products. No direct or indirect evidence exists for herb-drug interactions for fenugreek, guggul, Asian ginseng, and milk thistle (Table 6).

Study limitations

Although differences in study design, methodological quality, statistical methods, and subject populations create problems with interpretation of these figures, they appear to compare favorably with studies of garlic; the most recent meta-analysis suggested an average effect size of 4% to 6%.⁶ Studies of conventional therapeutic options for hypercholesterolemia (eg, statins) have demonstrated reductions of 20% to 30% in serum cholesterol.²⁹

Several shortcomings of the review need to be addressed. First, although attempts were made to obtain data from unpublished trials by contacting authors and manufacturers, none were located. There is evidence to suggest that studies with significant positive results are more likely to be published,³⁰ and this may be more pronounced with unfamiliar herbal therapies.

Second, because much of this research has been conducted in India and China, our extensive search strategy may not have located all the published material.

Third, there were several weaknesses with the original trials; of the 25 randomized clinical trials of herbal medicinal products for serum cholesterol reduction identified, only 12 scored 3 or more points on the Jadad scale. The most frequent methodological flaws were conduct of single-blind or open studies and incomplete reporting of methods of randomization, blinding, and subject withdrawals.

Conclusions

Evidence suggests that physicians do not ask their patients about complementary and alternative therapies and that patients are reticent to discuss these treatments with their physicians.^{31- 34} Surveys indicate widespread use of complementary and alternative therapies among patients undergoing cardiac surgery.^1,2 Although no equivalent surveys have been conducted for patients with hypercholesterolemia, in light of the relatively large number of herbal medicinal products with potential lipid-lowering properties available, it seems prudent for physicians to explore this area in their clinical decision-making process.

In conclusion, although 11 herbal medicinal products were identified with potential hypo-cholesterolemic activity, the evidence supporting individual plants is limited. In addition to lowering cholesterol, several of the herbs may exert beneficial effects in cardiovascular disease by elevating HDL levels and inhibiting lipid oxidation. The safety profiles of the products in question seems to be encouraging. Further research is therefore warranted to establish the therapeutic value of these herbs in the treatment of hypercholesterolemia.

Acknowledgments

The authors thank Jongbae Park, Barbara Wider, and Francesca Borelli, Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, for translation of papers from Chinese, Italian, and French, to and Esther Prati, Pharmaton, Lugano, for assistance with locating relevant articles. JTC received a research fellowship from Pharmaton SA, Lugano, Switzerland.

Although many medications are available for patients with asthma, inhaled corticosteroids are generally the preferred treatment.^1-4 Multiple studies have demonstrated that inhaled corticosteroid therapy improves patient outcomes.¹ Inhaled corticosteroids have been shown to decrease costs⁵ and use of medical care resources.^6-8

More recently, leukotriene modifiers have been introduced for asthma treatment. This class of medication has bronchodilator and anti-inflammatory effects.⁹ Although multiple studies have indicated improved outcomes and decreased costs associated with leukotriene modifier therapy incertain patient populations,^10,11 its role in asthmamanagement is uncertain.⁹

Several studies have compared the clinical outcomes of these therapies^12-15 and their impact on medical care resource use and costs.^16,17 However, these studies were not powered specifically to detect significant differences in resource use or costs.

We performed a meta-analysis to (1) compare the rate of hospitalization among patients with asthma treated with inhaled corticosteroids vs those treated with leukotriene modifiers and (2) evaluate other resource use rates and costs for these patients.

Methods

The meta-analysis consisted of a literature search, the development of inclusion criteria, form development, and literature review.

Literature search

We searched the MEDLINE, EMBASE, Cochrane Collaboration Study Registry, and GlaxoSmithKline databases and consulted experts in this field. The GlaxoSmithKline database consists of studies sponsored by GlaxoSmithKline that met companywide minimum quality thresholds and were published in full or abstract form.

We also contacted the manufacturers of leukotriene modifiers available in the United States, AstraZeneca and Merck, to request published and unpublished information on studies comparing leukotriene modifiers with inhaled corticosteroids. To provide results corresponding to current treatment patterns, only studies from 1991 to 2001 were included. Published and unpublished materials were included.^18,19

Inclusion criteria

Studies were included in the meta-analysis if they met the following criteria.

Population. Patients with diagnosed asthma. Only studies that did not restrict analyses to severe asthma patients or children were included.

Study design. Prospective and retrospective comparative studies of patients receiving inhaled corticosteroid or leukotriene modifier monotherapy (no other controller therapy) in the same study. Studies were required to have defined inclusion and exclusion criteria, defined number of patients in each study arm, defined treatment protocol (ie, medications and doses used), and separate results for each medication.

Only studies presenting primary research (hence excluding review articles and metaanalyses) were included. Only studies presenting data for at least 6 months on all participants were included.

Outcomes. Hospitalization visit rates and costs, emergency department visit rates and costs, pharmacy costs, total asthma-related costs, and total medical care costs. Because resource use patterns and medical care cost information differs substantially between countries, we only included US studies.

Study process

Each identified article was evaluated by 2 independent reviewers (KMS and MG); any differences were discussed with a project leader to reach a consensus. Documents selected for inclusion were then reviewed by the 2 reviewers, and differences in data abstraction were resolved before inclusion.

Analysis

We used the Q statistic²⁰ to assess heterogeneity and, when appropriate, combined data from included studies with the use of a random effects model. Random effects methodology was used to assess the impact of inhaled corticosteroid vs leukotriene modifier therapy on the overall asthma population, not just the subpopulation of patients participating in included studies.²¹

Two sets of meta-analyses were performed with the abstracted data. First, the specified outcome measures were compared for patients taking inhaled corticosteroid vs leukotriene modifier therapy. Second, the impact (before vs after) of each treatment initiation was compared for each outcome.

Assessment of statistically significant differences between meta-analysis results was performed with the Student t test, with an Α of .05. Charges were used in the included studies as proxies for costs. These costs were inflated to 2000 values by using the medical care component of the consumer price index before inclusion.

Results

We identified 49 documents and reviewed them for inclusion in the meta-analysis; 6 (12.2%) met the inclusion criteria (Table 1). Five were retrospective cohort studies; only 1 study was identified as a prospective trial comparing inhaled corticosteroid and leukotriene modifier therapies and including results on resource use or medical care costs.^16,17,22-25 All 6 studies were performed with support from GlaxoSmithKline.

Forty-three documents were excluded due to 1 or more of the following criteria: lack of primary results (9 documents, 21%); did not contain resource use rate or cost outcomes (22 documents, 51%); did not provide at least 6 months’ worth of data on resource use or cost outcomes (5 documents, 12%); did not meet the defined inclusion and exclusion criteria (primarily studies not including both inhaled corticosteroid and leukotriene modifiers or those restricted to patient clinical subgroups; 10 documents, 34%); or did not define the number of patients included in the study (1 document, 3%).

Because few studies presented data on the specified outcomes, we were unable to assess asthma-specific costs for subcategories of resource use. Too few studies included data on hospitalization costs (either asthma-specific or overall) to include in the analysis. Therefore, meta-analysis was performed on overall (ie, all causes) emergency department, pharmacy, and total medical care costs.

TABLE 1
Characteristics of studies included in the meta-analysis

Primary analysis

The primary objective of this study was to evaluate the impact of inhaled corticosteroid and leukotriene modifier treatment on the mean annual hospitalization rate. Four of the 6 included studies contained information on hospitalization rate for each treatment. Results from the primary analysis are presented in Table 2.

Patients taking inhaled corticosteroids had a significantly lower annual rate of hospitalization than did patients taking leukotriene modifiers (2.23% vs 4.30%, respectively; P<.005). The absolute risk reduction was 2.07% (number needed to treat=48 for 1 year).

The difference in annual hospitalization visit rates for each study in the primary analysis is presented in the Figure, where negative values reflect lower hospitalization rates among patients taking inhaled corticosteroids than among those taking leukotriene modifiers. Two studies^16,23 had statistically significant differences in hospitalization rates, whereas the differences in the other 2 studies were not statistically significant (P<.05). Combining studies with the use of a random effects model (the default methodology for this analysis) or a fixed effects model produced similar results. The Q statistic indicated no significant heterogeneity (P=.43).

TABLE 2
Meta-analysis results for inhaled corticosteroid vs leukotriene modifier therapy*

FIGURE
Difference in hospitalization rates (mean, confidence interval)

Secondary outcomes

Results of secondary analyses for 5 study outcomes (annual visits to the emergency department due to asthma, total emergency department costs, total drug costs, total asthma-related costs, and overall total cost) are presented in Table 2.

