Applied Evidence

A 35-year-old woman with no past medical or surgical history presents to your office with complaints consistent with oligomenorrhea. She also reports a 15-pound weight gain over this past year.

Your patient is married and sexually active, but has never been pregnant. Her menarche was at age 12, and she says she has had irregular, infrequent menses over the past year, with 4 to 5 days of medium flow. Her social/family history is unremarkable.

She denies using any drugs, medications, supplements, or herbs. She had a recent TSH, fasting blood glucose, CBC, basic metabolic panel, and Pap smear done by her previous physician during a routine physical and all were normal.

On exam, your patient is clinically obese (abdominal adiposity) and notably hirsute. Her skin exam is also positive for hyperpigmented lichenified plaques around her neck and axilla, consistent with acanthosis nigricans. The rest of her exam is unremarkable.

Her signs and symptoms prompt you to suspect polycystic ovarian syndrome (PCOS), which you confirm after ruling out type 2 diabetes mellitus, thyroid disease, hyperprolactinemia, congenital adrenal hyperplasia, and androgen secreting tumors.

Your next step, of course, is treatment and you consider your options. Would pharmacological treatment with metformin or a thiazolidenedione (TZD) be appropriate?

An answer that may surprise you

There is no evidence to support the routine use of either metformin or a TZD as first-line therapy for the treatment of PCOS, based on a meta-analysis of randomized controlled clinical trials (strength of recommendation [SOR]: C). Instead, you should individualize your approach to achieve the patient’s short- and long-term goals, as well as to minimize complications and comorbidities. A good approach at this time would be to educate your patient on lifestyle changes, such as diet and exercise, since the evidence supports their use (SOR: B).^1-4 A weight reduction of as little as 5% can help regulate the menstrual cycle and improve fertility, decrease insulin resistance, and reduce associated symptoms and comorbidities.⁴

PCOS is associated with features of insulin resistance, hyperandrogenism, and oligomenorrhea leading to anovulatory bleeding and infertility. Many—though not all—PCOS patients have ovarian cysts.

Why the shift away from metformin or a TZD?

This recommendation is based on a meta-analysis that we, the authors, recently conducted. The following review provides a more detailed look at our analysis of the evidence to date. But before we get to the study, let’s look at the syndrome that sparked our research.

Background

A syndrome with extensive variability

PCOS (also known as Stein-Leventhal syndrome) is associated with features of insulin resistance (obesity, acanthosis nigricans); hyperandrogenism (hirsutism, elevated androgen levels), and oligomenorrhea leading to anovulatory bleeding and infertility. PCOS has a prevalence of approximately 5% to 10% in women of reproductive age. Patients may have high serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). However, much variation exists clinically and a specific patient may have normal androgen levels.³ In addition, despite the syndrome’s name, not all women with PCOS have ovarian cysts.

The features of peripheral insulin resistance, hyperinsulinemia, oligomenorrhea, and infertility can be magnified in the presence of obesity. Insulin resistance is not due to defects in insulin binding to the insulin receptors; rather, it involves post-binding signaling pathways. The elevated insulin levels may have gonadotropin-augmenting effects on ovarian function.³

Numerous comorbidities play a role

There is a great deal of frustration for both physicians and patients regarding the various comorbidities associated with this syndrome. For patients, the problems include androgenic features, menstrual irregularities, and infertility. For clinicians, however, the concerns include cardiovascular risks⁴ (obesity, lipid abnormalities, elevated C-reactive protein and leptin levels, blood pressure changes), hyperinsulinemia, insulin resistance, and the theoretical risks for endometrial hyperplasia due to a hyperestrogenic state.

NIH criteria is used for diagnosis in trials

Although there are no definitive consensus criteria for the diagnosis of PCOS, the 1990 National Institutes of Health (NIH) criteria and its revision in 2003, the Rotterdam Criteria, have been used to make the diagnosis in clinical trials. Most trials however use the NIH criteria as there is disagreement regarding the Rotterdam Criteria.

The NIH criteria use the following for the diagnosis of PCOS:

• oligomenorrhea
• hyperandrogenism (clinical or laboratory evidence), and
• absence of other endocrine disorders (congenital adrenal hyperplasia, hyperprolactinemia, thyroid dysfunction, and androgen secreting tumors).

In reviewing the literature, most clinicians and researchers have noted that PCOS has been associated with various outcomes such as elevated body mass index (BMI),⁵ waist-to-hip ratio,^5,6 fasting blood glucose,⁷ insulin levels,⁷ testosterone levels,⁸ androstenedione levels,⁸ DHEAS levels,⁹ hirsutism scores,⁹ lipids,⁵ blood pressure,⁹ luteinizing hormone to follicle-stimulating hormone ratio (LH/FSH),⁹ C-peptide,⁵ and leptin,⁶ as well as decreased ovulatory and pregnancy rates.^4,5,10

Metformin/TZDs are used, but what about the evidence?

Both metformin and the TZDs (glitazones) including troglitazone—which was withdrawn from the market—pioglitazone, and rosiglitazone, are antidiabetic agents that also work as insulin sensitizers. These agents—especially metformin—are widely used by primary care physicians and specialists to treat the clinical and biochemical features of PCOS. However, the evidence-based data supporting this use is lacking. Although much research has been done on this topic, most published trials are of less than ideal quality and involve methodological issues. Often times they are nonrandomized, not controlled, involve a low number of subjects, provide no long-term follow up, and use nonstudy agents or ancillary treatments that were not randomized and could yield confounding results.

Objectives

Our primary objective was to assess whether there is evidence to support the use of metformin or TZDs, as well as to suggest any differences among the drugs. The secondary objective was to ascertain if, and to what extent, the studied drugs affected the studied parameters.

Methods

Search Strategy

We searched MD Consult, PubMed, Medline, Ovid, and Google Scholar through January 2007 with the following terms: “PCOS and metformin,” “PCOS and Glucophage,” “PCOS and troglitazone,” “PCOS and pioglitazone,” “PCOS and rosiglitazone,” “PCOS and thiazolidenediones.” These searches were also done by substituting “+” instead of the word “and,” as well as by using full form of the abbreviation PCOS—polycystic ovarian syndrome.

The following limits were placed on the search: randomized controlled trials, English language, human, and female subjects. We also searched articles from reference lists and made additional efforts to contact clinicians and researchers in this field.

Selection criteria

Our search resulted in 115 articles. From these articles, we included only those trials that:

• Used the NIH 1990 criteria for the diagnosis of PCOS
• Studied the effect of any of the following drugs: metformin, troglitazone, rosiglitazone, or pioglitazone
• Did not use or advocate adjunctive therapy—ie, diet or exercise
• Were randomized and controlled (based on a review of the methods section).

We also excluded studies that permitted confounding or concomitant treatments if it made it difficult to estimate the true effect of the medications studied.

This criteria resulted in 33 trials and ultimately 31 trials were included in the analysis (23 metformin, 2 rosiglitazone, 1 pioglitazone, 5 troglitazone) with a total of 1892 patients. Two metformin trials were unobtainable.

Outcome measures

We studied the parameters that are needed for the diagnosis of PCOS, as well as parameters that are associated with the syndrome’s comorbidities. The measured variables included: ovulation rates, pregnancy rates, BMI, waist-to-hip ratio, lipid panel, blood pressure, fasting insulin levels, fasting blood glucose, C-peptide, glycosylated hemoglobin (Hb A_1c), LH/FSH, total testosterone, free testosterone, androstenedione, DHEAS, leptin, C-reactive protein, hirsutism (based on the Ferriman-Gallwey [F-G] score), and weight.

Methods of the review

Each included trial was evaluated in detail regarding how well it met the inclusion and exclusion criteria, the number of participants, the follow-up period, quantitative reporting of the data, and the overall methodology. The principal author rated methodological quality as good, fair, or poor on the basis of an overall assessment of these features. We did not use explicit validity checklists with summary scores because they have not been shown to predict the effect of bias on treatment differences or to provide more reliable assessments of validity.^11,12

Description of studies

All included studies met the inclusion criteria. However, it is important to note that most of the studies had low numbers of participants (only 4 studies had a sample size [n] >50, 3 studies with n >100). Some of the trials shared the same patients but analyzed different end points so the fundamental “independence” assumption required for most standard statistical analyses, including meta-analysis, was likely violated.

A few of the trials used another pharmacological agent or invasive procedure as control treatment. Some trials had designs such that in the end, the treatment and control groups both received ovulation induction agents for the patients who failed to ovulate. Even with the strict inclusion and exclusion criteria, many of the included trials still were of less than satisfactory design quality for our purposes.

Data collection/extraction

The principal author reviewed the text, tables, and figures and then collected and extracted the data from relevant publications. The data set was reviewed by the secondary authors for errors in data entry, format, outliers, or implausible values.

Statistical analysis

For each analysis, we converted all data to the same metric based on conversion formulas provided by each individual trial. We also verified the conversion factors online via data provided by standard clinical and reference laboratory values.

Some trials provided standard deviations (SD), while others provided standard error (SE) or standard error of the mean (SEM). We derived pooled variances accordingly. We converted all SDs to SE using the equation SE=SD/square root (N), where N denotes the sample size. We created data sets in the above fashion for each parameter.

Trials that did not report SD, SE, or sample variance for a given parameter were not included in the corresponding meta-analysis. We did not conduct a statistical analysis if only a small number of trials existed (ie, n <5), as it would result in less reliable conclusions.

No article provided individual level data or SD/SE for the “change” in the selected endpoint before and after treatment in the control and treatment arm. Instead, most publications presented the summary statistics separately for before and after treatment.

Since covariance (or correlation) between before and after values was not available and variability of the difference measure could not be estimated from the majority of the trials, it was not possible to perform methodologically sound meta-analysis by addressing the absolute or percent change before and after treatment and comparing this difference measure between 2 competing treatments. This is an inherent problem in many meta-analyses due to limited raw data.

However, as all the trials were randomized, we felt justified in performing the statistical analysis using the mean difference after treatment in the control and intervention arms. Our assumption: the values before treatment should be reasonably balanced between the 2 arms. Thus, we calculated the pooled estimates of treatment effect with 95% confidence intervals (CIs) for the mean differences between the control and intervention arms after treatment. We adopted the random effects model approach.¹³

Next, statistical significance was evaluated for treatment effect and heterogeneity. Publication bias was also examined by two different tests.^14,15 Sensitivity analysis was also performed to assess the impact of the identification of potential hidden studies by the trim and fill method.¹⁶

A 2-sided hypothesis with type I error of 5% was employed in all statistical testing and CI construction. Statistical analyses were carried out by STATA version 8.2.¹⁷

Results

Of the 31 trials included for the meta-analysis, we judged that 7 were of good quality, 6 were of fair quality, and 18 were of poor quality.^2,5-10,18-41 (See TABLE W1.)

Not enough data to compare TZD vs metformin

As the TZDs had few trials for each drug (5 troglitazone, 2 rosiglitazone, 1 pioglitazone) and not enough of the TZD trials reported data on most parameters, it became unrealistic to perform a statistical comparison of the treatment effect between metformin and the TZDs. Moreover, there were not enough data from TZD trials to analyze the effect of TZDs on any studied parameter. Thus, only data from metformin trials were used in the meta-analysis.

Metformin linked to changes in 3 outcomes

Of the outcomes we evaluated, there were statistically significant changes in three: ovulation rate, LH/FSH ratio, and fasting insulin. (For complete details of our findings, see TABLE.)

After analyzing the ovulation rate in 9 trials, we found a change of –0.18% (95% CI, –0.35 to –0.01; P=.03) from the control group. Our analysis of the LH/FSH ratio in 7 trials revealed a change in value of –0.21 (–0.30 to –0.13; P<.001). We evaluated the fasting insulin levels in 14 trials and found an increase of 30.4 pmol/L (13.9 to 46.8; P<.001).

Insufficient trials (n ≤5) reported on total cholesterol, triglycerides, HDL, LDL, systolic blood pressure, diastolic blood pressure, C-peptide, C-reactive protein, leptin, and Hb A_1c. Thus, we did not conduct a meta-analysis for these outcomes.

We intentionally used type I error of 5% for individual tests, not for overall test. If we had adopted multiple testing adjustments, we would have had more conservative results with much wider CIs, which makes it harder to reject the null hypothesis. Specifically, only 2 comparisons (LH/FSH and fasting insulin) would still be significant after multiple testing adjustments, while all marginally significant results would no longer be significant. A second reason to use type I error of 5% for individual (not overall) test is that endpoints are expected to be correlated, since most data were from the same trials.^42,43

We did not find any major change in results in the sensitivity analyses we performed. It is worth mentioning, though, that there was significant heterogeneity and variability in the treatment effects from virtually all comparisons we made, though most comparisons revealed no publication bias. When heterogeneity is detected, combining the effects is not always advisable; and when effects are combined, they should be viewed with extreme caution.^44-46

At a minimum, we failed to find any homogeneous or consistent treatment effects. Our sensitivity analysis offers additional protection against publication bias or file drawer problems.⁴⁷

TABLE
Meta-analysis results by outcome

Findings don’t support a common practice

Much has been reported in the literature, as well as by the media, regarding the large role that metformin and the TZDs can play in helping to alleviate the alterations caused by the polycystic ovarian syndrome. However, this systematic review of the literature, focusing on randomized controlled trials, failed to find evidence supporting the claims made in the literature, by the media, or offered anecdotally.

Based on our analysis, there is insufficient evidence to assess a difference in effect sizes between the TZDs and metformin. There is also insufficient evidence to assess if either the TZDs or metformin have an effect on lipids, blood pressure, C-peptide, C-reactive protein, leptin, or Hb A_1c.

With regard to the analyzed parameters, there were minimal decreases of statistical significance in ovulation rates and LH/FSH, and minimal increase of statistical significance in fasting insulin with metformin. (We cannot account for the paradoxical and unexpected finding of an increase of fasting insulin with metformin, especially since metformin works as an insulin sensitizer.) There was, however, no clinically significant change with metformin in any of the parameters we studied (ovulation rate, pregnancy rate, body mass index, waist-to-hip ratio, hirsutism score, LH/FSH, total cholesterol, fasting insulin, fasting blood glucose, total testosterone, free testosterone, androstenedione, and DHEAS).

This systematic review provides a strong message that many of the trials were not of adequate methodological quality to make a definitive statement for clinical practice. In addition, most trials had a low sample size and used additional treatments with gonadotropins or ovulation induction agents that can yield altered results.

The primary aim of this study was to ascertain the evidence for the use of either TZDs or metformin in the treatment of patients with PCOS. This systematic review with the meta-analysis has found insufficient evidence to support the routine use of either. The secondary aim of this study was to obtain evidence to assess if either agent was superior in clinically reducing the various biochemical and clinical alterations due to this condition. Based on our analysis, we cannot claim either agent as superior.