Mean annual rates of visits to the emergency department and total annual drug costs were significantly higher for patients taking leukotriene modifiers than for those taking inhaled corticosteroids (P<.005 for each). Patients taking leukotriene modifiers had lower annual costs for visits to the emergency department than did those taking inhaled corticosteroids, although this difference was not statistically significant. The higher rate and lower cost of emergency department visits for patients taking leukotriene modifiers suggest that medical resources were used less at each visit as compared with those for patients taking inhaled corticosteroids.

Total asthma-related costs for patients taking inhaled corticosteroids were significantly lower than those for patients taking leukotriene modifiers (P<.05). Patients taking inhaled corticosteroids also incurred decreased annual total (allcause) medical care costs. Although this difference was qualitatively large (approximately $1900, or a decrease of over 17%), it did not reach statistical significance.

Pre- vs post-initiation of therapy

In addition to comparing the impact of the 2 therapies on resource use and costs, we were interested in the impact of initiating each therapy on the study outcomes. We therefore assessed resource use rates and costs before and after treatment initiation. These patients may have been receiving asthma therapies (or no asthma therapy) other than inhaled corticosteroids or leukotriene modifiers. The number of studies presenting data on costs was too small to allow comparison.

Results of this within-group analysis are presented in Table 3. For patients taking inhaled corticosteroids, hospitalization rates and emergency department visit rates decreased significantly after treatment initiation compared with the preinitiation values (P<.005 and P<.05, respectively). The decreases for patients taking leukotriene modifiers upon treatment initiation were smaller and not statistically significant.

Both groups showed similar small decreases in annual emergency department costs, neither of which was significant. The increases in annual total drug costs and annual total medical care costs after treatment initiation were significant for both groups of patients (all at P<.005). However, both increases were greater for patients taking leukotriene modifiers; the increase in drug costs was statistically significant (P<.001).

TABLE 3
Resource utilization and costs before and after therapy initiation for inhaled corticosteroids vs leukotriene modifiers*

Discussion

In this study, we used meta-analysis to combine data across studies and determine more robust estimates of the impact of inhaled corticosteroid vs leukotriene modifier therapy on medical resource use rates and costs. The primary analysis indicated that annual hospitalization rates among patients taking inhaled corticosteroids are significantly lower that those taking leukotriene modifiers. Other resource use rates and costs evaluated in this study also generally showed decreased values for patients taking inhaled corticosteroids.

Although meta-analysis generally has been used for clinical outcome measures, it is a highly appropriate method for resource use and cost outcomes. In general, studies of the impact of a particular treatment are powered to assess safety and efficacy or effectiveness; there is often insufficient power to detect differences in resource use or costs in any one study. Due to substantial variation in treatment patterns, the variance associated with resource use rates (and associated costs) may be substantially higher than that for clinical measures; such a wide variance adds to the difficulties in assessing differences for nonclinical outcomes.

Limitations

This study has a number of limitations. Only a few studies met inclusion criteria for the meta-analysis; the analysis should be replicated as additional studies become available. Data were abstracted from the included studies without modification (except for inflating costs to 2000 values when necessary). As in all meta-analyses, any problems present in the original data are present in the combined data; limitations of the original data are not addressed by this method.

Among the studies evaluated for the metaanalysis were a number published only as abstracts. Inclusion of unpublished literature in meta-analyses is controversial; however, several sources^18,19 now recommend inclusion of published and unpublished studies. Egger and Smith²⁶ found that studies with significant results are more likely to be published than are studies with nonsignificant results, leading to publication bias. Studies with significant results also may be more likely to be published in indexed journals, leading to “database bias.” As such, inclusion of unpublished studies is important to produce unbiased results.

Five of the 6 studies that met the inclusion criteria were observational, retrospective cohort analyses. Whereas many meta-analyses focus solely on prospective, randomized clinical trials, several have included retrospective data.^27,28 Retrospective analyses and observational data have a number of limitations, in particular the lack of randomization that can lead to differences in characteristics of specified treatment groups. Further, as discussed by Egger et al,²⁹ metaanalyses based on observational studies may involve bias and confounding.

However, observational data and retrospective analyses also have the advantage of reflecting “real world” treatment patterns and broader patient groups that increase the generalizability of the data, whereas clinical trials may include protocol-driven utilization and selected patient groups. Clinical trials also may occur in specialized health care settings, whereas observational (cohort) data may be more applicable to clinical practice. Due to these factors, meta-analysis of observational data has become common.²⁹

The pre-initiation vs post-initiation analysis indicated that values for each treatment group provide information on the similarities between treatment groups before initiation of controller therapy. Even though the treatment groups were not randomized to each therapy and we have no means to ensure compatibility between groups, having similar rates of resource use between groups provides some evidence regarding similarity. Nonetheless, given the limitations of the retrospective data and meta-analysis in general, it will be important to validate the results of this meta-analysis in the future with naturalistic prospective studies.

Despite these limitations, this study provides important information on the impact of asthma therapies on resource use and costs. Specifically, the resource use and cost outcomes assessed in this study were lower for inhaled corticosteroid patients than for leukotriene modifier patients. This study also illustrates the usefulness of metaanalysis in evaluating resource use and costs. By selecting and combining outcomes across studies in a standardized, rigorous, and transparent manner, the effects of different therapies can be evaluated with greater precision.

Acknowledgments

We thank John O’Donnell and Layne Gothard for their assistance with this manuscript.

Corresponding author
Michael T. Halpern, MD, PhD, Principal Scientist, Exponent, Inc., 1800 Diagonal Road, Alexandria, VA 22314. E-mail: [email protected]

Although many medications are available for patients with asthma, inhaled corticosteroids are generally the preferred treatment.^1-4 Multiple studies have demonstrated that inhaled corticosteroid therapy improves patient outcomes.¹ Inhaled corticosteroids have been shown to decrease costs⁵ and use of medical care resources.^6-8

More recently, leukotriene modifiers have been introduced for asthma treatment. This class of medication has bronchodilator and anti-inflammatory effects.⁹ Although multiple studies have indicated improved outcomes and decreased costs associated with leukotriene modifier therapy incertain patient populations,^10,11 its role in asthmamanagement is uncertain.⁹

Several studies have compared the clinical outcomes of these therapies^12-15 and their impact on medical care resource use and costs.^16,17 However, these studies were not powered specifically to detect significant differences in resource use or costs.

We performed a meta-analysis to (1) compare the rate of hospitalization among patients with asthma treated with inhaled corticosteroids vs those treated with leukotriene modifiers and (2) evaluate other resource use rates and costs for these patients.

Methods

The meta-analysis consisted of a literature search, the development of inclusion criteria, form development, and literature review.

Literature search

We searched the MEDLINE, EMBASE, Cochrane Collaboration Study Registry, and GlaxoSmithKline databases and consulted experts in this field. The GlaxoSmithKline database consists of studies sponsored by GlaxoSmithKline that met companywide minimum quality thresholds and were published in full or abstract form.

We also contacted the manufacturers of leukotriene modifiers available in the United States, AstraZeneca and Merck, to request published and unpublished information on studies comparing leukotriene modifiers with inhaled corticosteroids. To provide results corresponding to current treatment patterns, only studies from 1991 to 2001 were included. Published and unpublished materials were included.^18,19

Inclusion criteria

Studies were included in the meta-analysis if they met the following criteria.

Population. Patients with diagnosed asthma. Only studies that did not restrict analyses to severe asthma patients or children were included.

Study design. Prospective and retrospective comparative studies of patients receiving inhaled corticosteroid or leukotriene modifier monotherapy (no other controller therapy) in the same study. Studies were required to have defined inclusion and exclusion criteria, defined number of patients in each study arm, defined treatment protocol (ie, medications and doses used), and separate results for each medication.

Only studies presenting primary research (hence excluding review articles and metaanalyses) were included. Only studies presenting data for at least 6 months on all participants were included.

Outcomes. Hospitalization visit rates and costs, emergency department visit rates and costs, pharmacy costs, total asthma-related costs, and total medical care costs. Because resource use patterns and medical care cost information differs substantially between countries, we only included US studies.

Study process

Each identified article was evaluated by 2 independent reviewers (KMS and MG); any differences were discussed with a project leader to reach a consensus. Documents selected for inclusion were then reviewed by the 2 reviewers, and differences in data abstraction were resolved before inclusion.