Limitations

Few trials, sparse data

Any systematic review and meta-analysis will have inherent limitations as data from multiple trials, that might not be directly comparable, are combined to give an overview. Another limitation is that trials published in other languages were not included. We cannot exclude the possibility of selection or information bias because only one person reviewed all the articles to decide which would be included. However, we set the inclusion/exclusion criteria as well as endpoints very carefully prior to the study and literature search and had independent reviews by other authors during statistical analyses to minimize this problem.

The quality assessment of each trial is also subjective, even though strict inclusion/exclusion criteria were utilized. Assessing the efficacy of the TZDs could not be done as there were very few trials. Moreover, most of the TZD trials did not study or report on all the parameters. It is difficult to assess for publication bias or outliers and to justify combining the results when only a small number of trials are available or the data are sparse. In addition, although 5 trials with good sample size were available for troglitazone, this agent is no longer on the market, thus limiting clinical utility.

As most trials were not truly blinded upon careful review of the article, this may provide some bias. Furthermore, we could not conduct the meta-analysis for the gold standard method based on difference measures (before, after, and between treatment) due to data unavailability. Our alternative choice of analysis is justified based on the assumption that randomization will allow for baseline values in both groups to be approximately similar.

Finally, we used the SD or SE (or SEM) information as the original authors reported. Although SE is a function of sample size, SD is the population parameter so its variability should not be high. However, we found that the SDs varied considerably. It may be that the authors inadvertently used SD and SE interchangeably, thus leading to the heterogeneity of effect size.

Conclusions

Further study is needed

Carefully designed and sufficiently powered PCOS studies with large sample sizes, followed by the proper reporting of the study findings, are warranted. These studies, evaluating drug effects, should be done in a randomized placebo controlled fashion. Such trials should not be interfered with by using hormonal or ovulation induction agents other than the medication being studied. Diet and exercise should not be a part of the study’s design as these have been independently validated in similar contexts.⁴

For now, focus on lifestyle, and symptom-based treatment

PCOS encompasses a myriad of clinical and biochemical features, where each component adds to morbidity. The data, as per our study, are not sufficient to support the use of either of the studied agents in altering either the clinical or biochemical changes associated with the condition.

Thus, clinicians should tailor their treatment regimen to the individual patient’s short- and long-term goals. Clinicians should also educate patients regarding lifestyle changes, such as diet and exercise, since multiple trials^1-4 have justified their use. Other options include symptom-based treatment, such as oral contraceptives for the regulation of menses or hirsutism.⁴

Acknowledgments

We wish to thank Dr Jan Groft, Dr Zakia Niruddin, Dr Marc Silverstein, and Dr Madhu Mazumdar for their efforts and guidance.

Funding/Support

This research was conducted without any outside funding or support.

Correspondence
Anush S. Pillai, DO, 424 Hahlo, Houston, TX, 77020; [email protected].

A 35-year-old woman with no past medical or surgical history presents to your office with complaints consistent with oligomenorrhea. She also reports a 15-pound weight gain over this past year.

Your patient is married and sexually active, but has never been pregnant. Her menarche was at age 12, and she says she has had irregular, infrequent menses over the past year, with 4 to 5 days of medium flow. Her social/family history is unremarkable.

She denies using any drugs, medications, supplements, or herbs. She had a recent TSH, fasting blood glucose, CBC, basic metabolic panel, and Pap smear done by her previous physician during a routine physical and all were normal.

On exam, your patient is clinically obese (abdominal adiposity) and notably hirsute. Her skin exam is also positive for hyperpigmented lichenified plaques around her neck and axilla, consistent with acanthosis nigricans. The rest of her exam is unremarkable.

Her signs and symptoms prompt you to suspect polycystic ovarian syndrome (PCOS), which you confirm after ruling out type 2 diabetes mellitus, thyroid disease, hyperprolactinemia, congenital adrenal hyperplasia, and androgen secreting tumors.

Your next step, of course, is treatment and you consider your options. Would pharmacological treatment with metformin or a thiazolidenedione (TZD) be appropriate?

An answer that may surprise you

There is no evidence to support the routine use of either metformin or a TZD as first-line therapy for the treatment of PCOS, based on a meta-analysis of randomized controlled clinical trials (strength of recommendation [SOR]: C). Instead, you should individualize your approach to achieve the patient’s short- and long-term goals, as well as to minimize complications and comorbidities. A good approach at this time would be to educate your patient on lifestyle changes, such as diet and exercise, since the evidence supports their use (SOR: B).^1-4 A weight reduction of as little as 5% can help regulate the menstrual cycle and improve fertility, decrease insulin resistance, and reduce associated symptoms and comorbidities.⁴

PCOS is associated with features of insulin resistance, hyperandrogenism, and oligomenorrhea leading to anovulatory bleeding and infertility. Many—though not all—PCOS patients have ovarian cysts.

Why the shift away from metformin or a TZD?

This recommendation is based on a meta-analysis that we, the authors, recently conducted. The following review provides a more detailed look at our analysis of the evidence to date. But before we get to the study, let’s look at the syndrome that sparked our research.

Background

A syndrome with extensive variability

PCOS (also known as Stein-Leventhal syndrome) is associated with features of insulin resistance (obesity, acanthosis nigricans); hyperandrogenism (hirsutism, elevated androgen levels), and oligomenorrhea leading to anovulatory bleeding and infertility. PCOS has a prevalence of approximately 5% to 10% in women of reproductive age. Patients may have high serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). However, much variation exists clinically and a specific patient may have normal androgen levels.³ In addition, despite the syndrome’s name, not all women with PCOS have ovarian cysts.

The features of peripheral insulin resistance, hyperinsulinemia, oligomenorrhea, and infertility can be magnified in the presence of obesity. Insulin resistance is not due to defects in insulin binding to the insulin receptors; rather, it involves post-binding signaling pathways. The elevated insulin levels may have gonadotropin-augmenting effects on ovarian function.³

Numerous comorbidities play a role

There is a great deal of frustration for both physicians and patients regarding the various comorbidities associated with this syndrome. For patients, the problems include androgenic features, menstrual irregularities, and infertility. For clinicians, however, the concerns include cardiovascular risks⁴ (obesity, lipid abnormalities, elevated C-reactive protein and leptin levels, blood pressure changes), hyperinsulinemia, insulin resistance, and the theoretical risks for endometrial hyperplasia due to a hyperestrogenic state.

NIH criteria is used for diagnosis in trials

Although there are no definitive consensus criteria for the diagnosis of PCOS, the 1990 National Institutes of Health (NIH) criteria and its revision in 2003, the Rotterdam Criteria, have been used to make the diagnosis in clinical trials. Most trials however use the NIH criteria as there is disagreement regarding the Rotterdam Criteria.

The NIH criteria use the following for the diagnosis of PCOS:

• oligomenorrhea
• hyperandrogenism (clinical or laboratory evidence), and
• absence of other endocrine disorders (congenital adrenal hyperplasia, hyperprolactinemia, thyroid dysfunction, and androgen secreting tumors).

In reviewing the literature, most clinicians and researchers have noted that PCOS has been associated with various outcomes such as elevated body mass index (BMI),⁵ waist-to-hip ratio,^5,6 fasting blood glucose,⁷ insulin levels,⁷ testosterone levels,⁸ androstenedione levels,⁸ DHEAS levels,⁹ hirsutism scores,⁹ lipids,⁵ blood pressure,⁹ luteinizing hormone to follicle-stimulating hormone ratio (LH/FSH),⁹ C-peptide,⁵ and leptin,⁶ as well as decreased ovulatory and pregnancy rates.^4,5,10

Metformin/TZDs are used, but what about the evidence?

Both metformin and the TZDs (glitazones) including troglitazone—which was withdrawn from the market—pioglitazone, and rosiglitazone, are antidiabetic agents that also work as insulin sensitizers. These agents—especially metformin—are widely used by primary care physicians and specialists to treat the clinical and biochemical features of PCOS. However, the evidence-based data supporting this use is lacking. Although much research has been done on this topic, most published trials are of less than ideal quality and involve methodological issues. Often times they are nonrandomized, not controlled, involve a low number of subjects, provide no long-term follow up, and use nonstudy agents or ancillary treatments that were not randomized and could yield confounding results.

Objectives

Our primary objective was to assess whether there is evidence to support the use of metformin or TZDs, as well as to suggest any differences among the drugs. The secondary objective was to ascertain if, and to what extent, the studied drugs affected the studied parameters.

Methods

Search Strategy

We searched MD Consult, PubMed, Medline, Ovid, and Google Scholar through January 2007 with the following terms: “PCOS and metformin,” “PCOS and Glucophage,” “PCOS and troglitazone,” “PCOS and pioglitazone,” “PCOS and rosiglitazone,” “PCOS and thiazolidenediones.” These searches were also done by substituting “+” instead of the word “and,” as well as by using full form of the abbreviation PCOS—polycystic ovarian syndrome.

The following limits were placed on the search: randomized controlled trials, English language, human, and female subjects. We also searched articles from reference lists and made additional efforts to contact clinicians and researchers in this field.

Selection criteria

Our search resulted in 115 articles. From these articles, we included only those trials that:

• Used the NIH 1990 criteria for the diagnosis of PCOS
• Studied the effect of any of the following drugs: metformin, troglitazone, rosiglitazone, or pioglitazone
• Did not use or advocate adjunctive therapy—ie, diet or exercise
• Were randomized and controlled (based on a review of the methods section).

We also excluded studies that permitted confounding or concomitant treatments if it made it difficult to estimate the true effect of the medications studied.

This criteria resulted in 33 trials and ultimately 31 trials were included in the analysis (23 metformin, 2 rosiglitazone, 1 pioglitazone, 5 troglitazone) with a total of 1892 patients. Two metformin trials were unobtainable.

Outcome measures

We studied the parameters that are needed for the diagnosis of PCOS, as well as parameters that are associated with the syndrome’s comorbidities. The measured variables included: ovulation rates, pregnancy rates, BMI, waist-to-hip ratio, lipid panel, blood pressure, fasting insulin levels, fasting blood glucose, C-peptide, glycosylated hemoglobin (Hb A_1c), LH/FSH, total testosterone, free testosterone, androstenedione, DHEAS, leptin, C-reactive protein, hirsutism (based on the Ferriman-Gallwey [F-G] score), and weight.

Methods of the review

Each included trial was evaluated in detail regarding how well it met the inclusion and exclusion criteria, the number of participants, the follow-up period, quantitative reporting of the data, and the overall methodology. The principal author rated methodological quality as good, fair, or poor on the basis of an overall assessment of these features. We did not use explicit validity checklists with summary scores because they have not been shown to predict the effect of bias on treatment differences or to provide more reliable assessments of validity.^11,12

Description of studies

All included studies met the inclusion criteria. However, it is important to note that most of the studies had low numbers of participants (only 4 studies had a sample size [n] >50, 3 studies with n >100). Some of the trials shared the same patients but analyzed different end points so the fundamental “independence” assumption required for most standard statistical analyses, including meta-analysis, was likely violated.

A few of the trials used another pharmacological agent or invasive procedure as control treatment. Some trials had designs such that in the end, the treatment and control groups both received ovulation induction agents for the patients who failed to ovulate. Even with the strict inclusion and exclusion criteria, many of the included trials still were of less than satisfactory design quality for our purposes.

Data collection/extraction

The principal author reviewed the text, tables, and figures and then collected and extracted the data from relevant publications. The data set was reviewed by the secondary authors for errors in data entry, format, outliers, or implausible values.

Statistical analysis

For each analysis, we converted all data to the same metric based on conversion formulas provided by each individual trial. We also verified the conversion factors online via data provided by standard clinical and reference laboratory values.

Some trials provided standard deviations (SD), while others provided standard error (SE) or standard error of the mean (SEM). We derived pooled variances accordingly. We converted all SDs to SE using the equation SE=SD/square root (N), where N denotes the sample size. We created data sets in the above fashion for each parameter.

Trials that did not report SD, SE, or sample variance for a given parameter were not included in the corresponding meta-analysis. We did not conduct a statistical analysis if only a small number of trials existed (ie, n <5), as it would result in less reliable conclusions.

No article provided individual level data or SD/SE for the “change” in the selected endpoint before and after treatment in the control and treatment arm. Instead, most publications presented the summary statistics separately for before and after treatment.

Since covariance (or correlation) between before and after values was not available and variability of the difference measure could not be estimated from the majority of the trials, it was not possible to perform methodologically sound meta-analysis by addressing the absolute or percent change before and after treatment and comparing this difference measure between 2 competing treatments. This is an inherent problem in many meta-analyses due to limited raw data.

However, as all the trials were randomized, we felt justified in performing the statistical analysis using the mean difference after treatment in the control and intervention arms. Our assumption: the values before treatment should be reasonably balanced between the 2 arms. Thus, we calculated the pooled estimates of treatment effect with 95% confidence intervals (CIs) for the mean differences between the control and intervention arms after treatment. We adopted the random effects model approach.¹³

Next, statistical significance was evaluated for treatment effect and heterogeneity. Publication bias was also examined by two different tests.^14,15 Sensitivity analysis was also performed to assess the impact of the identification of potential hidden studies by the trim and fill method.¹⁶

A 2-sided hypothesis with type I error of 5% was employed in all statistical testing and CI construction. Statistical analyses were carried out by STATA version 8.2.¹⁷

Results

Of the 31 trials included for the meta-analysis, we judged that 7 were of good quality, 6 were of fair quality, and 18 were of poor quality.^2,5-10,18-41 (See TABLE W1.)

Not enough data to compare TZD vs metformin

As the TZDs had few trials for each drug (5 troglitazone, 2 rosiglitazone, 1 pioglitazone) and not enough of the TZD trials reported data on most parameters, it became unrealistic to perform a statistical comparison of the treatment effect between metformin and the TZDs. Moreover, there were not enough data from TZD trials to analyze the effect of TZDs on any studied parameter. Thus, only data from metformin trials were used in the meta-analysis.

Metformin linked to changes in 3 outcomes

Of the outcomes we evaluated, there were statistically significant changes in three: ovulation rate, LH/FSH ratio, and fasting insulin. (For complete details of our findings, see TABLE.)

After analyzing the ovulation rate in 9 trials, we found a change of –0.18% (95% CI, –0.35 to –0.01; P=.03) from the control group. Our analysis of the LH/FSH ratio in 7 trials revealed a change in value of –0.21 (–0.30 to –0.13; P<.001). We evaluated the fasting insulin levels in 14 trials and found an increase of 30.4 pmol/L (13.9 to 46.8; P<.001).

Insufficient trials (n ≤5) reported on total cholesterol, triglycerides, HDL, LDL, systolic blood pressure, diastolic blood pressure, C-peptide, C-reactive protein, leptin, and Hb A_1c. Thus, we did not conduct a meta-analysis for these outcomes.

We intentionally used type I error of 5% for individual tests, not for overall test. If we had adopted multiple testing adjustments, we would have had more conservative results with much wider CIs, which makes it harder to reject the null hypothesis. Specifically, only 2 comparisons (LH/FSH and fasting insulin) would still be significant after multiple testing adjustments, while all marginally significant results would no longer be significant. A second reason to use type I error of 5% for individual (not overall) test is that endpoints are expected to be correlated, since most data were from the same trials.^42,43

We did not find any major change in results in the sensitivity analyses we performed. It is worth mentioning, though, that there was significant heterogeneity and variability in the treatment effects from virtually all comparisons we made, though most comparisons revealed no publication bias. When heterogeneity is detected, combining the effects is not always advisable; and when effects are combined, they should be viewed with extreme caution.^44-46

At a minimum, we failed to find any homogeneous or consistent treatment effects. Our sensitivity analysis offers additional protection against publication bias or file drawer problems.⁴⁷

TABLE
Meta-analysis results by outcome

Findings don’t support a common practice

Much has been reported in the literature, as well as by the media, regarding the large role that metformin and the TZDs can play in helping to alleviate the alterations caused by the polycystic ovarian syndrome. However, this systematic review of the literature, focusing on randomized controlled trials, failed to find evidence supporting the claims made in the literature, by the media, or offered anecdotally.

Based on our analysis, there is insufficient evidence to assess a difference in effect sizes between the TZDs and metformin. There is also insufficient evidence to assess if either the TZDs or metformin have an effect on lipids, blood pressure, C-peptide, C-reactive protein, leptin, or Hb A_1c.

With regard to the analyzed parameters, there were minimal decreases of statistical significance in ovulation rates and LH/FSH, and minimal increase of statistical significance in fasting insulin with metformin. (We cannot account for the paradoxical and unexpected finding of an increase of fasting insulin with metformin, especially since metformin works as an insulin sensitizer.) There was, however, no clinically significant change with metformin in any of the parameters we studied (ovulation rate, pregnancy rate, body mass index, waist-to-hip ratio, hirsutism score, LH/FSH, total cholesterol, fasting insulin, fasting blood glucose, total testosterone, free testosterone, androstenedione, and DHEAS).

This systematic review provides a strong message that many of the trials were not of adequate methodological quality to make a definitive statement for clinical practice. In addition, most trials had a low sample size and used additional treatments with gonadotropins or ovulation induction agents that can yield altered results.

The primary aim of this study was to ascertain the evidence for the use of either TZDs or metformin in the treatment of patients with PCOS. This systematic review with the meta-analysis has found insufficient evidence to support the routine use of either. The secondary aim of this study was to obtain evidence to assess if either agent was superior in clinically reducing the various biochemical and clinical alterations due to this condition. Based on our analysis, we cannot claim either agent as superior.

Limitations

Few trials, sparse data

Any systematic review and meta-analysis will have inherent limitations as data from multiple trials, that might not be directly comparable, are combined to give an overview. Another limitation is that trials published in other languages were not included. We cannot exclude the possibility of selection or information bias because only one person reviewed all the articles to decide which would be included. However, we set the inclusion/exclusion criteria as well as endpoints very carefully prior to the study and literature search and had independent reviews by other authors during statistical analyses to minimize this problem.

The quality assessment of each trial is also subjective, even though strict inclusion/exclusion criteria were utilized. Assessing the efficacy of the TZDs could not be done as there were very few trials. Moreover, most of the TZD trials did not study or report on all the parameters. It is difficult to assess for publication bias or outliers and to justify combining the results when only a small number of trials are available or the data are sparse. In addition, although 5 trials with good sample size were available for troglitazone, this agent is no longer on the market, thus limiting clinical utility.

As most trials were not truly blinded upon careful review of the article, this may provide some bias. Furthermore, we could not conduct the meta-analysis for the gold standard method based on difference measures (before, after, and between treatment) due to data unavailability. Our alternative choice of analysis is justified based on the assumption that randomization will allow for baseline values in both groups to be approximately similar.

Finally, we used the SD or SE (or SEM) information as the original authors reported. Although SE is a function of sample size, SD is the population parameter so its variability should not be high. However, we found that the SDs varied considerably. It may be that the authors inadvertently used SD and SE interchangeably, thus leading to the heterogeneity of effect size.

Conclusions

Further study is needed

Carefully designed and sufficiently powered PCOS studies with large sample sizes, followed by the proper reporting of the study findings, are warranted. These studies, evaluating drug effects, should be done in a randomized placebo controlled fashion. Such trials should not be interfered with by using hormonal or ovulation induction agents other than the medication being studied. Diet and exercise should not be a part of the study’s design as these have been independently validated in similar contexts.⁴

For now, focus on lifestyle, and symptom-based treatment

PCOS encompasses a myriad of clinical and biochemical features, where each component adds to morbidity. The data, as per our study, are not sufficient to support the use of either of the studied agents in altering either the clinical or biochemical changes associated with the condition.

Thus, clinicians should tailor their treatment regimen to the individual patient’s short- and long-term goals. Clinicians should also educate patients regarding lifestyle changes, such as diet and exercise, since multiple trials^1-4 have justified their use. Other options include symptom-based treatment, such as oral contraceptives for the regulation of menses or hirsutism.⁴

Acknowledgments

We wish to thank Dr Jan Groft, Dr Zakia Niruddin, Dr Marc Silverstein, and Dr Madhu Mazumdar for their efforts and guidance.

Funding/Support

This research was conducted without any outside funding or support.

Correspondence
Anush S. Pillai, DO, 424 Hahlo, Houston, TX, 77020; [email protected].

A 35-year-old woman with no past medical or surgical history presents to your office with complaints consistent with oligomenorrhea. She also reports a 15-pound weight gain over this past year.

Your patient is married and sexually active, but has never been pregnant. Her menarche was at age 12, and she says she has had irregular, infrequent menses over the past year, with 4 to 5 days of medium flow. Her social/family history is unremarkable.

She denies using any drugs, medications, supplements, or herbs. She had a recent TSH, fasting blood glucose, CBC, basic metabolic panel, and Pap smear done by her previous physician during a routine physical and all were normal.

On exam, your patient is clinically obese (abdominal adiposity) and notably hirsute. Her skin exam is also positive for hyperpigmented lichenified plaques around her neck and axilla, consistent with acanthosis nigricans. The rest of her exam is unremarkable.

Her signs and symptoms prompt you to suspect polycystic ovarian syndrome (PCOS), which you confirm after ruling out type 2 diabetes mellitus, thyroid disease, hyperprolactinemia, congenital adrenal hyperplasia, and androgen secreting tumors.

Your next step, of course, is treatment and you consider your options. Would pharmacological treatment with metformin or a thiazolidenedione (TZD) be appropriate?

An answer that may surprise you

There is no evidence to support the routine use of either metformin or a TZD as first-line therapy for the treatment of PCOS, based on a meta-analysis of randomized controlled clinical trials (strength of recommendation [SOR]: C). Instead, you should individualize your approach to achieve the patient’s short- and long-term goals, as well as to minimize complications and comorbidities. A good approach at this time would be to educate your patient on lifestyle changes, such as diet and exercise, since the evidence supports their use (SOR: B).^1-4 A weight reduction of as little as 5% can help regulate the menstrual cycle and improve fertility, decrease insulin resistance, and reduce associated symptoms and comorbidities.⁴

PCOS is associated with features of insulin resistance, hyperandrogenism, and oligomenorrhea leading to anovulatory bleeding and infertility. Many—though not all—PCOS patients have ovarian cysts.

Why the shift away from metformin or a TZD?

This recommendation is based on a meta-analysis that we, the authors, recently conducted. The following review provides a more detailed look at our analysis of the evidence to date. But before we get to the study, let’s look at the syndrome that sparked our research.

Background

A syndrome with extensive variability

PCOS (also known as Stein-Leventhal syndrome) is associated with features of insulin resistance (obesity, acanthosis nigricans); hyperandrogenism (hirsutism, elevated androgen levels), and oligomenorrhea leading to anovulatory bleeding and infertility. PCOS has a prevalence of approximately 5% to 10% in women of reproductive age. Patients may have high serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). However, much variation exists clinically and a specific patient may have normal androgen levels.³ In addition, despite the syndrome’s name, not all women with PCOS have ovarian cysts.

The features of peripheral insulin resistance, hyperinsulinemia, oligomenorrhea, and infertility can be magnified in the presence of obesity. Insulin resistance is not due to defects in insulin binding to the insulin receptors; rather, it involves post-binding signaling pathways. The elevated insulin levels may have gonadotropin-augmenting effects on ovarian function.³

Numerous comorbidities play a role

There is a great deal of frustration for both physicians and patients regarding the various comorbidities associated with this syndrome. For patients, the problems include androgenic features, menstrual irregularities, and infertility. For clinicians, however, the concerns include cardiovascular risks⁴ (obesity, lipid abnormalities, elevated C-reactive protein and leptin levels, blood pressure changes), hyperinsulinemia, insulin resistance, and the theoretical risks for endometrial hyperplasia due to a hyperestrogenic state.

NIH criteria is used for diagnosis in trials

Although there are no definitive consensus criteria for the diagnosis of PCOS, the 1990 National Institutes of Health (NIH) criteria and its revision in 2003, the Rotterdam Criteria, have been used to make the diagnosis in clinical trials. Most trials however use the NIH criteria as there is disagreement regarding the Rotterdam Criteria.

The NIH criteria use the following for the diagnosis of PCOS:

• oligomenorrhea
• hyperandrogenism (clinical or laboratory evidence), and
• absence of other endocrine disorders (congenital adrenal hyperplasia, hyperprolactinemia, thyroid dysfunction, and androgen secreting tumors).

In reviewing the literature, most clinicians and researchers have noted that PCOS has been associated with various outcomes such as elevated body mass index (BMI),⁵ waist-to-hip ratio,^5,6 fasting blood glucose,⁷ insulin levels,⁷ testosterone levels,⁸ androstenedione levels,⁸ DHEAS levels,⁹ hirsutism scores,⁹ lipids,⁵ blood pressure,⁹ luteinizing hormone to follicle-stimulating hormone ratio (LH/FSH),⁹ C-peptide,⁵ and leptin,⁶ as well as decreased ovulatory and pregnancy rates.^4,5,10

Metformin/TZDs are used, but what about the evidence?

Both metformin and the TZDs (glitazones) including troglitazone—which was withdrawn from the market—pioglitazone, and rosiglitazone, are antidiabetic agents that also work as insulin sensitizers. These agents—especially metformin—are widely used by primary care physicians and specialists to treat the clinical and biochemical features of PCOS. However, the evidence-based data supporting this use is lacking. Although much research has been done on this topic, most published trials are of less than ideal quality and involve methodological issues. Often times they are nonrandomized, not controlled, involve a low number of subjects, provide no long-term follow up, and use nonstudy agents or ancillary treatments that were not randomized and could yield confounding results.

Objectives

Our primary objective was to assess whether there is evidence to support the use of metformin or TZDs, as well as to suggest any differences among the drugs. The secondary objective was to ascertain if, and to what extent, the studied drugs affected the studied parameters.

Methods

Search Strategy

We searched MD Consult, PubMed, Medline, Ovid, and Google Scholar through January 2007 with the following terms: “PCOS and metformin,” “PCOS and Glucophage,” “PCOS and troglitazone,” “PCOS and pioglitazone,” “PCOS and rosiglitazone,” “PCOS and thiazolidenediones.” These searches were also done by substituting “+” instead of the word “and,” as well as by using full form of the abbreviation PCOS—polycystic ovarian syndrome.

The following limits were placed on the search: randomized controlled trials, English language, human, and female subjects. We also searched articles from reference lists and made additional efforts to contact clinicians and researchers in this field.

Selection criteria

Our search resulted in 115 articles. From these articles, we included only those trials that:

• Used the NIH 1990 criteria for the diagnosis of PCOS
• Studied the effect of any of the following drugs: metformin, troglitazone, rosiglitazone, or pioglitazone
• Did not use or advocate adjunctive therapy—ie, diet or exercise
• Were randomized and controlled (based on a review of the methods section).

We also excluded studies that permitted confounding or concomitant treatments if it made it difficult to estimate the true effect of the medications studied.

This criteria resulted in 33 trials and ultimately 31 trials were included in the analysis (23 metformin, 2 rosiglitazone, 1 pioglitazone, 5 troglitazone) with a total of 1892 patients. Two metformin trials were unobtainable.

Outcome measures

We studied the parameters that are needed for the diagnosis of PCOS, as well as parameters that are associated with the syndrome’s comorbidities. The measured variables included: ovulation rates, pregnancy rates, BMI, waist-to-hip ratio, lipid panel, blood pressure, fasting insulin levels, fasting blood glucose, C-peptide, glycosylated hemoglobin (Hb A_1c), LH/FSH, total testosterone, free testosterone, androstenedione, DHEAS, leptin, C-reactive protein, hirsutism (based on the Ferriman-Gallwey [F-G] score), and weight.

Methods of the review

Each included trial was evaluated in detail regarding how well it met the inclusion and exclusion criteria, the number of participants, the follow-up period, quantitative reporting of the data, and the overall methodology. The principal author rated methodological quality as good, fair, or poor on the basis of an overall assessment of these features. We did not use explicit validity checklists with summary scores because they have not been shown to predict the effect of bias on treatment differences or to provide more reliable assessments of validity.^11,12

Description of studies

All included studies met the inclusion criteria. However, it is important to note that most of the studies had low numbers of participants (only 4 studies had a sample size [n] >50, 3 studies with n >100). Some of the trials shared the same patients but analyzed different end points so the fundamental “independence” assumption required for most standard statistical analyses, including meta-analysis, was likely violated.

A few of the trials used another pharmacological agent or invasive procedure as control treatment. Some trials had designs such that in the end, the treatment and control groups both received ovulation induction agents for the patients who failed to ovulate. Even with the strict inclusion and exclusion criteria, many of the included trials still were of less than satisfactory design quality for our purposes.

Data collection/extraction

The principal author reviewed the text, tables, and figures and then collected and extracted the data from relevant publications. The data set was reviewed by the secondary authors for errors in data entry, format, outliers, or implausible values.

Statistical analysis

For each analysis, we converted all data to the same metric based on conversion formulas provided by each individual trial. We also verified the conversion factors online via data provided by standard clinical and reference laboratory values.