Analysis

We used the Q statistic²⁰ to assess heterogeneity and, when appropriate, combined data from included studies with the use of a random effects model. Random effects methodology was used to assess the impact of inhaled corticosteroid vs leukotriene modifier therapy on the overall asthma population, not just the subpopulation of patients participating in included studies.²¹

Two sets of meta-analyses were performed with the abstracted data. First, the specified outcome measures were compared for patients taking inhaled corticosteroid vs leukotriene modifier therapy. Second, the impact (before vs after) of each treatment initiation was compared for each outcome.

Assessment of statistically significant differences between meta-analysis results was performed with the Student t test, with an Α of .05. Charges were used in the included studies as proxies for costs. These costs were inflated to 2000 values by using the medical care component of the consumer price index before inclusion.

Results

We identified 49 documents and reviewed them for inclusion in the meta-analysis; 6 (12.2%) met the inclusion criteria (Table 1). Five were retrospective cohort studies; only 1 study was identified as a prospective trial comparing inhaled corticosteroid and leukotriene modifier therapies and including results on resource use or medical care costs.^16,17,22-25 All 6 studies were performed with support from GlaxoSmithKline.

Forty-three documents were excluded due to 1 or more of the following criteria: lack of primary results (9 documents, 21%); did not contain resource use rate or cost outcomes (22 documents, 51%); did not provide at least 6 months’ worth of data on resource use or cost outcomes (5 documents, 12%); did not meet the defined inclusion and exclusion criteria (primarily studies not including both inhaled corticosteroid and leukotriene modifiers or those restricted to patient clinical subgroups; 10 documents, 34%); or did not define the number of patients included in the study (1 document, 3%).

Because few studies presented data on the specified outcomes, we were unable to assess asthma-specific costs for subcategories of resource use. Too few studies included data on hospitalization costs (either asthma-specific or overall) to include in the analysis. Therefore, meta-analysis was performed on overall (ie, all causes) emergency department, pharmacy, and total medical care costs.

TABLE 1
Characteristics of studies included in the meta-analysis

Primary analysis

The primary objective of this study was to evaluate the impact of inhaled corticosteroid and leukotriene modifier treatment on the mean annual hospitalization rate. Four of the 6 included studies contained information on hospitalization rate for each treatment. Results from the primary analysis are presented in Table 2.

Patients taking inhaled corticosteroids had a significantly lower annual rate of hospitalization than did patients taking leukotriene modifiers (2.23% vs 4.30%, respectively; P<.005). The absolute risk reduction was 2.07% (number needed to treat=48 for 1 year).

The difference in annual hospitalization visit rates for each study in the primary analysis is presented in the Figure, where negative values reflect lower hospitalization rates among patients taking inhaled corticosteroids than among those taking leukotriene modifiers. Two studies^16,23 had statistically significant differences in hospitalization rates, whereas the differences in the other 2 studies were not statistically significant (P<.05). Combining studies with the use of a random effects model (the default methodology for this analysis) or a fixed effects model produced similar results. The Q statistic indicated no significant heterogeneity (P=.43).

TABLE 2
Meta-analysis results for inhaled corticosteroid vs leukotriene modifier therapy*

FIGURE
Difference in hospitalization rates (mean, confidence interval)

Secondary outcomes

Results of secondary analyses for 5 study outcomes (annual visits to the emergency department due to asthma, total emergency department costs, total drug costs, total asthma-related costs, and overall total cost) are presented in Table 2.

Mean annual rates of visits to the emergency department and total annual drug costs were significantly higher for patients taking leukotriene modifiers than for those taking inhaled corticosteroids (P<.005 for each). Patients taking leukotriene modifiers had lower annual costs for visits to the emergency department than did those taking inhaled corticosteroids, although this difference was not statistically significant. The higher rate and lower cost of emergency department visits for patients taking leukotriene modifiers suggest that medical resources were used less at each visit as compared with those for patients taking inhaled corticosteroids.

Total asthma-related costs for patients taking inhaled corticosteroids were significantly lower than those for patients taking leukotriene modifiers (P<.05). Patients taking inhaled corticosteroids also incurred decreased annual total (allcause) medical care costs. Although this difference was qualitatively large (approximately $1900, or a decrease of over 17%), it did not reach statistical significance.

Pre- vs post-initiation of therapy

In addition to comparing the impact of the 2 therapies on resource use and costs, we were interested in the impact of initiating each therapy on the study outcomes. We therefore assessed resource use rates and costs before and after treatment initiation. These patients may have been receiving asthma therapies (or no asthma therapy) other than inhaled corticosteroids or leukotriene modifiers. The number of studies presenting data on costs was too small to allow comparison.

Results of this within-group analysis are presented in Table 3. For patients taking inhaled corticosteroids, hospitalization rates and emergency department visit rates decreased significantly after treatment initiation compared with the preinitiation values (P<.005 and P<.05, respectively). The decreases for patients taking leukotriene modifiers upon treatment initiation were smaller and not statistically significant.

Both groups showed similar small decreases in annual emergency department costs, neither of which was significant. The increases in annual total drug costs and annual total medical care costs after treatment initiation were significant for both groups of patients (all at P<.005). However, both increases were greater for patients taking leukotriene modifiers; the increase in drug costs was statistically significant (P<.001).

TABLE 3
Resource utilization and costs before and after therapy initiation for inhaled corticosteroids vs leukotriene modifiers*

Discussion

In this study, we used meta-analysis to combine data across studies and determine more robust estimates of the impact of inhaled corticosteroid vs leukotriene modifier therapy on medical resource use rates and costs. The primary analysis indicated that annual hospitalization rates among patients taking inhaled corticosteroids are significantly lower that those taking leukotriene modifiers. Other resource use rates and costs evaluated in this study also generally showed decreased values for patients taking inhaled corticosteroids.

Although meta-analysis generally has been used for clinical outcome measures, it is a highly appropriate method for resource use and cost outcomes. In general, studies of the impact of a particular treatment are powered to assess safety and efficacy or effectiveness; there is often insufficient power to detect differences in resource use or costs in any one study. Due to substantial variation in treatment patterns, the variance associated with resource use rates (and associated costs) may be substantially higher than that for clinical measures; such a wide variance adds to the difficulties in assessing differences for nonclinical outcomes.

Limitations

This study has a number of limitations. Only a few studies met inclusion criteria for the meta-analysis; the analysis should be replicated as additional studies become available. Data were abstracted from the included studies without modification (except for inflating costs to 2000 values when necessary). As in all meta-analyses, any problems present in the original data are present in the combined data; limitations of the original data are not addressed by this method.

Among the studies evaluated for the metaanalysis were a number published only as abstracts. Inclusion of unpublished literature in meta-analyses is controversial; however, several sources^18,19 now recommend inclusion of published and unpublished studies. Egger and Smith²⁶ found that studies with significant results are more likely to be published than are studies with nonsignificant results, leading to publication bias. Studies with significant results also may be more likely to be published in indexed journals, leading to “database bias.” As such, inclusion of unpublished studies is important to produce unbiased results.

Five of the 6 studies that met the inclusion criteria were observational, retrospective cohort analyses. Whereas many meta-analyses focus solely on prospective, randomized clinical trials, several have included retrospective data.^27,28 Retrospective analyses and observational data have a number of limitations, in particular the lack of randomization that can lead to differences in characteristics of specified treatment groups. Further, as discussed by Egger et al,²⁹ metaanalyses based on observational studies may involve bias and confounding.

However, observational data and retrospective analyses also have the advantage of reflecting “real world” treatment patterns and broader patient groups that increase the generalizability of the data, whereas clinical trials may include protocol-driven utilization and selected patient groups. Clinical trials also may occur in specialized health care settings, whereas observational (cohort) data may be more applicable to clinical practice. Due to these factors, meta-analysis of observational data has become common.²⁹

The pre-initiation vs post-initiation analysis indicated that values for each treatment group provide information on the similarities between treatment groups before initiation of controller therapy. Even though the treatment groups were not randomized to each therapy and we have no means to ensure compatibility between groups, having similar rates of resource use between groups provides some evidence regarding similarity. Nonetheless, given the limitations of the retrospective data and meta-analysis in general, it will be important to validate the results of this meta-analysis in the future with naturalistic prospective studies.