Some trials provided standard deviations (SD), while others provided standard error (SE) or standard error of the mean (SEM). We derived pooled variances accordingly. We converted all SDs to SE using the equation SE=SD/square root (N), where N denotes the sample size. We created data sets in the above fashion for each parameter.

Trials that did not report SD, SE, or sample variance for a given parameter were not included in the corresponding meta-analysis. We did not conduct a statistical analysis if only a small number of trials existed (ie, n <5), as it would result in less reliable conclusions.

No article provided individual level data or SD/SE for the “change” in the selected endpoint before and after treatment in the control and treatment arm. Instead, most publications presented the summary statistics separately for before and after treatment.

Since covariance (or correlation) between before and after values was not available and variability of the difference measure could not be estimated from the majority of the trials, it was not possible to perform methodologically sound meta-analysis by addressing the absolute or percent change before and after treatment and comparing this difference measure between 2 competing treatments. This is an inherent problem in many meta-analyses due to limited raw data.

However, as all the trials were randomized, we felt justified in performing the statistical analysis using the mean difference after treatment in the control and intervention arms. Our assumption: the values before treatment should be reasonably balanced between the 2 arms. Thus, we calculated the pooled estimates of treatment effect with 95% confidence intervals (CIs) for the mean differences between the control and intervention arms after treatment. We adopted the random effects model approach.¹³

Next, statistical significance was evaluated for treatment effect and heterogeneity. Publication bias was also examined by two different tests.^14,15 Sensitivity analysis was also performed to assess the impact of the identification of potential hidden studies by the trim and fill method.¹⁶

A 2-sided hypothesis with type I error of 5% was employed in all statistical testing and CI construction. Statistical analyses were carried out by STATA version 8.2.¹⁷

Results

Of the 31 trials included for the meta-analysis, we judged that 7 were of good quality, 6 were of fair quality, and 18 were of poor quality.^2,5-10,18-41 (See TABLE W1.)

Not enough data to compare TZD vs metformin

As the TZDs had few trials for each drug (5 troglitazone, 2 rosiglitazone, 1 pioglitazone) and not enough of the TZD trials reported data on most parameters, it became unrealistic to perform a statistical comparison of the treatment effect between metformin and the TZDs. Moreover, there were not enough data from TZD trials to analyze the effect of TZDs on any studied parameter. Thus, only data from metformin trials were used in the meta-analysis.

Metformin linked to changes in 3 outcomes

Of the outcomes we evaluated, there were statistically significant changes in three: ovulation rate, LH/FSH ratio, and fasting insulin. (For complete details of our findings, see TABLE.)

After analyzing the ovulation rate in 9 trials, we found a change of –0.18% (95% CI, –0.35 to –0.01; P=.03) from the control group. Our analysis of the LH/FSH ratio in 7 trials revealed a change in value of –0.21 (–0.30 to –0.13; P<.001). We evaluated the fasting insulin levels in 14 trials and found an increase of 30.4 pmol/L (13.9 to 46.8; P<.001).

Insufficient trials (n ≤5) reported on total cholesterol, triglycerides, HDL, LDL, systolic blood pressure, diastolic blood pressure, C-peptide, C-reactive protein, leptin, and Hb A_1c. Thus, we did not conduct a meta-analysis for these outcomes.

We intentionally used type I error of 5% for individual tests, not for overall test. If we had adopted multiple testing adjustments, we would have had more conservative results with much wider CIs, which makes it harder to reject the null hypothesis. Specifically, only 2 comparisons (LH/FSH and fasting insulin) would still be significant after multiple testing adjustments, while all marginally significant results would no longer be significant. A second reason to use type I error of 5% for individual (not overall) test is that endpoints are expected to be correlated, since most data were from the same trials.^42,43

We did not find any major change in results in the sensitivity analyses we performed. It is worth mentioning, though, that there was significant heterogeneity and variability in the treatment effects from virtually all comparisons we made, though most comparisons revealed no publication bias. When heterogeneity is detected, combining the effects is not always advisable; and when effects are combined, they should be viewed with extreme caution.^44-46

At a minimum, we failed to find any homogeneous or consistent treatment effects. Our sensitivity analysis offers additional protection against publication bias or file drawer problems.⁴⁷

TABLE
Meta-analysis results by outcome

Findings don’t support a common practice

Much has been reported in the literature, as well as by the media, regarding the large role that metformin and the TZDs can play in helping to alleviate the alterations caused by the polycystic ovarian syndrome. However, this systematic review of the literature, focusing on randomized controlled trials, failed to find evidence supporting the claims made in the literature, by the media, or offered anecdotally.

Based on our analysis, there is insufficient evidence to assess a difference in effect sizes between the TZDs and metformin. There is also insufficient evidence to assess if either the TZDs or metformin have an effect on lipids, blood pressure, C-peptide, C-reactive protein, leptin, or Hb A_1c.

With regard to the analyzed parameters, there were minimal decreases of statistical significance in ovulation rates and LH/FSH, and minimal increase of statistical significance in fasting insulin with metformin. (We cannot account for the paradoxical and unexpected finding of an increase of fasting insulin with metformin, especially since metformin works as an insulin sensitizer.) There was, however, no clinically significant change with metformin in any of the parameters we studied (ovulation rate, pregnancy rate, body mass index, waist-to-hip ratio, hirsutism score, LH/FSH, total cholesterol, fasting insulin, fasting blood glucose, total testosterone, free testosterone, androstenedione, and DHEAS).

This systematic review provides a strong message that many of the trials were not of adequate methodological quality to make a definitive statement for clinical practice. In addition, most trials had a low sample size and used additional treatments with gonadotropins or ovulation induction agents that can yield altered results.

The primary aim of this study was to ascertain the evidence for the use of either TZDs or metformin in the treatment of patients with PCOS. This systematic review with the meta-analysis has found insufficient evidence to support the routine use of either. The secondary aim of this study was to obtain evidence to assess if either agent was superior in clinically reducing the various biochemical and clinical alterations due to this condition. Based on our analysis, we cannot claim either agent as superior.

Limitations

Few trials, sparse data

Any systematic review and meta-analysis will have inherent limitations as data from multiple trials, that might not be directly comparable, are combined to give an overview. Another limitation is that trials published in other languages were not included. We cannot exclude the possibility of selection or information bias because only one person reviewed all the articles to decide which would be included. However, we set the inclusion/exclusion criteria as well as endpoints very carefully prior to the study and literature search and had independent reviews by other authors during statistical analyses to minimize this problem.

The quality assessment of each trial is also subjective, even though strict inclusion/exclusion criteria were utilized. Assessing the efficacy of the TZDs could not be done as there were very few trials. Moreover, most of the TZD trials did not study or report on all the parameters. It is difficult to assess for publication bias or outliers and to justify combining the results when only a small number of trials are available or the data are sparse. In addition, although 5 trials with good sample size were available for troglitazone, this agent is no longer on the market, thus limiting clinical utility.

As most trials were not truly blinded upon careful review of the article, this may provide some bias. Furthermore, we could not conduct the meta-analysis for the gold standard method based on difference measures (before, after, and between treatment) due to data unavailability. Our alternative choice of analysis is justified based on the assumption that randomization will allow for baseline values in both groups to be approximately similar.

Finally, we used the SD or SE (or SEM) information as the original authors reported. Although SE is a function of sample size, SD is the population parameter so its variability should not be high. However, we found that the SDs varied considerably. It may be that the authors inadvertently used SD and SE interchangeably, thus leading to the heterogeneity of effect size.

Conclusions

Further study is needed

Carefully designed and sufficiently powered PCOS studies with large sample sizes, followed by the proper reporting of the study findings, are warranted. These studies, evaluating drug effects, should be done in a randomized placebo controlled fashion. Such trials should not be interfered with by using hormonal or ovulation induction agents other than the medication being studied. Diet and exercise should not be a part of the study’s design as these have been independently validated in similar contexts.⁴

For now, focus on lifestyle, and symptom-based treatment

PCOS encompasses a myriad of clinical and biochemical features, where each component adds to morbidity. The data, as per our study, are not sufficient to support the use of either of the studied agents in altering either the clinical or biochemical changes associated with the condition.

Thus, clinicians should tailor their treatment regimen to the individual patient’s short- and long-term goals. Clinicians should also educate patients regarding lifestyle changes, such as diet and exercise, since multiple trials^1-4 have justified their use. Other options include symptom-based treatment, such as oral contraceptives for the regulation of menses or hirsutism.⁴

Acknowledgments

We wish to thank Dr Jan Groft, Dr Zakia Niruddin, Dr Marc Silverstein, and Dr Madhu Mazumdar for their efforts and guidance.

Funding/Support

This research was conducted without any outside funding or support.

Correspondence
Anush S. Pillai, DO, 424 Hahlo, Houston, TX, 77020; [email protected].

The package insert (PI) is getting an FDA-mandated “makeover”—one that should make it faster and easier to locate the piece of information you need before writing a prescription.

PIs for newly approved drugs will now feature a Highlights section at the top, a Contents section to help you find what you’re looking for, and a Patient Counseling section. Also new: manufacturer and FDA contact information near the top of the PI to facilitate adverse drug reaction reporting (FIGURE).

These revisions—the first that the FDA has mandated for the PI in 25 years¹—are designed to save time and reduce adverse drug events. Evidence suggests that physicians could save approximately 15 seconds each time they refer to the new PI, thereby increasing the extent to which prescribing information is consulted.²

Additionally, the FDA anticipates healthcare system savings of approximately $400 million in the next 10 years resulting from adverse drug events avoided,² presumably because prescribers will be better informed. The new format should also help increase adverse drug reaction reporting by providing toll-free contact information.³

Lack of Rx information caused many mistakes

Changing the PI became an FDA priority in 2000, after the Institute of Medicine (IOM) published its report, “To err is human: Building a safer health system.”⁴ In this report, the IOM indicated that medication errors accounted for almost 98,000 deaths annually and that some of these deaths were a result of confusing medical information.⁴ A July 2006 IOM report estimated that there are at least 1.5 million preventable adverse drug events resulting from medication errors in the US each year.⁵

One study demonstrated that the most common cause of medication errors was a lack of drug information at the time the prescription was written, resulting in 22% of the errors.⁶ A subsequent report released by the IOM in September 2006 identified the importance of improving the FDA’s role in monitoring drug safety in the postmarketing stage and conveying the risks and benefits of medications to the public.⁷

To help address this growing list of concerns, the FDA issued new regulations for the PI format in January 2006.¹ Among its goals: Prompt pharmaceutical companies to create PIs that read more like a drug information reference, and less like a sophisticated legal document.

The new FDA regulations apply to all New Drug Applications (NDAs), supplemental NDAs, and Biologics License Applications (BLAs) submitted on or after June 30, 2006.¹ In addition, drugs approved in the 5 years prior to the effective date, and older drugs for which there is a major change in the prescribing information (ie, new indication), will need to adopt the revised format over the next several years.^2,8 Medications that are exempt from these requirements include over-the-counter products, generic drugs, and existing drugs with minor labeling changes.

To get the word out to the healthcare community, the FDA and Institute for Safe Medication Practices kicked off a national educational campaign last fall by providing an overview of the new labeling format during a live teleconference.⁸ In addition, this PI information is being posted on the Web. (See “New PI makes its way online”^3,9)

Immediate access to important information

The revised PI contains 3 new sections: Highlights, Contents, and Patient Counseling Information.¹⁰

Highlights. The Highlights section is the most significant change to the PI, and provides immediate access to the most important prescribing information.^1,11,12 It’s displayed prominently at the top of the PI and is a concise half-page summary that includes references to detailed sections in the Full Prescribing Information.^2,3

The Highlights section is analogous to a structured abstract in a published clinical trial (FIGURE).¹³ It contains recent major changes to the following sections: Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions.¹² Additionally, the original FDA drug approval date of the product is listed, enabling physicians to easily identify new medications.^2,3 Manufacturer and FDA contact information is also provided to encourage and facilitate adverse drug reaction reporting.¹²

Contents. Physicians will be able to locate information more quickly with the Contents section. This section, which is analogous to the table of contents of a book, references all sections and subsections in the Full Prescribing Information section.¹²

Patient counseling. The new format now requires a Patient Counseling Information section that places a greater emphasis on the importance of communication between physicians and patients. This section provides key points, including information on dosing instructions, laboratory tests, and drug safety. This section is designed to help physicians by providing efficient and concise talking points involving drug usage.¹

New design bids laundry lists farewell

The overall structure of the PI has been revised to allow easier access to important information and to group related sections.³ Information physicians frequently consult and consider most critical (ie, Boxed Warnings, Indications and Usage, Dosage Forms and Strengths, Dosage and Administration) are located at the beginning.^3,12

The Adverse Reactions section no longer contains a laundry list of adverse reactions and is divided into 2 parts: clinical trials experience (adverse events identified during clinical trials) and postmarketing experience (adverse events reported spontaneously by physicians and patients).⁸ Additionally, the Warnings and Precautions are now consolidated into 1 section instead of being listed separately.⁸

The new regulations also require that the PI text be formatted in a certain way. The FDA requires that certain elements be in bold, and that there be a minimum font size to enhance the communication of important information.^2,3 (Previously, there was no minimum font size requirement.) Type in the PI can now be no smaller than 6 points and labeling on promotional materials and product samples can be no smaller than 8 points.

Manufacturers worry that details will be overlooked

Manufacturers have expressed concern over the addition of the Highlights section to the PI, noting that physicians might rely too heavily on the condensed information when making prescribing decisions.^2,14 Manufacturers are also concerned that they will be forced to choose certain information for the Highlights section while excluding other valuable points, increasing their liability.^2,14 The FDA, though, seems to have addressed this issue: The Highlights section includes a limitation statement emphasizing that physicians should still refer to the complete prescribing information.^2,14

Another concern: The revisions to the PI come at a price, albeit a relatively small one. Updating the PI is expected to cost manufacturers approximately $6190 for each new product and $8700 for each existing product.²

Overall, though, the revisions to the PI should lead to positive change by providing physicians with access to up-to-date information in a clear, concise, and easy-to-read format. Though not a panacea for medication errors, the new PI should serve as an improved tool in the physician’s arsenal.

Correspondence
Jennifer A. Fass, PharmD, Nova Southeastern University, College of Pharmacy, 3200 South university Drive, Fort lauderdale, FL 33328; [email protected].

The package insert (PI) is getting an FDA-mandated “makeover”—one that should make it faster and easier to locate the piece of information you need before writing a prescription.

PIs for newly approved drugs will now feature a Highlights section at the top, a Contents section to help you find what you’re looking for, and a Patient Counseling section. Also new: manufacturer and FDA contact information near the top of the PI to facilitate adverse drug reaction reporting (FIGURE).