Despite these limitations, this study provides important information on the impact of asthma therapies on resource use and costs. Specifically, the resource use and cost outcomes assessed in this study were lower for inhaled corticosteroid patients than for leukotriene modifier patients. This study also illustrates the usefulness of metaanalysis in evaluating resource use and costs. By selecting and combining outcomes across studies in a standardized, rigorous, and transparent manner, the effects of different therapies can be evaluated with greater precision.

Acknowledgments

We thank John O’Donnell and Layne Gothard for their assistance with this manuscript.

Corresponding author
Michael T. Halpern, MD, PhD, Principal Scientist, Exponent, Inc., 1800 Diagonal Road, Alexandria, VA 22314. E-mail: [email protected]

Although many medications are available for patients with asthma, inhaled corticosteroids are generally the preferred treatment.^1-4 Multiple studies have demonstrated that inhaled corticosteroid therapy improves patient outcomes.¹ Inhaled corticosteroids have been shown to decrease costs⁵ and use of medical care resources.^6-8

More recently, leukotriene modifiers have been introduced for asthma treatment. This class of medication has bronchodilator and anti-inflammatory effects.⁹ Although multiple studies have indicated improved outcomes and decreased costs associated with leukotriene modifier therapy incertain patient populations,^10,11 its role in asthmamanagement is uncertain.⁹

Several studies have compared the clinical outcomes of these therapies^12-15 and their impact on medical care resource use and costs.^16,17 However, these studies were not powered specifically to detect significant differences in resource use or costs.

We performed a meta-analysis to (1) compare the rate of hospitalization among patients with asthma treated with inhaled corticosteroids vs those treated with leukotriene modifiers and (2) evaluate other resource use rates and costs for these patients.

Methods

The meta-analysis consisted of a literature search, the development of inclusion criteria, form development, and literature review.

Literature search

We searched the MEDLINE, EMBASE, Cochrane Collaboration Study Registry, and GlaxoSmithKline databases and consulted experts in this field. The GlaxoSmithKline database consists of studies sponsored by GlaxoSmithKline that met companywide minimum quality thresholds and were published in full or abstract form.

We also contacted the manufacturers of leukotriene modifiers available in the United States, AstraZeneca and Merck, to request published and unpublished information on studies comparing leukotriene modifiers with inhaled corticosteroids. To provide results corresponding to current treatment patterns, only studies from 1991 to 2001 were included. Published and unpublished materials were included.^18,19

Inclusion criteria

Studies were included in the meta-analysis if they met the following criteria.

Population. Patients with diagnosed asthma. Only studies that did not restrict analyses to severe asthma patients or children were included.

Study design. Prospective and retrospective comparative studies of patients receiving inhaled corticosteroid or leukotriene modifier monotherapy (no other controller therapy) in the same study. Studies were required to have defined inclusion and exclusion criteria, defined number of patients in each study arm, defined treatment protocol (ie, medications and doses used), and separate results for each medication.

Only studies presenting primary research (hence excluding review articles and metaanalyses) were included. Only studies presenting data for at least 6 months on all participants were included.

Outcomes. Hospitalization visit rates and costs, emergency department visit rates and costs, pharmacy costs, total asthma-related costs, and total medical care costs. Because resource use patterns and medical care cost information differs substantially between countries, we only included US studies.

Study process

Each identified article was evaluated by 2 independent reviewers (KMS and MG); any differences were discussed with a project leader to reach a consensus. Documents selected for inclusion were then reviewed by the 2 reviewers, and differences in data abstraction were resolved before inclusion.

Analysis

We used the Q statistic²⁰ to assess heterogeneity and, when appropriate, combined data from included studies with the use of a random effects model. Random effects methodology was used to assess the impact of inhaled corticosteroid vs leukotriene modifier therapy on the overall asthma population, not just the subpopulation of patients participating in included studies.²¹

Two sets of meta-analyses were performed with the abstracted data. First, the specified outcome measures were compared for patients taking inhaled corticosteroid vs leukotriene modifier therapy. Second, the impact (before vs after) of each treatment initiation was compared for each outcome.

Assessment of statistically significant differences between meta-analysis results was performed with the Student t test, with an Α of .05. Charges were used in the included studies as proxies for costs. These costs were inflated to 2000 values by using the medical care component of the consumer price index before inclusion.

Results

We identified 49 documents and reviewed them for inclusion in the meta-analysis; 6 (12.2%) met the inclusion criteria (Table 1). Five were retrospective cohort studies; only 1 study was identified as a prospective trial comparing inhaled corticosteroid and leukotriene modifier therapies and including results on resource use or medical care costs.^16,17,22-25 All 6 studies were performed with support from GlaxoSmithKline.

Forty-three documents were excluded due to 1 or more of the following criteria: lack of primary results (9 documents, 21%); did not contain resource use rate or cost outcomes (22 documents, 51%); did not provide at least 6 months’ worth of data on resource use or cost outcomes (5 documents, 12%); did not meet the defined inclusion and exclusion criteria (primarily studies not including both inhaled corticosteroid and leukotriene modifiers or those restricted to patient clinical subgroups; 10 documents, 34%); or did not define the number of patients included in the study (1 document, 3%).

Because few studies presented data on the specified outcomes, we were unable to assess asthma-specific costs for subcategories of resource use. Too few studies included data on hospitalization costs (either asthma-specific or overall) to include in the analysis. Therefore, meta-analysis was performed on overall (ie, all causes) emergency department, pharmacy, and total medical care costs.

TABLE 1
Characteristics of studies included in the meta-analysis

Primary analysis

The primary objective of this study was to evaluate the impact of inhaled corticosteroid and leukotriene modifier treatment on the mean annual hospitalization rate. Four of the 6 included studies contained information on hospitalization rate for each treatment. Results from the primary analysis are presented in Table 2.

Patients taking inhaled corticosteroids had a significantly lower annual rate of hospitalization than did patients taking leukotriene modifiers (2.23% vs 4.30%, respectively; P<.005). The absolute risk reduction was 2.07% (number needed to treat=48 for 1 year).

The difference in annual hospitalization visit rates for each study in the primary analysis is presented in the Figure, where negative values reflect lower hospitalization rates among patients taking inhaled corticosteroids than among those taking leukotriene modifiers. Two studies^16,23 had statistically significant differences in hospitalization rates, whereas the differences in the other 2 studies were not statistically significant (P<.05). Combining studies with the use of a random effects model (the default methodology for this analysis) or a fixed effects model produced similar results. The Q statistic indicated no significant heterogeneity (P=.43).

TABLE 2
Meta-analysis results for inhaled corticosteroid vs leukotriene modifier therapy*

FIGURE
Difference in hospitalization rates (mean, confidence interval)

Secondary outcomes

Results of secondary analyses for 5 study outcomes (annual visits to the emergency department due to asthma, total emergency department costs, total drug costs, total asthma-related costs, and overall total cost) are presented in Table 2.

Mean annual rates of visits to the emergency department and total annual drug costs were significantly higher for patients taking leukotriene modifiers than for those taking inhaled corticosteroids (P<.005 for each). Patients taking leukotriene modifiers had lower annual costs for visits to the emergency department than did those taking inhaled corticosteroids, although this difference was not statistically significant. The higher rate and lower cost of emergency department visits for patients taking leukotriene modifiers suggest that medical resources were used less at each visit as compared with those for patients taking inhaled corticosteroids.

Total asthma-related costs for patients taking inhaled corticosteroids were significantly lower than those for patients taking leukotriene modifiers (P<.05). Patients taking inhaled corticosteroids also incurred decreased annual total (allcause) medical care costs. Although this difference was qualitatively large (approximately $1900, or a decrease of over 17%), it did not reach statistical significance.

Pre- vs post-initiation of therapy

In addition to comparing the impact of the 2 therapies on resource use and costs, we were interested in the impact of initiating each therapy on the study outcomes. We therefore assessed resource use rates and costs before and after treatment initiation. These patients may have been receiving asthma therapies (or no asthma therapy) other than inhaled corticosteroids or leukotriene modifiers. The number of studies presenting data on costs was too small to allow comparison.

Results of this within-group analysis are presented in Table 3. For patients taking inhaled corticosteroids, hospitalization rates and emergency department visit rates decreased significantly after treatment initiation compared with the preinitiation values (P<.005 and P<.05, respectively). The decreases for patients taking leukotriene modifiers upon treatment initiation were smaller and not statistically significant.

Both groups showed similar small decreases in annual emergency department costs, neither of which was significant. The increases in annual total drug costs and annual total medical care costs after treatment initiation were significant for both groups of patients (all at P<.005). However, both increases were greater for patients taking leukotriene modifiers; the increase in drug costs was statistically significant (P<.001).