These revisions—the first that the FDA has mandated for the PI in 25 years¹—are designed to save time and reduce adverse drug events. Evidence suggests that physicians could save approximately 15 seconds each time they refer to the new PI, thereby increasing the extent to which prescribing information is consulted.²

Additionally, the FDA anticipates healthcare system savings of approximately $400 million in the next 10 years resulting from adverse drug events avoided,² presumably because prescribers will be better informed. The new format should also help increase adverse drug reaction reporting by providing toll-free contact information.³

Lack of Rx information caused many mistakes

Changing the PI became an FDA priority in 2000, after the Institute of Medicine (IOM) published its report, “To err is human: Building a safer health system.”⁴ In this report, the IOM indicated that medication errors accounted for almost 98,000 deaths annually and that some of these deaths were a result of confusing medical information.⁴ A July 2006 IOM report estimated that there are at least 1.5 million preventable adverse drug events resulting from medication errors in the US each year.⁵

One study demonstrated that the most common cause of medication errors was a lack of drug information at the time the prescription was written, resulting in 22% of the errors.⁶ A subsequent report released by the IOM in September 2006 identified the importance of improving the FDA’s role in monitoring drug safety in the postmarketing stage and conveying the risks and benefits of medications to the public.⁷

To help address this growing list of concerns, the FDA issued new regulations for the PI format in January 2006.¹ Among its goals: Prompt pharmaceutical companies to create PIs that read more like a drug information reference, and less like a sophisticated legal document.

The new FDA regulations apply to all New Drug Applications (NDAs), supplemental NDAs, and Biologics License Applications (BLAs) submitted on or after June 30, 2006.¹ In addition, drugs approved in the 5 years prior to the effective date, and older drugs for which there is a major change in the prescribing information (ie, new indication), will need to adopt the revised format over the next several years.^2,8 Medications that are exempt from these requirements include over-the-counter products, generic drugs, and existing drugs with minor labeling changes.

To get the word out to the healthcare community, the FDA and Institute for Safe Medication Practices kicked off a national educational campaign last fall by providing an overview of the new labeling format during a live teleconference.⁸ In addition, this PI information is being posted on the Web. (See “New PI makes its way online”^3,9)

Immediate access to important information

The revised PI contains 3 new sections: Highlights, Contents, and Patient Counseling Information.¹⁰

Highlights. The Highlights section is the most significant change to the PI, and provides immediate access to the most important prescribing information.^1,11,12 It’s displayed prominently at the top of the PI and is a concise half-page summary that includes references to detailed sections in the Full Prescribing Information.^2,3

The Highlights section is analogous to a structured abstract in a published clinical trial (FIGURE).¹³ It contains recent major changes to the following sections: Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions.¹² Additionally, the original FDA drug approval date of the product is listed, enabling physicians to easily identify new medications.^2,3 Manufacturer and FDA contact information is also provided to encourage and facilitate adverse drug reaction reporting.¹²

Contents. Physicians will be able to locate information more quickly with the Contents section. This section, which is analogous to the table of contents of a book, references all sections and subsections in the Full Prescribing Information section.¹²

Patient counseling. The new format now requires a Patient Counseling Information section that places a greater emphasis on the importance of communication between physicians and patients. This section provides key points, including information on dosing instructions, laboratory tests, and drug safety. This section is designed to help physicians by providing efficient and concise talking points involving drug usage.¹

New design bids laundry lists farewell

The overall structure of the PI has been revised to allow easier access to important information and to group related sections.³ Information physicians frequently consult and consider most critical (ie, Boxed Warnings, Indications and Usage, Dosage Forms and Strengths, Dosage and Administration) are located at the beginning.^3,12

The Adverse Reactions section no longer contains a laundry list of adverse reactions and is divided into 2 parts: clinical trials experience (adverse events identified during clinical trials) and postmarketing experience (adverse events reported spontaneously by physicians and patients).⁸ Additionally, the Warnings and Precautions are now consolidated into 1 section instead of being listed separately.⁸

The new regulations also require that the PI text be formatted in a certain way. The FDA requires that certain elements be in bold, and that there be a minimum font size to enhance the communication of important information.^2,3 (Previously, there was no minimum font size requirement.) Type in the PI can now be no smaller than 6 points and labeling on promotional materials and product samples can be no smaller than 8 points.

Manufacturers worry that details will be overlooked

Manufacturers have expressed concern over the addition of the Highlights section to the PI, noting that physicians might rely too heavily on the condensed information when making prescribing decisions.^2,14 Manufacturers are also concerned that they will be forced to choose certain information for the Highlights section while excluding other valuable points, increasing their liability.^2,14 The FDA, though, seems to have addressed this issue: The Highlights section includes a limitation statement emphasizing that physicians should still refer to the complete prescribing information.^2,14

Another concern: The revisions to the PI come at a price, albeit a relatively small one. Updating the PI is expected to cost manufacturers approximately $6190 for each new product and $8700 for each existing product.²

Overall, though, the revisions to the PI should lead to positive change by providing physicians with access to up-to-date information in a clear, concise, and easy-to-read format. Though not a panacea for medication errors, the new PI should serve as an improved tool in the physician’s arsenal.

Correspondence
Jennifer A. Fass, PharmD, Nova Southeastern University, College of Pharmacy, 3200 South university Drive, Fort lauderdale, FL 33328; [email protected].

The package insert (PI) is getting an FDA-mandated “makeover”—one that should make it faster and easier to locate the piece of information you need before writing a prescription.

PIs for newly approved drugs will now feature a Highlights section at the top, a Contents section to help you find what you’re looking for, and a Patient Counseling section. Also new: manufacturer and FDA contact information near the top of the PI to facilitate adverse drug reaction reporting (FIGURE).

These revisions—the first that the FDA has mandated for the PI in 25 years¹—are designed to save time and reduce adverse drug events. Evidence suggests that physicians could save approximately 15 seconds each time they refer to the new PI, thereby increasing the extent to which prescribing information is consulted.²

Additionally, the FDA anticipates healthcare system savings of approximately $400 million in the next 10 years resulting from adverse drug events avoided,² presumably because prescribers will be better informed. The new format should also help increase adverse drug reaction reporting by providing toll-free contact information.³

Lack of Rx information caused many mistakes

Changing the PI became an FDA priority in 2000, after the Institute of Medicine (IOM) published its report, “To err is human: Building a safer health system.”⁴ In this report, the IOM indicated that medication errors accounted for almost 98,000 deaths annually and that some of these deaths were a result of confusing medical information.⁴ A July 2006 IOM report estimated that there are at least 1.5 million preventable adverse drug events resulting from medication errors in the US each year.⁵

One study demonstrated that the most common cause of medication errors was a lack of drug information at the time the prescription was written, resulting in 22% of the errors.⁶ A subsequent report released by the IOM in September 2006 identified the importance of improving the FDA’s role in monitoring drug safety in the postmarketing stage and conveying the risks and benefits of medications to the public.⁷

To help address this growing list of concerns, the FDA issued new regulations for the PI format in January 2006.¹ Among its goals: Prompt pharmaceutical companies to create PIs that read more like a drug information reference, and less like a sophisticated legal document.

The new FDA regulations apply to all New Drug Applications (NDAs), supplemental NDAs, and Biologics License Applications (BLAs) submitted on or after June 30, 2006.¹ In addition, drugs approved in the 5 years prior to the effective date, and older drugs for which there is a major change in the prescribing information (ie, new indication), will need to adopt the revised format over the next several years.^2,8 Medications that are exempt from these requirements include over-the-counter products, generic drugs, and existing drugs with minor labeling changes.

To get the word out to the healthcare community, the FDA and Institute for Safe Medication Practices kicked off a national educational campaign last fall by providing an overview of the new labeling format during a live teleconference.⁸ In addition, this PI information is being posted on the Web. (See “New PI makes its way online”^3,9)

Immediate access to important information

The revised PI contains 3 new sections: Highlights, Contents, and Patient Counseling Information.¹⁰

Highlights. The Highlights section is the most significant change to the PI, and provides immediate access to the most important prescribing information.^1,11,12 It’s displayed prominently at the top of the PI and is a concise half-page summary that includes references to detailed sections in the Full Prescribing Information.^2,3

The Highlights section is analogous to a structured abstract in a published clinical trial (FIGURE).¹³ It contains recent major changes to the following sections: Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions.¹² Additionally, the original FDA drug approval date of the product is listed, enabling physicians to easily identify new medications.^2,3 Manufacturer and FDA contact information is also provided to encourage and facilitate adverse drug reaction reporting.¹²

Contents. Physicians will be able to locate information more quickly with the Contents section. This section, which is analogous to the table of contents of a book, references all sections and subsections in the Full Prescribing Information section.¹²

Patient counseling. The new format now requires a Patient Counseling Information section that places a greater emphasis on the importance of communication between physicians and patients. This section provides key points, including information on dosing instructions, laboratory tests, and drug safety. This section is designed to help physicians by providing efficient and concise talking points involving drug usage.¹

New design bids laundry lists farewell

The overall structure of the PI has been revised to allow easier access to important information and to group related sections.³ Information physicians frequently consult and consider most critical (ie, Boxed Warnings, Indications and Usage, Dosage Forms and Strengths, Dosage and Administration) are located at the beginning.^3,12

The Adverse Reactions section no longer contains a laundry list of adverse reactions and is divided into 2 parts: clinical trials experience (adverse events identified during clinical trials) and postmarketing experience (adverse events reported spontaneously by physicians and patients).⁸ Additionally, the Warnings and Precautions are now consolidated into 1 section instead of being listed separately.⁸

The new regulations also require that the PI text be formatted in a certain way. The FDA requires that certain elements be in bold, and that there be a minimum font size to enhance the communication of important information.^2,3 (Previously, there was no minimum font size requirement.) Type in the PI can now be no smaller than 6 points and labeling on promotional materials and product samples can be no smaller than 8 points.

Manufacturers worry that details will be overlooked

Manufacturers have expressed concern over the addition of the Highlights section to the PI, noting that physicians might rely too heavily on the condensed information when making prescribing decisions.^2,14 Manufacturers are also concerned that they will be forced to choose certain information for the Highlights section while excluding other valuable points, increasing their liability.^2,14 The FDA, though, seems to have addressed this issue: The Highlights section includes a limitation statement emphasizing that physicians should still refer to the complete prescribing information.^2,14

Another concern: The revisions to the PI come at a price, albeit a relatively small one. Updating the PI is expected to cost manufacturers approximately $6190 for each new product and $8700 for each existing product.²

Overall, though, the revisions to the PI should lead to positive change by providing physicians with access to up-to-date information in a clear, concise, and easy-to-read format. Though not a panacea for medication errors, the new PI should serve as an improved tool in the physician’s arsenal.

Correspondence
Jennifer A. Fass, PharmD, Nova Southeastern University, College of Pharmacy, 3200 South university Drive, Fort lauderdale, FL 33328; [email protected].

• What treatment strategy is most effective at reducing mortality?
• What patient characteristics are associated with increased mortality?
• What are the indications for stent placement?

The answers to these questions are summarized below and in the Comparative Effectiveness Review: Comparative Effectiveness of Management Strategies for Renal Artery Stenosis, funded and published by Agency for Healthcare Research and Quality (AHRQ). The review summarizes the current evidence concerning the effectiveness and safety of angioplasty with stent placement compared with medical therapy in the treatment of atherosclerotic renal artery stenosis.

The review team accepted the patient population of original authors, without clearly defining the level of renal artery stenosis. “The population of interest for this report is adults with atherosclerotic renal artery stenosis that is of sufficient severity to warrant aggressive management, either due to resistant hypertension, evidence of kidney damage, or the high likelihood of poor outcomes.” The team considered the following outcomes: blood pressure control, preservation of kidney function, incidence of flash pulmonary edema, and survival rates. Adverse events associated with therapies were also considered.

Review is commissioned to tackle controversy

The Comparative Effectiveness Review notes that 12% to 14% of new dialysis patients in the United States have atherosclerotic renal artery stenosis. It also points out that the utilization of renal artery angioplasty has increased considerably over the last few years, from 7660 cases in 1996 to 18,520 in 2000. The review was commissioned because of the controversy regarding optimal strategies for the evaluation and management of patients with atherosclerotic renal artery stenosis. The Comparative Effectiveness Review is strengthened by excellent summary tables, a review of treatment-associated harm, and an extensive discussion of methods.

In addition to this review of the literature, the government is sponsoring a more definitive trial to determine which patients with atherosclerotic renal artery stenosis would most benefit from angioplasty with stent placement, as opposed to continued aggressive medical treatment. The results of the Cardiovascular Outcomes in Renal Atherosclerotic Lesion (CORAL) Trial, a large, multicenter trial sponsored by the National Institutes of Health, will not be available until 2010.

A review of nearly 40 years of research

The Tufts–New England Medical Center Evidence-Based Practice Center was commissioned by AHRQ to conduct the review. A comprehensive search of the literature included Medline from 1966 to September 6, 2005. A technical expert panel held teleconferences to refine key questions and define parameters for review of the evidence. Researchers gave priority to meta-analyses and systemic reviews. Abstracts of research presented at conferences and symposiums were not considered adequate to be considered. There were 76 references.

Quality assessment of the literature was designated by a 3-category grading system (A—good, B—fair/moderate, and C—poor). For our purposes, the evidence rating is updated to comply with the SORT taxonomy.¹

A search of the literature did not identify any other guidelines for comparison.

Source for this guideline

Balk E, Raman G, Chung M, et al. Comparative Effectiveness Review: Comparative Effectiveness of Management Strategies for Renal Artery Stenosis. (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022). Rockville, Md: Agency for Healthcare Research and Quality; October 2006. Available at: effectivehealthcare.ahrq.gov/repFiles/RAS_Final.pdf. Accessed on April 11, 2007.

Correspondence
Keith B. Holten, MD, 825 Locust Street, Wilmington, Ohio 45177; [email protected].

• What treatment strategy is most effective at reducing mortality?
• What patient characteristics are associated with increased mortality?
• What are the indications for stent placement?

The answers to these questions are summarized below and in the Comparative Effectiveness Review: Comparative Effectiveness of Management Strategies for Renal Artery Stenosis, funded and published by Agency for Healthcare Research and Quality (AHRQ). The review summarizes the current evidence concerning the effectiveness and safety of angioplasty with stent placement compared with medical therapy in the treatment of atherosclerotic renal artery stenosis.