TABLE 3
Resource utilization and costs before and after therapy initiation for inhaled corticosteroids vs leukotriene modifiers*

Discussion

In this study, we used meta-analysis to combine data across studies and determine more robust estimates of the impact of inhaled corticosteroid vs leukotriene modifier therapy on medical resource use rates and costs. The primary analysis indicated that annual hospitalization rates among patients taking inhaled corticosteroids are significantly lower that those taking leukotriene modifiers. Other resource use rates and costs evaluated in this study also generally showed decreased values for patients taking inhaled corticosteroids.

Although meta-analysis generally has been used for clinical outcome measures, it is a highly appropriate method for resource use and cost outcomes. In general, studies of the impact of a particular treatment are powered to assess safety and efficacy or effectiveness; there is often insufficient power to detect differences in resource use or costs in any one study. Due to substantial variation in treatment patterns, the variance associated with resource use rates (and associated costs) may be substantially higher than that for clinical measures; such a wide variance adds to the difficulties in assessing differences for nonclinical outcomes.

Limitations

This study has a number of limitations. Only a few studies met inclusion criteria for the meta-analysis; the analysis should be replicated as additional studies become available. Data were abstracted from the included studies without modification (except for inflating costs to 2000 values when necessary). As in all meta-analyses, any problems present in the original data are present in the combined data; limitations of the original data are not addressed by this method.

Among the studies evaluated for the metaanalysis were a number published only as abstracts. Inclusion of unpublished literature in meta-analyses is controversial; however, several sources^18,19 now recommend inclusion of published and unpublished studies. Egger and Smith²⁶ found that studies with significant results are more likely to be published than are studies with nonsignificant results, leading to publication bias. Studies with significant results also may be more likely to be published in indexed journals, leading to “database bias.” As such, inclusion of unpublished studies is important to produce unbiased results.

Five of the 6 studies that met the inclusion criteria were observational, retrospective cohort analyses. Whereas many meta-analyses focus solely on prospective, randomized clinical trials, several have included retrospective data.^27,28 Retrospective analyses and observational data have a number of limitations, in particular the lack of randomization that can lead to differences in characteristics of specified treatment groups. Further, as discussed by Egger et al,²⁹ metaanalyses based on observational studies may involve bias and confounding.

However, observational data and retrospective analyses also have the advantage of reflecting “real world” treatment patterns and broader patient groups that increase the generalizability of the data, whereas clinical trials may include protocol-driven utilization and selected patient groups. Clinical trials also may occur in specialized health care settings, whereas observational (cohort) data may be more applicable to clinical practice. Due to these factors, meta-analysis of observational data has become common.²⁹

The pre-initiation vs post-initiation analysis indicated that values for each treatment group provide information on the similarities between treatment groups before initiation of controller therapy. Even though the treatment groups were not randomized to each therapy and we have no means to ensure compatibility between groups, having similar rates of resource use between groups provides some evidence regarding similarity. Nonetheless, given the limitations of the retrospective data and meta-analysis in general, it will be important to validate the results of this meta-analysis in the future with naturalistic prospective studies.

Despite these limitations, this study provides important information on the impact of asthma therapies on resource use and costs. Specifically, the resource use and cost outcomes assessed in this study were lower for inhaled corticosteroid patients than for leukotriene modifier patients. This study also illustrates the usefulness of metaanalysis in evaluating resource use and costs. By selecting and combining outcomes across studies in a standardized, rigorous, and transparent manner, the effects of different therapies can be evaluated with greater precision.

Acknowledgments

We thank John O’Donnell and Layne Gothard for their assistance with this manuscript.

Corresponding author
Michael T. Halpern, MD, PhD, Principal Scientist, Exponent, Inc., 1800 Diagonal Road, Alexandria, VA 22314. E-mail: [email protected]

Telemedicine enables doctors in rural areas or areas with poor medical service to consult with experts at distant locations. Telecolposcopy and cervicography both enable remote diagnoses of the cervix. The 2 methods differ in equipment, operations, image format, timeliness of consultation, and probably cost. However, these diagnostic approaches have not been compared previously. The purpose of this study was to compare the accuracy of telecolposcopy and cervicography with on-site colposcopy in the remote evaluation of women with potential cervical neoplasia.

Telecolposcopy and cervicography

Telecolposcopy involves a distant expert colposcopist’s evaluation of women with potential lower genital tract neoplasia.¹ Existing telemedicine network and computer systems provide an audiovisual interface between local colposcopists and expert colposcopists at other locations.² For health systems already using computer or video networks, telecolposcopic consultation can be implemented with only small additional charges per examination.² Telecolposcopy services may improve health care access for women in medically underserved areas.¹

Cervicography is distant evaluation of 2 photographs taken of the cervix following 5% acetic acid application.³ A special 35-mm camera is used to take these images. The end product, developed at a central processing center, resembles a low-magnification colposcopic photograph. Certified evaluators interpret these images, classifying them as negative, atypical, or positive. Cervicography is used primarily as an adjunct test to the Papanicolaou (Pap) smear.⁴ It has also been evaluated as an intermediate triage test for evaluating women with mildly abnormal Pap smear results.^5-8

Methods

Women aged 18 years or older who came to 1 of 2 rural clinic sites for a colposcopic examination were enrolled in the trial after signing an institutional review board–approved informed consent document. We included women with a recent abnormal Pap smear report or a lower genital tract finding that required further evaluation by colposcopy. The exclusion criteria were pregnancy, severe cervicitis, heavy menses, refusal to participate, or technical problems with the telecolposcopy or cervicography equipment.

Both clinics were part of the Medical College of Georgia Telemedicine Network. This system uses sophisticated telecommunications equipment to provide distant consultation services to clinicians practicing in rural areas of the state.¹ Small change-coupled device cameras were attached to the colposcopes at the 2 clinics.

For network telecolposcopy, images were transmitted using the network’s existing hardware and high-speed telecommunication lines. For computer telecolposcopy, personal computers (DIMS, DenVu, Tucson, Ariz) were also used to capture and transmit images to a computer at the Telemedicine Center. These digitized images were transmitted by modem via telephone lines.² Cerviscopes (35-mm cameras) supplied by the manufacturer (NTL Worldwide, Fenton, Mo) were used to acquire cervigrams (photographs).

Pertinent clinicians received appropriate training to take cervigrams. Certified evaluators interpreted the images according to company protocol and returned a standardized report to the investigators at a later date.

Study design

The study design has been described in detail previously.^1,2 Briefly, subjects were initially examined by 1 of 3 on-site, university-based expert colposcopists, who took 2 cervigrams of each patient, and then conducted a colposcopic examination independently.

A local clinician then completed another colposcopic examination, including histologic sampling, if indicated. This examination was observed simultaneously by another expert at a telemedicine center. Prior to obtaining histologic samples or using dilute Lugol’s iodine solution, the local clinician captured 2 cervical images (low and high magnification) using the computer telemedicine system. These images were then transmitted to the expert at the telemedicine center for independent interpretation.

A third expert colposcopist interpreted the video and computer images at a later time. However, these third interpretations were not considered in this report. Colposcopists were blinded to each other’s clinical diagnoses. However, all colposcopists were informed of the subject’s referral cervical cytology results and other pertinent history.

Data analysis

Each subject had 2 observations using each of the 3 colposcopy methods (on-site, network, and computer-based), and a single observation using cervicography. On-site colposcopy, consisting of the observations of the on-site expert and local colposcopist, was considered for reference purposes. Agreement with histologic results was calculated for each method, across all histologic diagnoses together and separately by diagnosis.

Sensitivity and specificity estimates were calculated using 2 definitions of disease: (1) normal versus any other histologic diagnosis, and (2) normal or cervical intraepithelial neoplasia 1 (CIN 1) versus any more severe diagnosis. The primary analysis model was complete block analysis of variance, with subjects included as blocks in the analysis to account for the multiple observations on the same subjects. Nonparametric comparisons of proportions of agreement with histology, sensitivity, and specificity among the methods were made using permutation tests. Post-hoc comparisons were made using a Tukey test; 95% confidence intervals (CIs) were calculated for all point estimates. Adjustment for dependence among multiple observations per subject was made by basing these tests and CIs on least-squares means.