The review team accepted the patient population of original authors, without clearly defining the level of renal artery stenosis. “The population of interest for this report is adults with atherosclerotic renal artery stenosis that is of sufficient severity to warrant aggressive management, either due to resistant hypertension, evidence of kidney damage, or the high likelihood of poor outcomes.” The team considered the following outcomes: blood pressure control, preservation of kidney function, incidence of flash pulmonary edema, and survival rates. Adverse events associated with therapies were also considered.

Review is commissioned to tackle controversy

The Comparative Effectiveness Review notes that 12% to 14% of new dialysis patients in the United States have atherosclerotic renal artery stenosis. It also points out that the utilization of renal artery angioplasty has increased considerably over the last few years, from 7660 cases in 1996 to 18,520 in 2000. The review was commissioned because of the controversy regarding optimal strategies for the evaluation and management of patients with atherosclerotic renal artery stenosis. The Comparative Effectiveness Review is strengthened by excellent summary tables, a review of treatment-associated harm, and an extensive discussion of methods.

In addition to this review of the literature, the government is sponsoring a more definitive trial to determine which patients with atherosclerotic renal artery stenosis would most benefit from angioplasty with stent placement, as opposed to continued aggressive medical treatment. The results of the Cardiovascular Outcomes in Renal Atherosclerotic Lesion (CORAL) Trial, a large, multicenter trial sponsored by the National Institutes of Health, will not be available until 2010.

A review of nearly 40 years of research

The Tufts–New England Medical Center Evidence-Based Practice Center was commissioned by AHRQ to conduct the review. A comprehensive search of the literature included Medline from 1966 to September 6, 2005. A technical expert panel held teleconferences to refine key questions and define parameters for review of the evidence. Researchers gave priority to meta-analyses and systemic reviews. Abstracts of research presented at conferences and symposiums were not considered adequate to be considered. There were 76 references.

Quality assessment of the literature was designated by a 3-category grading system (A—good, B—fair/moderate, and C—poor). For our purposes, the evidence rating is updated to comply with the SORT taxonomy.¹

A search of the literature did not identify any other guidelines for comparison.

Source for this guideline

Balk E, Raman G, Chung M, et al. Comparative Effectiveness Review: Comparative Effectiveness of Management Strategies for Renal Artery Stenosis. (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022). Rockville, Md: Agency for Healthcare Research and Quality; October 2006. Available at: effectivehealthcare.ahrq.gov/repFiles/RAS_Final.pdf. Accessed on April 11, 2007.

Correspondence
Keith B. Holten, MD, 825 Locust Street, Wilmington, Ohio 45177; [email protected].

• What treatment strategy is most effective at reducing mortality?
• What patient characteristics are associated with increased mortality?
• What are the indications for stent placement?

The answers to these questions are summarized below and in the Comparative Effectiveness Review: Comparative Effectiveness of Management Strategies for Renal Artery Stenosis, funded and published by Agency for Healthcare Research and Quality (AHRQ). The review summarizes the current evidence concerning the effectiveness and safety of angioplasty with stent placement compared with medical therapy in the treatment of atherosclerotic renal artery stenosis.

The review team accepted the patient population of original authors, without clearly defining the level of renal artery stenosis. “The population of interest for this report is adults with atherosclerotic renal artery stenosis that is of sufficient severity to warrant aggressive management, either due to resistant hypertension, evidence of kidney damage, or the high likelihood of poor outcomes.” The team considered the following outcomes: blood pressure control, preservation of kidney function, incidence of flash pulmonary edema, and survival rates. Adverse events associated with therapies were also considered.

Review is commissioned to tackle controversy

The Comparative Effectiveness Review notes that 12% to 14% of new dialysis patients in the United States have atherosclerotic renal artery stenosis. It also points out that the utilization of renal artery angioplasty has increased considerably over the last few years, from 7660 cases in 1996 to 18,520 in 2000. The review was commissioned because of the controversy regarding optimal strategies for the evaluation and management of patients with atherosclerotic renal artery stenosis. The Comparative Effectiveness Review is strengthened by excellent summary tables, a review of treatment-associated harm, and an extensive discussion of methods.

In addition to this review of the literature, the government is sponsoring a more definitive trial to determine which patients with atherosclerotic renal artery stenosis would most benefit from angioplasty with stent placement, as opposed to continued aggressive medical treatment. The results of the Cardiovascular Outcomes in Renal Atherosclerotic Lesion (CORAL) Trial, a large, multicenter trial sponsored by the National Institutes of Health, will not be available until 2010.

A review of nearly 40 years of research

The Tufts–New England Medical Center Evidence-Based Practice Center was commissioned by AHRQ to conduct the review. A comprehensive search of the literature included Medline from 1966 to September 6, 2005. A technical expert panel held teleconferences to refine key questions and define parameters for review of the evidence. Researchers gave priority to meta-analyses and systemic reviews. Abstracts of research presented at conferences and symposiums were not considered adequate to be considered. There were 76 references.

Quality assessment of the literature was designated by a 3-category grading system (A—good, B—fair/moderate, and C—poor). For our purposes, the evidence rating is updated to comply with the SORT taxonomy.¹

A search of the literature did not identify any other guidelines for comparison.

Source for this guideline

Balk E, Raman G, Chung M, et al. Comparative Effectiveness Review: Comparative Effectiveness of Management Strategies for Renal Artery Stenosis. (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022). Rockville, Md: Agency for Healthcare Research and Quality; October 2006. Available at: effectivehealthcare.ahrq.gov/repFiles/RAS_Final.pdf. Accessed on April 11, 2007.

Correspondence
Keith B. Holten, MD, 825 Locust Street, Wilmington, Ohio 45177; [email protected].

Janice L, 41, comes into her physician’s office complaining that she’s “feeling anxious all the time” at her job at a local bank. She tells him that she’s been treated for depression in the past, though she’s not currently taking any antidepressants. As her physician takes a more thorough history, he notices that her alcohol consumption seems a bit excessive. Her demeanor, which he had previously chalked up to as “shyness,” comes into focus. He begins to suspect that his patient is more than just “quiet and unassuming” and may, in fact, be suffering from social anxiety disorder.

To confirm his suspicions, he excuses himself to retrieve an article he’d saved on the topic—one that identifies a quick screening tool for social anxiety disorder.¹ He then asks his patient to rate the following statements on a scale of 0 to 4, with 0 being “not at all” and 4 being “extremely present”:

• Fear of embarrassment causes me to avoid doing things or speaking to people.
• I avoid activities in which I am the center of attention.
• Being embarrassed or looking stupid are among my worst fears.

His suspicions are confirmed when she scores a 10—well above the 6 that is highly suggestive of social anxiety disorder.

A debilitating disorder that’s all too common

Social anxiety, also known as social phobia, is the most common anxiety disorder, and is the third most common psychiatric disorder after depression and alcohol dependence.² The Epidemiological Catchment Area Study revealed that 2% to 4% of the sample suffered from social anxiety with a lifetime prevalence of 2.8%. Other studies have found that as many at 10% of the sample suffer from social anxiety when a more appropriate diagnostic interview is used.^3-5 Similarly, Kessler et al conducted a study investigating the prevalence of DSM-IV disorders and concluded that 6.8% of the entire sample suffered from social anxiety disorder.⁶

Social anxiety disorder is characterized as a persistent and debilitating fear of social interaction where patients fear negative evaluations by others. As a result, these patients may have trouble building and maintaining social relationships, which can result in a particularly isolated and depressed lifestyle.⁷

There are 2 subtypes of social anxiety disorder:

• Generalized social anxiety is generally more severe and more generalized and therefore, more disabling to patients. The majority of patients seen by the medical community tend to exhibit this sub-type of the disorder.
• Nongeneralized anxiety (also known as specific or discrete social phobia) is the less common and usually includes a fear associated with 1 or a few specific situations.

Although nongeneralized anxiety may be less likely to cause severe impairment in the patient’s life, it still may lead to significant underachievement in school or work.⁸ Still, patients with public speaking–only social anxiety are more likely to recover spontaneously, while patients with generalized social anxiety rarely recover spontaneously from the disorder.

The 2 subtypes also differ in their origin. Generalized social anxiety—the focus of this article—is significantly more prevalent among relatives who also suffer from the disorder, while patients with nongeneralized social anxiety disorder do not necessarily have relatives with the condition.⁹

“Shyness” in childhood that’s often overlooked

Social anxiety is a lifelong disorder that may begin as early as childhood, but is often described as beginning at age 13. At this age, though, the social anxiety is often mistaken for extreme shyness and therefore goes untreated.¹⁰ (See “Distinguishing shyness from social anxiety in kids,”.)

Overlooking shyness in such a young patient is particularly problematic as the avoidance that characterizes the social anxiety disorder can result in a lost opportunity to acquire social skills that are needed to ease the transition from adolescence to adulthood. This relative loss of social skills often facilitates the development of social dysfunction that is characteristic of this illness.¹¹ As time goes by, sufferers eventually become accustomed to their fears and create a way of life that accommodates them.

Social anxiety can interrupt education or job success, cause financial dependence, and impair relationships.¹⁰ (See “Fear of embarrassment hinders relationships and careers”.) Sufferers tend to miss out on important social events and activities in their lives,¹² and they begin to accumulate comorbidities such as depression and substance abuse.¹³ In fact, while many cases of social anxiety are overlooked as shyness, others are misdiagnosed as depression.

Complicating matters further is the issue of substance abuse. The Epidemiological Catchment Area Study found that alcohol abuse was reported in 17% of social anxiety cases and drug abuse was reported in 13%.⁵ In the study conducted by Kessler et al, results indicated that 8.8% of individuals suffering from a substance abuse problem also suffered from comorbid social anxiety.⁶

The substance abuse evolves slowly,¹⁴ and tends to arise as an inappropriate coping mechanism because so many cases of social anxiety go untreated.¹⁵

Symptoms to watch for, questions to ask

The primary indicator of social anxiety is intense fear of social situations. A patient suffering from social anxiety fears that he or she will act in a way that will be humiliating when confronted with unfamiliar situations or people or by the possibility of being scrutinized by others.¹⁶ While many people with social anxiety realize that their fears are excessive or unreasonable, they are unable to overcome them.¹⁷

There are also a number of physical, cognitive, and behavioral symptoms that are associated with social anxiety. The physical symptoms may include rapid heart rate, trembling, shortness of breath, sweating, and abdominal pain. The cognitive symptoms include maladaptive thoughts and beliefs about social situations (ie, irrational thought processes), that increase the anxiety when in the situation. Finally, behavioral symptoms include phobic avoidance of the feared situation.¹⁸

There are many screening devices that you can use to identify patients with social anxiety disorder or to assess the severity of symptoms. Some examples include the Liebowitz Social Phobia Scale,¹⁹ the Social Phobia Inventory (SPIN),²⁰ Fear of Negative Evaluation Scale,²¹ and the Social Avoidance and Distress Scale.²² These tools, however, can be a bit time consuming.

A more handy—though admittedly less comprehensive—screening device is the “mini SPIN” that was used by the physician in our opener. In a study of 7165 managed care patients, 89% of the cases meeting criteria for social anxiety disorder were detected (with a score of 6 or better) using this screening method.¹

To review, you’ll need to ask patients to rate the following statements on a scale of 0 “not at all” to 4 “extremely present”:

1. Fear of embarrassment causes me to avoid doing things or speaking to people.
2. I avoid activities in which I am the center of attention.
3. Being embarrassed or looking stupid are among my worst fears.

TABLE
Pharmacologic options for treating social anxiety disorder

A score of 6 or higher should prompt you to further evaluate the patient using one of the screening devices listed earlier.

Treatments of choice: CBT and drug therapy

Although social anxiety most commonly spans a lifetime, studies indicate that treatment—typically cognitive behavioral therapy (CBT) with drug therapy—can help sufferers deal with their fears and function more efficiently in their everyday lives. The best effects in treating social anxiety, therefore, are in combining the different treatment strategies.¹⁴

Cognitive begavioral therapy

Heimberg and colleagues found that 75% of social anxiety patients who participated in a cognitive behavioral therapy group experienced improved function and saw a reduction in symptoms of social anxiety.²³ Successful CBT seems to not only alleviate symptomatic distress, but improve the patients’ perceptions of their general quality of life.²⁴ Including behavioral components such as reinforcement or conditioning in CBT appears to be effective in helping sufferers minimize their symptoms. In addition, cognitive restructuring (ie, changing a patient’s thought process) has also been shown to be a helpful treatment.²³

Some of the basic elements of CBT include anxiety management skills (ie, breathing and relaxation techniques), social skills training (ie, maintaining conversation with the patient while monitoring the patient’s eye contact), and gradual exposure to the feared situation (ie, exposure to social situations).

Drug therapy

Studies have also demonstrated the effectiveness of a variety of medications (including Venlafaxine XR [Effexor XR], Paroxetine [Paxil], Paroxetine CR [Paxil CR], Sertraline [Zoloft], and Fluvoxamine [Luvox]) in managing social anxiety disorder.^25-28 If you are caring for a patient with social anxiety disorder, you’ll want to start him on a selective serotonin reuptake inhibitor (SSRI) or serotoninnorepinephrine reuptake inhibitor (SNRI).

If this doesn’t achieve the desired results, the next step is a monoamine oxidase inhibitor, such as phenelzine (Nardil), or a reverse inhibitor of monoamine oxidase A, such as moclobemide. Additionally, some benzodiazepines and anticonvulsants (clonazepam and pregabalin [Lyrica]) may also be effective if the other options do not achieve the desired results. The TABLE outlines common medications used to treat social anxiety, as well as recommended dosages.²⁹

When putting your patient on any of these medications, patient teaching will be important. You’ll need to advise the patient that common antidepressant side effects include, but are not limited to, nausea, diarrhea, sexual dysfunction (ie, delayed orgasm), and headaches. These effects, however, typically disappear by the second week of intake.¹⁵ If the patient is taking a benzodiazepine, you’ll need to warn him about the risk of psychomotor or cognitive impairment.

If the patient has a comorbid substance abuse problem, you and the patient will also need to adjust your expectations somewhat. That’s because patients with a substance abuse problem are likely to have a poorer response to some of these medications than patients without a substance abuse problem.³⁰

Though the time it takes to manage the condition is variable, patients with social anxiety disorder can improve their situation and go on to live more fulfilling and happy lives. The trick, really, is spotting the disorder early, rather than assuming your patient is simply the “quiet type.”

Correspondence
Martin A. Katzman, MD, FRCPC, START Clinic for Mood and Anxiety Disorders, 790 Bay St, Toronto, Ontario, Canada M5G 1N8 [email protected]

Janice L, 41, comes into her physician’s office complaining that she’s “feeling anxious all the time” at her job at a local bank. She tells him that she’s been treated for depression in the past, though she’s not currently taking any antidepressants. As her physician takes a more thorough history, he notices that her alcohol consumption seems a bit excessive. Her demeanor, which he had previously chalked up to as “shyness,” comes into focus. He begins to suspect that his patient is more than just “quiet and unassuming” and may, in fact, be suffering from social anxiety disorder.

To confirm his suspicions, he excuses himself to retrieve an article he’d saved on the topic—one that identifies a quick screening tool for social anxiety disorder.¹ He then asks his patient to rate the following statements on a scale of 0 to 4, with 0 being “not at all” and 4 being “extremely present”:

• Fear of embarrassment causes me to avoid doing things or speaking to people.
• I avoid activities in which I am the center of attention.
• Being embarrassed or looking stupid are among my worst fears.

His suspicions are confirmed when she scores a 10—well above the 6 that is highly suggestive of social anxiety disorder.

A debilitating disorder that’s all too common

Social anxiety, also known as social phobia, is the most common anxiety disorder, and is the third most common psychiatric disorder after depression and alcohol dependence.² The Epidemiological Catchment Area Study revealed that 2% to 4% of the sample suffered from social anxiety with a lifetime prevalence of 2.8%. Other studies have found that as many at 10% of the sample suffer from social anxiety when a more appropriate diagnostic interview is used.^3-5 Similarly, Kessler et al conducted a study investigating the prevalence of DSM-IV disorders and concluded that 6.8% of the entire sample suffered from social anxiety disorder.⁶

Social anxiety disorder is characterized as a persistent and debilitating fear of social interaction where patients fear negative evaluations by others. As a result, these patients may have trouble building and maintaining social relationships, which can result in a particularly isolated and depressed lifestyle.⁷

There are 2 subtypes of social anxiety disorder:

• Generalized social anxiety is generally more severe and more generalized and therefore, more disabling to patients. The majority of patients seen by the medical community tend to exhibit this sub-type of the disorder.
• Nongeneralized anxiety (also known as specific or discrete social phobia) is the less common and usually includes a fear associated with 1 or a few specific situations.

Although nongeneralized anxiety may be less likely to cause severe impairment in the patient’s life, it still may lead to significant underachievement in school or work.⁸ Still, patients with public speaking–only social anxiety are more likely to recover spontaneously, while patients with generalized social anxiety rarely recover spontaneously from the disorder.

The 2 subtypes also differ in their origin. Generalized social anxiety—the focus of this article—is significantly more prevalent among relatives who also suffer from the disorder, while patients with nongeneralized social anxiety disorder do not necessarily have relatives with the condition.⁹

“Shyness” in childhood that’s often overlooked

Social anxiety is a lifelong disorder that may begin as early as childhood, but is often described as beginning at age 13. At this age, though, the social anxiety is often mistaken for extreme shyness and therefore goes untreated.¹⁰ (See “Distinguishing shyness from social anxiety in kids,”.)

Overlooking shyness in such a young patient is particularly problematic as the avoidance that characterizes the social anxiety disorder can result in a lost opportunity to acquire social skills that are needed to ease the transition from adolescence to adulthood. This relative loss of social skills often facilitates the development of social dysfunction that is characteristic of this illness.¹¹ As time goes by, sufferers eventually become accustomed to their fears and create a way of life that accommodates them.

Social anxiety can interrupt education or job success, cause financial dependence, and impair relationships.¹⁰ (See “Fear of embarrassment hinders relationships and careers”.) Sufferers tend to miss out on important social events and activities in their lives,¹² and they begin to accumulate comorbidities such as depression and substance abuse.¹³ In fact, while many cases of social anxiety are overlooked as shyness, others are misdiagnosed as depression.

Complicating matters further is the issue of substance abuse. The Epidemiological Catchment Area Study found that alcohol abuse was reported in 17% of social anxiety cases and drug abuse was reported in 13%.⁵ In the study conducted by Kessler et al, results indicated that 8.8% of individuals suffering from a substance abuse problem also suffered from comorbid social anxiety.⁶

The substance abuse evolves slowly,¹⁴ and tends to arise as an inappropriate coping mechanism because so many cases of social anxiety go untreated.¹⁵

Symptoms to watch for, questions to ask

The primary indicator of social anxiety is intense fear of social situations. A patient suffering from social anxiety fears that he or she will act in a way that will be humiliating when confronted with unfamiliar situations or people or by the possibility of being scrutinized by others.¹⁶ While many people with social anxiety realize that their fears are excessive or unreasonable, they are unable to overcome them.¹⁷

There are also a number of physical, cognitive, and behavioral symptoms that are associated with social anxiety. The physical symptoms may include rapid heart rate, trembling, shortness of breath, sweating, and abdominal pain. The cognitive symptoms include maladaptive thoughts and beliefs about social situations (ie, irrational thought processes), that increase the anxiety when in the situation. Finally, behavioral symptoms include phobic avoidance of the feared situation.¹⁸

There are many screening devices that you can use to identify patients with social anxiety disorder or to assess the severity of symptoms. Some examples include the Liebowitz Social Phobia Scale,¹⁹ the Social Phobia Inventory (SPIN),²⁰ Fear of Negative Evaluation Scale,²¹ and the Social Avoidance and Distress Scale.²² These tools, however, can be a bit time consuming.

A more handy—though admittedly less comprehensive—screening device is the “mini SPIN” that was used by the physician in our opener. In a study of 7165 managed care patients, 89% of the cases meeting criteria for social anxiety disorder were detected (with a score of 6 or better) using this screening method.¹

To review, you’ll need to ask patients to rate the following statements on a scale of 0 “not at all” to 4 “extremely present”:

1. Fear of embarrassment causes me to avoid doing things or speaking to people.
2. I avoid activities in which I am the center of attention.
3. Being embarrassed or looking stupid are among my worst fears.

TABLE
Pharmacologic options for treating social anxiety disorder

A score of 6 or higher should prompt you to further evaluate the patient using one of the screening devices listed earlier.

Treatments of choice: CBT and drug therapy

Although social anxiety most commonly spans a lifetime, studies indicate that treatment—typically cognitive behavioral therapy (CBT) with drug therapy—can help sufferers deal with their fears and function more efficiently in their everyday lives. The best effects in treating social anxiety, therefore, are in combining the different treatment strategies.¹⁴

Cognitive begavioral therapy

Heimberg and colleagues found that 75% of social anxiety patients who participated in a cognitive behavioral therapy group experienced improved function and saw a reduction in symptoms of social anxiety.²³ Successful CBT seems to not only alleviate symptomatic distress, but improve the patients’ perceptions of their general quality of life.²⁴ Including behavioral components such as reinforcement or conditioning in CBT appears to be effective in helping sufferers minimize their symptoms. In addition, cognitive restructuring (ie, changing a patient’s thought process) has also been shown to be a helpful treatment.²³

Some of the basic elements of CBT include anxiety management skills (ie, breathing and relaxation techniques), social skills training (ie, maintaining conversation with the patient while monitoring the patient’s eye contact), and gradual exposure to the feared situation (ie, exposure to social situations).

Drug therapy

Studies have also demonstrated the effectiveness of a variety of medications (including Venlafaxine XR [Effexor XR], Paroxetine [Paxil], Paroxetine CR [Paxil CR], Sertraline [Zoloft], and Fluvoxamine [Luvox]) in managing social anxiety disorder.^25-28 If you are caring for a patient with social anxiety disorder, you’ll want to start him on a selective serotonin reuptake inhibitor (SSRI) or serotoninnorepinephrine reuptake inhibitor (SNRI).

If this doesn’t achieve the desired results, the next step is a monoamine oxidase inhibitor, such as phenelzine (Nardil), or a reverse inhibitor of monoamine oxidase A, such as moclobemide. Additionally, some benzodiazepines and anticonvulsants (clonazepam and pregabalin [Lyrica]) may also be effective if the other options do not achieve the desired results. The TABLE outlines common medications used to treat social anxiety, as well as recommended dosages.²⁹

When putting your patient on any of these medications, patient teaching will be important. You’ll need to advise the patient that common antidepressant side effects include, but are not limited to, nausea, diarrhea, sexual dysfunction (ie, delayed orgasm), and headaches. These effects, however, typically disappear by the second week of intake.¹⁵ If the patient is taking a benzodiazepine, you’ll need to warn him about the risk of psychomotor or cognitive impairment.

If the patient has a comorbid substance abuse problem, you and the patient will also need to adjust your expectations somewhat. That’s because patients with a substance abuse problem are likely to have a poorer response to some of these medications than patients without a substance abuse problem.³⁰

Though the time it takes to manage the condition is variable, patients with social anxiety disorder can improve their situation and go on to live more fulfilling and happy lives. The trick, really, is spotting the disorder early, rather than assuming your patient is simply the “quiet type.”

Correspondence
Martin A. Katzman, MD, FRCPC, START Clinic for Mood and Anxiety Disorders, 790 Bay St, Toronto, Ontario, Canada M5G 1N8 [email protected]

Janice L, 41, comes into her physician’s office complaining that she’s “feeling anxious all the time” at her job at a local bank. She tells him that she’s been treated for depression in the past, though she’s not currently taking any antidepressants. As her physician takes a more thorough history, he notices that her alcohol consumption seems a bit excessive. Her demeanor, which he had previously chalked up to as “shyness,” comes into focus. He begins to suspect that his patient is more than just “quiet and unassuming” and may, in fact, be suffering from social anxiety disorder.

To confirm his suspicions, he excuses himself to retrieve an article he’d saved on the topic—one that identifies a quick screening tool for social anxiety disorder.¹ He then asks his patient to rate the following statements on a scale of 0 to 4, with 0 being “not at all” and 4 being “extremely present”:

• Fear of embarrassment causes me to avoid doing things or speaking to people.
• I avoid activities in which I am the center of attention.
• Being embarrassed or looking stupid are among my worst fears.

His suspicions are confirmed when she scores a 10—well above the 6 that is highly suggestive of social anxiety disorder.

A debilitating disorder that’s all too common

Social anxiety, also known as social phobia, is the most common anxiety disorder, and is the third most common psychiatric disorder after depression and alcohol dependence.² The Epidemiological Catchment Area Study revealed that 2% to 4% of the sample suffered from social anxiety with a lifetime prevalence of 2.8%. Other studies have found that as many at 10% of the sample suffer from social anxiety when a more appropriate diagnostic interview is used.^3-5 Similarly, Kessler et al conducted a study investigating the prevalence of DSM-IV disorders and concluded that 6.8% of the entire sample suffered from social anxiety disorder.⁶

Social anxiety disorder is characterized as a persistent and debilitating fear of social interaction where patients fear negative evaluations by others. As a result, these patients may have trouble building and maintaining social relationships, which can result in a particularly isolated and depressed lifestyle.⁷

There are 2 subtypes of social anxiety disorder:

• Generalized social anxiety is generally more severe and more generalized and therefore, more disabling to patients. The majority of patients seen by the medical community tend to exhibit this sub-type of the disorder.
• Nongeneralized anxiety (also known as specific or discrete social phobia) is the less common and usually includes a fear associated with 1 or a few specific situations.

Although nongeneralized anxiety may be less likely to cause severe impairment in the patient’s life, it still may lead to significant underachievement in school or work.⁸ Still, patients with public speaking–only social anxiety are more likely to recover spontaneously, while patients with generalized social anxiety rarely recover spontaneously from the disorder.

The 2 subtypes also differ in their origin. Generalized social anxiety—the focus of this article—is significantly more prevalent among relatives who also suffer from the disorder, while patients with nongeneralized social anxiety disorder do not necessarily have relatives with the condition.⁹

“Shyness” in childhood that’s often overlooked

Social anxiety is a lifelong disorder that may begin as early as childhood, but is often described as beginning at age 13. At this age, though, the social anxiety is often mistaken for extreme shyness and therefore goes untreated.¹⁰ (See “Distinguishing shyness from social anxiety in kids,”.)

Overlooking shyness in such a young patient is particularly problematic as the avoidance that characterizes the social anxiety disorder can result in a lost opportunity to acquire social skills that are needed to ease the transition from adolescence to adulthood. This relative loss of social skills often facilitates the development of social dysfunction that is characteristic of this illness.¹¹ As time goes by, sufferers eventually become accustomed to their fears and create a way of life that accommodates them.

Social anxiety can interrupt education or job success, cause financial dependence, and impair relationships.¹⁰ (See “Fear of embarrassment hinders relationships and careers”.) Sufferers tend to miss out on important social events and activities in their lives,¹² and they begin to accumulate comorbidities such as depression and substance abuse.¹³ In fact, while many cases of social anxiety are overlooked as shyness, others are misdiagnosed as depression.

Complicating matters further is the issue of substance abuse. The Epidemiological Catchment Area Study found that alcohol abuse was reported in 17% of social anxiety cases and drug abuse was reported in 13%.⁵ In the study conducted by Kessler et al, results indicated that 8.8% of individuals suffering from a substance abuse problem also suffered from comorbid social anxiety.⁶

The substance abuse evolves slowly,¹⁴ and tends to arise as an inappropriate coping mechanism because so many cases of social anxiety go untreated.¹⁵

Symptoms to watch for, questions to ask

The primary indicator of social anxiety is intense fear of social situations. A patient suffering from social anxiety fears that he or she will act in a way that will be humiliating when confronted with unfamiliar situations or people or by the possibility of being scrutinized by others.¹⁶ While many people with social anxiety realize that their fears are excessive or unreasonable, they are unable to overcome them.¹⁷

There are also a number of physical, cognitive, and behavioral symptoms that are associated with social anxiety. The physical symptoms may include rapid heart rate, trembling, shortness of breath, sweating, and abdominal pain. The cognitive symptoms include maladaptive thoughts and beliefs about social situations (ie, irrational thought processes), that increase the anxiety when in the situation. Finally, behavioral symptoms include phobic avoidance of the feared situation.¹⁸

There are many screening devices that you can use to identify patients with social anxiety disorder or to assess the severity of symptoms. Some examples include the Liebowitz Social Phobia Scale,¹⁹ the Social Phobia Inventory (SPIN),²⁰ Fear of Negative Evaluation Scale,²¹ and the Social Avoidance and Distress Scale.²² These tools, however, can be a bit time consuming.

A more handy—though admittedly less comprehensive—screening device is the “mini SPIN” that was used by the physician in our opener. In a study of 7165 managed care patients, 89% of the cases meeting criteria for social anxiety disorder were detected (with a score of 6 or better) using this screening method.¹

To review, you’ll need to ask patients to rate the following statements on a scale of 0 “not at all” to 4 “extremely present”:

1. Fear of embarrassment causes me to avoid doing things or speaking to people.
2. I avoid activities in which I am the center of attention.
3. Being embarrassed or looking stupid are among my worst fears.