The available sample sizes for all analyses were adequate to ensure approximate normality of the estimated means. Power to detect, at Α=.05, a difference in agreement of 15% between cervigram and the other evaluation methods, was estimated using Monte Carlo simulations. Data were simulated using the observed levels of agreement for on-site, network, and computer telecolposcopy, and specifying a difference of 15% between cervicography agreement and the maximum of the other methods’ agreement. Power estimates were based on analysis of 1000 simulations. SAS release 8.02 was used for all calculations (SAS, Inc, Cary, NC).

Results

A total of 264 subjects were enrolled in the trial, but the total number of subjects considered differed depending on the various analyses of interest. The demographic data of this study cohort have been published previously.¹

Briefly, the subjects’ mean age was 31.7 years and mean parity was 2.1. Subjects presented with a wide range of prior cervical cytology results: 20.4% normal, 29.2% atypical squamous cells of undetermined significance, 40.4% low-grade squamous intraepithelial lesion, 7.3% high-grade squamous intraepithelial lesion, and 2.7% atypical glandular cells of undetermined significance. Histology results included all levels of CIN (52.9% CIN 1 and 13.4% CIN 2 or 3), and endocervical histologic sampling results were reported as both positive and negative for neoplasia.

The agreement between telecolposcopic/cervicography impressions and histology were estimated (Table 1). Data for on-site colposcopy was also considered for reference purposes.

When all histologic diagnoses were considered, there was no statistically significant difference in the rates of agreement for colposcopy, the 2 types of telecolposcopy, and cervicography. This was also true if only cases of CIN 1 were examined.

However, a statistically significant difference was noted between agreement rates for computer-based telecolposcopy (63.95%) and on-site colposcopy (47.7%, P=.03, Tukey test) for normal histology. A statistically significant difference was also found between agreement rates for on-site colposcopy (50.0%) and cervicography (19.1%, P=.04, Tukey test) for women with biopsy-proven CIN 2 or 3. If all histologic diagnoses were considered, the study provided 85% power to detect a difference in agreement of 15% among the evaluation methods.

We also estimated the sensitivity and specificity of the four diagnostic methods to detect cervical neoplasia (Table 2). A statistically significant difference was found in observed sensitivity between on-site colposcopy (47.7%) and cervicography (18.2%, P=.04, Tukey test) when a positive threshold of at least CIN 2 was considered. The difference was not significant, however, if the lower positive test threshold of at least CIN 1 was considered.

A statistically significant difference in specificity was noted between computer-based telecolposcopy (64.0%) and on-site colposcopy (47.7%, P=.03, Tukey test) at a positive threshold of at least CIN 1. The study provided a power of 71% and 60% to detect differences of 15% in sensitivity and specificity, respectively, using the CIN 1 threshold. Using CIN 2 as the positive threshold, the power to detect this 15% difference was 24% and 81% for sensitivity and specificity, respectively.

TABLE 1
Colposcopic, telecolposcopic, and cervicographic agreement with histology

TABLE 2
Sensitivity and specificity of tests to detect cervical neoplasia

Discussion

Until recently, cervicography had been the only type of remote diagnostic system available for the evaluation of women with potential lower genital tract neoplasia. With the advent of telemedicine during the past decade, expert-level health care has now become more readily available to patients previously isolated from this important resource.

The future of telecolposcopy

Because of its nature, telecolposcopy may also be well suited to assist in the evaluation and management of women with lower genital tract neoplasia. Computer-based telecolposcopy has the potential to support clinical sites located wherever standard telephone service exists. Cellular telephone systems now broaden access to nearglobal availability. Soon, assuming sufficient funding is obtained, the provision of expertenhanced colposcopy may become a reality for all women. However, universal availability may be irrelevant if computer-based telecolposcopy performs at a substandard level.

Telecolposcopy vs cervicography

We have demonstrated that telecolposcopy was at least as effective as cervicography for detecting cervical cancer precursors. Although the difference was not statistically significant, both network and computer-based telecolposcopy systems detected a higher percentage of women with CIN 2 or 3 than cervicography.

Our results also included on-site colposcopy. As anticipated, on-site colposcopy had the greatest sensitivity for disease detection at either positive test thresholds (at least CIN 1 and CIN 2). Ability to manipulate the cervix, stereoscopic viewing, longitudinal observation after 5% acetic acid application, and better resolution of the cervical epithelium and vascularity all favor on-site colposcopic diagnoses. Of the 2 telecolposcopy systems, network telecolposcopy had a slightly, but not significantly, greater sensitivity for detecting cervical cancer precursors compared with computer-based telecolposcopy.

Expert colposcopists’ accuracy with interpretation of network (real-time) cervical images was similar to that for on-site colposcopy, as might be expected. Network telecolposcopy might be equated with remote video colposcopy. Previously we have shown that traditional optical colposcopy is equivalent to video colposcopy with respect to colposcopic/histologic agreement.⁹

Comparison of telecolposcopy systems

The computer-based telecolposcopy system used in our study was, in all fairness, more similar to cervicography. Each method involves evaluation of 2 static images. Computer-based telecolposcopy provides 2 digitized images, but of a low- and high-power magnification view of the cervix. In comparison, cervicography produces dual low-power magnification celluloid images (2 x 2 slides) of the cervix. The provision of a high-power cervical image may explain the better sensitivity of computer-based telecolposcopy. This one feature may be more valuable than the better image resolution obtained from cervicography. However, computer-based resolution appears to be sufficient to render diagnoses at a level equivalent to or better than cervicography.

These 2 “static” systems differ in other aspects as well. First, computer-based systems are nonproprietary. Several systems are commercially available and other colposcopists have devised their own unique systems using modifications of off-the-shelf technology. Although not available at the initiation of our trial, computerbased systems now have the capability of capturing short video streams. These video segments should help improve the diagnostic ability of consulting colposcopists as demonstrated by our study.

Second, computer-based telecolposcopy can provide instantaneous consultation as opposed to cervicography, which generally takes a minimum of several weeks to receive a report. Computerbased telecolposcopy also allows interaction between the on-site provider and remote expert.

Third, cervicography is a screening test adjunct. The computer-based system was used as a colposcopy diagnostic adjunct. However, colposcopy could easily be adapted to provide the function of cervicography. A simple handheld miniature change-coupled device camera and light source could potentially replace a more expensive colposcope and video camera, or video colposcope. With an average laptop computer (with appropriate software) and cellular phone, health care providers of potentially all women in the world could have access to expert-level cervical evaluation services.

Finally, computer-based telecolposcopy images and associated data automatically become part of a modern electronic medical record. This format is more conducive to the direction toward which contemporary medicine is rapidly shifting. Consequently, computer-based telecolposcopy may offer clinicians superior, modern diagnostic services not previously available to women.

Acknowledgments

Special thanks to Dr. Debra Crawley and Diane Watson, MSN, for rural site participation.

Telemedicine enables doctors in rural areas or areas with poor medical service to consult with experts at distant locations. Telecolposcopy and cervicography both enable remote diagnoses of the cervix. The 2 methods differ in equipment, operations, image format, timeliness of consultation, and probably cost. However, these diagnostic approaches have not been compared previously. The purpose of this study was to compare the accuracy of telecolposcopy and cervicography with on-site colposcopy in the remote evaluation of women with potential cervical neoplasia.

Telecolposcopy and cervicography

Telecolposcopy involves a distant expert colposcopist’s evaluation of women with potential lower genital tract neoplasia.¹ Existing telemedicine network and computer systems provide an audiovisual interface between local colposcopists and expert colposcopists at other locations.² For health systems already using computer or video networks, telecolposcopic consultation can be implemented with only small additional charges per examination.² Telecolposcopy services may improve health care access for women in medically underserved areas.¹

Cervicography is distant evaluation of 2 photographs taken of the cervix following 5% acetic acid application.³ A special 35-mm camera is used to take these images. The end product, developed at a central processing center, resembles a low-magnification colposcopic photograph. Certified evaluators interpret these images, classifying them as negative, atypical, or positive. Cervicography is used primarily as an adjunct test to the Papanicolaou (Pap) smear.⁴ It has also been evaluated as an intermediate triage test for evaluating women with mildly abnormal Pap smear results.^5-8

Methods

Women aged 18 years or older who came to 1 of 2 rural clinic sites for a colposcopic examination were enrolled in the trial after signing an institutional review board–approved informed consent document. We included women with a recent abnormal Pap smear report or a lower genital tract finding that required further evaluation by colposcopy. The exclusion criteria were pregnancy, severe cervicitis, heavy menses, refusal to participate, or technical problems with the telecolposcopy or cervicography equipment.

Both clinics were part of the Medical College of Georgia Telemedicine Network. This system uses sophisticated telecommunications equipment to provide distant consultation services to clinicians practicing in rural areas of the state.¹ Small change-coupled device cameras were attached to the colposcopes at the 2 clinics.

For network telecolposcopy, images were transmitted using the network’s existing hardware and high-speed telecommunication lines. For computer telecolposcopy, personal computers (DIMS, DenVu, Tucson, Ariz) were also used to capture and transmit images to a computer at the Telemedicine Center. These digitized images were transmitted by modem via telephone lines.² Cerviscopes (35-mm cameras) supplied by the manufacturer (NTL Worldwide, Fenton, Mo) were used to acquire cervigrams (photographs).

Pertinent clinicians received appropriate training to take cervigrams. Certified evaluators interpreted the images according to company protocol and returned a standardized report to the investigators at a later date.

Study design

The study design has been described in detail previously.^1,2 Briefly, subjects were initially examined by 1 of 3 on-site, university-based expert colposcopists, who took 2 cervigrams of each patient, and then conducted a colposcopic examination independently.

A local clinician then completed another colposcopic examination, including histologic sampling, if indicated. This examination was observed simultaneously by another expert at a telemedicine center. Prior to obtaining histologic samples or using dilute Lugol’s iodine solution, the local clinician captured 2 cervical images (low and high magnification) using the computer telemedicine system. These images were then transmitted to the expert at the telemedicine center for independent interpretation.

A third expert colposcopist interpreted the video and computer images at a later time. However, these third interpretations were not considered in this report. Colposcopists were blinded to each other’s clinical diagnoses. However, all colposcopists were informed of the subject’s referral cervical cytology results and other pertinent history.

Data analysis

Each subject had 2 observations using each of the 3 colposcopy methods (on-site, network, and computer-based), and a single observation using cervicography. On-site colposcopy, consisting of the observations of the on-site expert and local colposcopist, was considered for reference purposes. Agreement with histologic results was calculated for each method, across all histologic diagnoses together and separately by diagnosis.

Sensitivity and specificity estimates were calculated using 2 definitions of disease: (1) normal versus any other histologic diagnosis, and (2) normal or cervical intraepithelial neoplasia 1 (CIN 1) versus any more severe diagnosis. The primary analysis model was complete block analysis of variance, with subjects included as blocks in the analysis to account for the multiple observations on the same subjects. Nonparametric comparisons of proportions of agreement with histology, sensitivity, and specificity among the methods were made using permutation tests. Post-hoc comparisons were made using a Tukey test; 95% confidence intervals (CIs) were calculated for all point estimates. Adjustment for dependence among multiple observations per subject was made by basing these tests and CIs on least-squares means.

The available sample sizes for all analyses were adequate to ensure approximate normality of the estimated means. Power to detect, at Α=.05, a difference in agreement of 15% between cervigram and the other evaluation methods, was estimated using Monte Carlo simulations. Data were simulated using the observed levels of agreement for on-site, network, and computer telecolposcopy, and specifying a difference of 15% between cervicography agreement and the maximum of the other methods’ agreement. Power estimates were based on analysis of 1000 simulations. SAS release 8.02 was used for all calculations (SAS, Inc, Cary, NC).

Results

A total of 264 subjects were enrolled in the trial, but the total number of subjects considered differed depending on the various analyses of interest. The demographic data of this study cohort have been published previously.¹

Briefly, the subjects’ mean age was 31.7 years and mean parity was 2.1. Subjects presented with a wide range of prior cervical cytology results: 20.4% normal, 29.2% atypical squamous cells of undetermined significance, 40.4% low-grade squamous intraepithelial lesion, 7.3% high-grade squamous intraepithelial lesion, and 2.7% atypical glandular cells of undetermined significance. Histology results included all levels of CIN (52.9% CIN 1 and 13.4% CIN 2 or 3), and endocervical histologic sampling results were reported as both positive and negative for neoplasia.

The agreement between telecolposcopic/cervicography impressions and histology were estimated (Table 1). Data for on-site colposcopy was also considered for reference purposes.

When all histologic diagnoses were considered, there was no statistically significant difference in the rates of agreement for colposcopy, the 2 types of telecolposcopy, and cervicography. This was also true if only cases of CIN 1 were examined.

However, a statistically significant difference was noted between agreement rates for computer-based telecolposcopy (63.95%) and on-site colposcopy (47.7%, P=.03, Tukey test) for normal histology. A statistically significant difference was also found between agreement rates for on-site colposcopy (50.0%) and cervicography (19.1%, P=.04, Tukey test) for women with biopsy-proven CIN 2 or 3. If all histologic diagnoses were considered, the study provided 85% power to detect a difference in agreement of 15% among the evaluation methods.

We also estimated the sensitivity and specificity of the four diagnostic methods to detect cervical neoplasia (Table 2). A statistically significant difference was found in observed sensitivity between on-site colposcopy (47.7%) and cervicography (18.2%, P=.04, Tukey test) when a positive threshold of at least CIN 2 was considered. The difference was not significant, however, if the lower positive test threshold of at least CIN 1 was considered.

A statistically significant difference in specificity was noted between computer-based telecolposcopy (64.0%) and on-site colposcopy (47.7%, P=.03, Tukey test) at a positive threshold of at least CIN 1. The study provided a power of 71% and 60% to detect differences of 15% in sensitivity and specificity, respectively, using the CIN 1 threshold. Using CIN 2 as the positive threshold, the power to detect this 15% difference was 24% and 81% for sensitivity and specificity, respectively.

TABLE 1
Colposcopic, telecolposcopic, and cervicographic agreement with histology

TABLE 2
Sensitivity and specificity of tests to detect cervical neoplasia

Discussion

Until recently, cervicography had been the only type of remote diagnostic system available for the evaluation of women with potential lower genital tract neoplasia. With the advent of telemedicine during the past decade, expert-level health care has now become more readily available to patients previously isolated from this important resource.

The future of telecolposcopy

Because of its nature, telecolposcopy may also be well suited to assist in the evaluation and management of women with lower genital tract neoplasia. Computer-based telecolposcopy has the potential to support clinical sites located wherever standard telephone service exists. Cellular telephone systems now broaden access to nearglobal availability. Soon, assuming sufficient funding is obtained, the provision of expertenhanced colposcopy may become a reality for all women. However, universal availability may be irrelevant if computer-based telecolposcopy performs at a substandard level.

Telecolposcopy vs cervicography

We have demonstrated that telecolposcopy was at least as effective as cervicography for detecting cervical cancer precursors. Although the difference was not statistically significant, both network and computer-based telecolposcopy systems detected a higher percentage of women with CIN 2 or 3 than cervicography.

Our results also included on-site colposcopy. As anticipated, on-site colposcopy had the greatest sensitivity for disease detection at either positive test thresholds (at least CIN 1 and CIN 2). Ability to manipulate the cervix, stereoscopic viewing, longitudinal observation after 5% acetic acid application, and better resolution of the cervical epithelium and vascularity all favor on-site colposcopic diagnoses. Of the 2 telecolposcopy systems, network telecolposcopy had a slightly, but not significantly, greater sensitivity for detecting cervical cancer precursors compared with computer-based telecolposcopy.

Expert colposcopists’ accuracy with interpretation of network (real-time) cervical images was similar to that for on-site colposcopy, as might be expected. Network telecolposcopy might be equated with remote video colposcopy. Previously we have shown that traditional optical colposcopy is equivalent to video colposcopy with respect to colposcopic/histologic agreement.⁹

Comparison of telecolposcopy systems

The computer-based telecolposcopy system used in our study was, in all fairness, more similar to cervicography. Each method involves evaluation of 2 static images. Computer-based telecolposcopy provides 2 digitized images, but of a low- and high-power magnification view of the cervix. In comparison, cervicography produces dual low-power magnification celluloid images (2 x 2 slides) of the cervix. The provision of a high-power cervical image may explain the better sensitivity of computer-based telecolposcopy. This one feature may be more valuable than the better image resolution obtained from cervicography. However, computer-based resolution appears to be sufficient to render diagnoses at a level equivalent to or better than cervicography.

These 2 “static” systems differ in other aspects as well. First, computer-based systems are nonproprietary. Several systems are commercially available and other colposcopists have devised their own unique systems using modifications of off-the-shelf technology. Although not available at the initiation of our trial, computerbased systems now have the capability of capturing short video streams. These video segments should help improve the diagnostic ability of consulting colposcopists as demonstrated by our study.

Second, computer-based telecolposcopy can provide instantaneous consultation as opposed to cervicography, which generally takes a minimum of several weeks to receive a report. Computerbased telecolposcopy also allows interaction between the on-site provider and remote expert.

Third, cervicography is a screening test adjunct. The computer-based system was used as a colposcopy diagnostic adjunct. However, colposcopy could easily be adapted to provide the function of cervicography. A simple handheld miniature change-coupled device camera and light source could potentially replace a more expensive colposcope and video camera, or video colposcope. With an average laptop computer (with appropriate software) and cellular phone, health care providers of potentially all women in the world could have access to expert-level cervical evaluation services.

Finally, computer-based telecolposcopy images and associated data automatically become part of a modern electronic medical record. This format is more conducive to the direction toward which contemporary medicine is rapidly shifting. Consequently, computer-based telecolposcopy may offer clinicians superior, modern diagnostic services not previously available to women.

Acknowledgments

Special thanks to Dr. Debra Crawley and Diane Watson, MSN, for rural site participation.

Telemedicine enables doctors in rural areas or areas with poor medical service to consult with experts at distant locations. Telecolposcopy and cervicography both enable remote diagnoses of the cervix. The 2 methods differ in equipment, operations, image format, timeliness of consultation, and probably cost. However, these diagnostic approaches have not been compared previously. The purpose of this study was to compare the accuracy of telecolposcopy and cervicography with on-site colposcopy in the remote evaluation of women with potential cervical neoplasia.

Telecolposcopy and cervicography

Telecolposcopy involves a distant expert colposcopist’s evaluation of women with potential lower genital tract neoplasia.¹ Existing telemedicine network and computer systems provide an audiovisual interface between local colposcopists and expert colposcopists at other locations.² For health systems already using computer or video networks, telecolposcopic consultation can be implemented with only small additional charges per examination.² Telecolposcopy services may improve health care access for women in medically underserved areas.¹

Cervicography is distant evaluation of 2 photographs taken of the cervix following 5% acetic acid application.³ A special 35-mm camera is used to take these images. The end product, developed at a central processing center, resembles a low-magnification colposcopic photograph. Certified evaluators interpret these images, classifying them as negative, atypical, or positive. Cervicography is used primarily as an adjunct test to the Papanicolaou (Pap) smear.⁴ It has also been evaluated as an intermediate triage test for evaluating women with mildly abnormal Pap smear results.^5-8

Methods

Women aged 18 years or older who came to 1 of 2 rural clinic sites for a colposcopic examination were enrolled in the trial after signing an institutional review board–approved informed consent document. We included women with a recent abnormal Pap smear report or a lower genital tract finding that required further evaluation by colposcopy. The exclusion criteria were pregnancy, severe cervicitis, heavy menses, refusal to participate, or technical problems with the telecolposcopy or cervicography equipment.

Both clinics were part of the Medical College of Georgia Telemedicine Network. This system uses sophisticated telecommunications equipment to provide distant consultation services to clinicians practicing in rural areas of the state.¹ Small change-coupled device cameras were attached to the colposcopes at the 2 clinics.

For network telecolposcopy, images were transmitted using the network’s existing hardware and high-speed telecommunication lines. For computer telecolposcopy, personal computers (DIMS, DenVu, Tucson, Ariz) were also used to capture and transmit images to a computer at the Telemedicine Center. These digitized images were transmitted by modem via telephone lines.² Cerviscopes (35-mm cameras) supplied by the manufacturer (NTL Worldwide, Fenton, Mo) were used to acquire cervigrams (photographs).

Pertinent clinicians received appropriate training to take cervigrams. Certified evaluators interpreted the images according to company protocol and returned a standardized report to the investigators at a later date.

Study design

The study design has been described in detail previously.^1,2 Briefly, subjects were initially examined by 1 of 3 on-site, university-based expert colposcopists, who took 2 cervigrams of each patient, and then conducted a colposcopic examination independently.

A local clinician then completed another colposcopic examination, including histologic sampling, if indicated. This examination was observed simultaneously by another expert at a telemedicine center. Prior to obtaining histologic samples or using dilute Lugol’s iodine solution, the local clinician captured 2 cervical images (low and high magnification) using the computer telemedicine system. These images were then transmitted to the expert at the telemedicine center for independent interpretation.

A third expert colposcopist interpreted the video and computer images at a later time. However, these third interpretations were not considered in this report. Colposcopists were blinded to each other’s clinical diagnoses. However, all colposcopists were informed of the subject’s referral cervical cytology results and other pertinent history.

Data analysis

Each subject had 2 observations using each of the 3 colposcopy methods (on-site, network, and computer-based), and a single observation using cervicography. On-site colposcopy, consisting of the observations of the on-site expert and local colposcopist, was considered for reference purposes. Agreement with histologic results was calculated for each method, across all histologic diagnoses together and separately by diagnosis.

Sensitivity and specificity estimates were calculated using 2 definitions of disease: (1) normal versus any other histologic diagnosis, and (2) normal or cervical intraepithelial neoplasia 1 (CIN 1) versus any more severe diagnosis. The primary analysis model was complete block analysis of variance, with subjects included as blocks in the analysis to account for the multiple observations on the same subjects. Nonparametric comparisons of proportions of agreement with histology, sensitivity, and specificity among the methods were made using permutation tests. Post-hoc comparisons were made using a Tukey test; 95% confidence intervals (CIs) were calculated for all point estimates. Adjustment for dependence among multiple observations per subject was made by basing these tests and CIs on least-squares means.

The available sample sizes for all analyses were adequate to ensure approximate normality of the estimated means. Power to detect, at Α=.05, a difference in agreement of 15% between cervigram and the other evaluation methods, was estimated using Monte Carlo simulations. Data were simulated using the observed levels of agreement for on-site, network, and computer telecolposcopy, and specifying a difference of 15% between cervicography agreement and the maximum of the other methods’ agreement. Power estimates were based on analysis of 1000 simulations. SAS release 8.02 was used for all calculations (SAS, Inc, Cary, NC).

Results

A total of 264 subjects were enrolled in the trial, but the total number of subjects considered differed depending on the various analyses of interest. The demographic data of this study cohort have been published previously.¹

Briefly, the subjects’ mean age was 31.7 years and mean parity was 2.1. Subjects presented with a wide range of prior cervical cytology results: 20.4% normal, 29.2% atypical squamous cells of undetermined significance, 40.4% low-grade squamous intraepithelial lesion, 7.3% high-grade squamous intraepithelial lesion, and 2.7% atypical glandular cells of undetermined significance. Histology results included all levels of CIN (52.9% CIN 1 and 13.4% CIN 2 or 3), and endocervical histologic sampling results were reported as both positive and negative for neoplasia.

The agreement between telecolposcopic/cervicography impressions and histology were estimated (Table 1). Data for on-site colposcopy was also considered for reference purposes.

When all histologic diagnoses were considered, there was no statistically significant difference in the rates of agreement for colposcopy, the 2 types of telecolposcopy, and cervicography. This was also true if only cases of CIN 1 were examined.

However, a statistically significant difference was noted between agreement rates for computer-based telecolposcopy (63.95%) and on-site colposcopy (47.7%, P=.03, Tukey test) for normal histology. A statistically significant difference was also found between agreement rates for on-site colposcopy (50.0%) and cervicography (19.1%, P=.04, Tukey test) for women with biopsy-proven CIN 2 or 3. If all histologic diagnoses were considered, the study provided 85% power to detect a difference in agreement of 15% among the evaluation methods.

We also estimated the sensitivity and specificity of the four diagnostic methods to detect cervical neoplasia (Table 2). A statistically significant difference was found in observed sensitivity between on-site colposcopy (47.7%) and cervicography (18.2%, P=.04, Tukey test) when a positive threshold of at least CIN 2 was considered. The difference was not significant, however, if the lower positive test threshold of at least CIN 1 was considered.

A statistically significant difference in specificity was noted between computer-based telecolposcopy (64.0%) and on-site colposcopy (47.7%, P=.03, Tukey test) at a positive threshold of at least CIN 1. The study provided a power of 71% and 60% to detect differences of 15% in sensitivity and specificity, respectively, using the CIN 1 threshold. Using CIN 2 as the positive threshold, the power to detect this 15% difference was 24% and 81% for sensitivity and specificity, respectively.

TABLE 1
Colposcopic, telecolposcopic, and cervicographic agreement with histology

TABLE 2
Sensitivity and specificity of tests to detect cervical neoplasia