TABLE
Pharmacologic options for treating social anxiety disorder

A score of 6 or higher should prompt you to further evaluate the patient using one of the screening devices listed earlier.

Treatments of choice: CBT and drug therapy

Although social anxiety most commonly spans a lifetime, studies indicate that treatment—typically cognitive behavioral therapy (CBT) with drug therapy—can help sufferers deal with their fears and function more efficiently in their everyday lives. The best effects in treating social anxiety, therefore, are in combining the different treatment strategies.¹⁴

Cognitive begavioral therapy

Heimberg and colleagues found that 75% of social anxiety patients who participated in a cognitive behavioral therapy group experienced improved function and saw a reduction in symptoms of social anxiety.²³ Successful CBT seems to not only alleviate symptomatic distress, but improve the patients’ perceptions of their general quality of life.²⁴ Including behavioral components such as reinforcement or conditioning in CBT appears to be effective in helping sufferers minimize their symptoms. In addition, cognitive restructuring (ie, changing a patient’s thought process) has also been shown to be a helpful treatment.²³

Some of the basic elements of CBT include anxiety management skills (ie, breathing and relaxation techniques), social skills training (ie, maintaining conversation with the patient while monitoring the patient’s eye contact), and gradual exposure to the feared situation (ie, exposure to social situations).

Drug therapy

Studies have also demonstrated the effectiveness of a variety of medications (including Venlafaxine XR [Effexor XR], Paroxetine [Paxil], Paroxetine CR [Paxil CR], Sertraline [Zoloft], and Fluvoxamine [Luvox]) in managing social anxiety disorder.^25-28 If you are caring for a patient with social anxiety disorder, you’ll want to start him on a selective serotonin reuptake inhibitor (SSRI) or serotoninnorepinephrine reuptake inhibitor (SNRI).

If this doesn’t achieve the desired results, the next step is a monoamine oxidase inhibitor, such as phenelzine (Nardil), or a reverse inhibitor of monoamine oxidase A, such as moclobemide. Additionally, some benzodiazepines and anticonvulsants (clonazepam and pregabalin [Lyrica]) may also be effective if the other options do not achieve the desired results. The TABLE outlines common medications used to treat social anxiety, as well as recommended dosages.²⁹

When putting your patient on any of these medications, patient teaching will be important. You’ll need to advise the patient that common antidepressant side effects include, but are not limited to, nausea, diarrhea, sexual dysfunction (ie, delayed orgasm), and headaches. These effects, however, typically disappear by the second week of intake.¹⁵ If the patient is taking a benzodiazepine, you’ll need to warn him about the risk of psychomotor or cognitive impairment.

If the patient has a comorbid substance abuse problem, you and the patient will also need to adjust your expectations somewhat. That’s because patients with a substance abuse problem are likely to have a poorer response to some of these medications than patients without a substance abuse problem.³⁰

Though the time it takes to manage the condition is variable, patients with social anxiety disorder can improve their situation and go on to live more fulfilling and happy lives. The trick, really, is spotting the disorder early, rather than assuming your patient is simply the “quiet type.”

Correspondence
Martin A. Katzman, MD, FRCPC, START Clinic for Mood and Anxiety Disorders, 790 Bay St, Toronto, Ontario, Canada M5G 1N8 [email protected]

Two things about calcaneal “apophysitis” are a bit misleading. The first is its name. Although this common cause of heel pain in adolescents and teenagers was once considered a true osteochondritis, we now know that it’s actually a mechanical overuse pain syndrome with a self-limited, benign prognosis.^1-3 The second area of confusion is what you’ll see on x-ray: an increased density and irregular fragmentation that was once viewed with suspicion, but is actually a normal pattern of ossification for this particular apophysis.

Don’t let the x-ray fool you

Primary care physicians can properly manage this common pain condition, given an understanding of the features, natural history, and treatment principles presented here.

Orthopedic referral is indicated for only a few recalcitrant cases.

Shoes aren’t to blame, but activity level is

Adolescents with calcaneal apophysitis—also known as Sever’s disease—will typically come into the office complaining of pain, often in both heels, particularly with mechanical activities such as running, jumping, and long-distance walking. Patients may walk on tiptoe to avoid the pain.⁴

The condition is common in both boys and girls, although personal experience indicates it’s more common in boys. The typical age of the patient is 8 to 15 years. The condition is most commonly seen in patients who are engaged in athletic endeavors,^5,6 including soccer, basketball, and gymnastics,^7,8 though no specific athletic endeavor has been directly implicated in the pathogenesis. Likewise, no specific foot structure or type of shoe wear has been directly related to the symptomatology.

Should Johnny quit the track team?

An otherwise healthy boy, age 12, walks into your office—on tiptoe. His problem is pain in both heels, especially when running. It’s his first season on his school track team, and he says he’s been practicing hard for the 50-yard dash, “my best event.” his parents express to you their concern about possible sports-related injuries or underlying disease, and their son’s distress about the possibilty of “letting down the team” if he quits. You find no swelling, no skin changes, no erythema, and no other local abnormalities. Symptoms of marked pain are produced by medial and lateral compression (squeezing) of the heel at the site where the calcaneal apophysis attaches to the main body of the os calcis. There is no pain on plantar, posterior, or retrocalcaneal pressure, or adjacent to the Achilles tendon.

Exquisite heel pain produced by medial and lateral compression of the heel is the most distinguishing feature of calcaneal apophysitis

Is this x-ray normal? You order a lateral x-ray of the calcaneus to exclude other pathology. You observe a pattern of increased density and apparent irregular fragmentation on the x-ray. The radiologist reports no abnormal findings. The above x-ray typifies calcaneal apophysitis, an overuse syndrome often seen in children 8 to 15 years of age. The “dense” area is actually a secondary ossification center of the calcaneus, not an indication of pathology.

The ossification of the calcaneus is different from that of the tarsal bones, which are each ossified from a single center. In the case of the calcaneus, a secondary center of ossification typically appears in girls by age 6, and in boys by age 8.^14,15 During adolescence, a C-shaped cartilage develops between the metaphyseal bone of the body of the calcaneus and the secondary center (or centers) of ossification. Then, at around age 10 or 11, a more superior tertiary ossification center appears in the apophysis of the calcaneus.

As the calcaneal apophysis progressively ossifies, it presents as a very dense radiographic pattern in an adolescent. For years, this was thought to represent a form of osteochondritis.¹⁶ In fact, this is a normal pattern of ossification for this particular apophysis.^17-22

What do you tell the patient and parents? You advise an in-shoe orthotic, no limits on physical activity, and no surgery. You explain that the pain is due to recurrent impact (overuse), and that the orthotic will “unload” the heel and permit symtoms to resolve, typically within 60 days. If asked about discomfort, you may advise anti-inflammatories and ice/heat.

Patients typically have no swelling, skin changes, erythema, or other local abnormalities.⁸ The most characteristic distinguishing feature on physical examination is exquisite pain produced on medial and lateral compression (“squeezing”) of the heel at the site where the calcaneal apophysis attaches to the main body of the os calcis. The pain is not on plantar pressure (as you would see with plantar fasciitis), or posterior, retrocalcaneal, or adjacent to the Achilles tendon (as you would see on Achilles tendinitis), but on medial and lateral compression.³

Researchers found microfractures. Magnetic resonance imaging (MRI) evidence suggests that the true pathogenesis of calcaneal apophysitis is a stress microfracture related to chronic repetitive microtrauma.⁹ In addition, MRI evidence suggests that the location of the stress microfractures is in the metaphysis of the body of the calcaneus adjacent to—but not directly involving—the apophysis.^1,7 This more recent evidence replaces the historical hypotheses that the condition is primarily an inflammatory process. As a consequence of the microtrauma, however, it’s possible that an inflammatory process may occur secondarily.

Should you order x-rays? X-rays are not essential to the diagnosis, though they may be used to rule out other conditions, such as fracture, infection, or a bone cyst. Keep in mind, though, that patients with calcaneal pain will have a normal x-ray.⁷ What is normal, however, is another matter, and has been the subject of confusion in the past.

Pain stops in a few weeks

Usually, the symptoms of calcaneal apophysitis resolve fairly quickly, and with relatively simple treatment. (The symptoms also disappear as the child gets older and the calcaneal apophysis amalgamates with the main body of the calcaneus.)

Physiotherapy, forced ankle dorsiflexion stretching, gastrocsoleus stretching, ice, heat, heel cups and pads,^1,10-13 and anti-inflammatories have all been used in the management of the condition.^3,8 Clinicians have also historically restricted the patients’ activity, but this is unnecessary.

Rx for relief: ⅝″ compression orthotic

An in-shoe soft orthotic is helpful in treating calcaneal apophysitis. The prescription that the lead author writes is for a ⅝″ compressible, sponge-filled leather orthotic that is made in the form of a heel wedge or heel pad. Pain relief is believed to occur as a result of relaxation of the tension on the gastrocsoleus complex inserting onto the calcaneal apophysis and by “cushioning” the impact of heel strike.³ The orthotic, which typically lasts for 3 to 6 months, generally abrogates the need for anti-inflammatories as a primary treatment. However, relief of discomfort during this period may include use of antiflammatories.

For many years, the lead author has utilized a simple in-shoe, wedge-shaped orthotic consisting of a sponge material covered by leather, and compressible down to ⅝″. It raises the heel and cushions the impact of weightbearing. It can be transferred from shoe to shoe, and the patient can resume full activities while wearing the orthotic. Pain relief is generally achieved within 6 weeks to 3 months. Recalcitrant cases may require a 4 to 6 week period of casting in a plantar flexed position. Surgery is not necessary, nor are there any surgical cases reported in the literature. Orthopaedic referral is indicated for recalcitrant cases.

Acknowledgments

The Audio-Visual Department, Children’s Hospital Medical Center, Akron and Adeline Weiner assisted in preparing this paper.

Correspondence
Dennis S. Weiner, MD, 300 Locust Street, Suite 160, Akron, OH 44302-1821. [email protected]

Two things about calcaneal “apophysitis” are a bit misleading. The first is its name. Although this common cause of heel pain in adolescents and teenagers was once considered a true osteochondritis, we now know that it’s actually a mechanical overuse pain syndrome with a self-limited, benign prognosis.^1-3 The second area of confusion is what you’ll see on x-ray: an increased density and irregular fragmentation that was once viewed with suspicion, but is actually a normal pattern of ossification for this particular apophysis.

Don’t let the x-ray fool you

Primary care physicians can properly manage this common pain condition, given an understanding of the features, natural history, and treatment principles presented here.

Orthopedic referral is indicated for only a few recalcitrant cases.

Shoes aren’t to blame, but activity level is

Adolescents with calcaneal apophysitis—also known as Sever’s disease—will typically come into the office complaining of pain, often in both heels, particularly with mechanical activities such as running, jumping, and long-distance walking. Patients may walk on tiptoe to avoid the pain.⁴

The condition is common in both boys and girls, although personal experience indicates it’s more common in boys. The typical age of the patient is 8 to 15 years. The condition is most commonly seen in patients who are engaged in athletic endeavors,^5,6 including soccer, basketball, and gymnastics,^7,8 though no specific athletic endeavor has been directly implicated in the pathogenesis. Likewise, no specific foot structure or type of shoe wear has been directly related to the symptomatology.

Should Johnny quit the track team?

An otherwise healthy boy, age 12, walks into your office—on tiptoe. His problem is pain in both heels, especially when running. It’s his first season on his school track team, and he says he’s been practicing hard for the 50-yard dash, “my best event.” his parents express to you their concern about possible sports-related injuries or underlying disease, and their son’s distress about the possibilty of “letting down the team” if he quits. You find no swelling, no skin changes, no erythema, and no other local abnormalities. Symptoms of marked pain are produced by medial and lateral compression (squeezing) of the heel at the site where the calcaneal apophysis attaches to the main body of the os calcis. There is no pain on plantar, posterior, or retrocalcaneal pressure, or adjacent to the Achilles tendon.

Exquisite heel pain produced by medial and lateral compression of the heel is the most distinguishing feature of calcaneal apophysitis

Is this x-ray normal? You order a lateral x-ray of the calcaneus to exclude other pathology. You observe a pattern of increased density and apparent irregular fragmentation on the x-ray. The radiologist reports no abnormal findings. The above x-ray typifies calcaneal apophysitis, an overuse syndrome often seen in children 8 to 15 years of age. The “dense” area is actually a secondary ossification center of the calcaneus, not an indication of pathology.

The ossification of the calcaneus is different from that of the tarsal bones, which are each ossified from a single center. In the case of the calcaneus, a secondary center of ossification typically appears in girls by age 6, and in boys by age 8.^14,15 During adolescence, a C-shaped cartilage develops between the metaphyseal bone of the body of the calcaneus and the secondary center (or centers) of ossification. Then, at around age 10 or 11, a more superior tertiary ossification center appears in the apophysis of the calcaneus.

As the calcaneal apophysis progressively ossifies, it presents as a very dense radiographic pattern in an adolescent. For years, this was thought to represent a form of osteochondritis.¹⁶ In fact, this is a normal pattern of ossification for this particular apophysis.^17-22

What do you tell the patient and parents? You advise an in-shoe orthotic, no limits on physical activity, and no surgery. You explain that the pain is due to recurrent impact (overuse), and that the orthotic will “unload” the heel and permit symtoms to resolve, typically within 60 days. If asked about discomfort, you may advise anti-inflammatories and ice/heat.

Patients typically have no swelling, skin changes, erythema, or other local abnormalities.⁸ The most characteristic distinguishing feature on physical examination is exquisite pain produced on medial and lateral compression (“squeezing”) of the heel at the site where the calcaneal apophysis attaches to the main body of the os calcis. The pain is not on plantar pressure (as you would see with plantar fasciitis), or posterior, retrocalcaneal, or adjacent to the Achilles tendon (as you would see on Achilles tendinitis), but on medial and lateral compression.³

Researchers found microfractures. Magnetic resonance imaging (MRI) evidence suggests that the true pathogenesis of calcaneal apophysitis is a stress microfracture related to chronic repetitive microtrauma.⁹ In addition, MRI evidence suggests that the location of the stress microfractures is in the metaphysis of the body of the calcaneus adjacent to—but not directly involving—the apophysis.^1,7 This more recent evidence replaces the historical hypotheses that the condition is primarily an inflammatory process. As a consequence of the microtrauma, however, it’s possible that an inflammatory process may occur secondarily.

Should you order x-rays? X-rays are not essential to the diagnosis, though they may be used to rule out other conditions, such as fracture, infection, or a bone cyst. Keep in mind, though, that patients with calcaneal pain will have a normal x-ray.⁷ What is normal, however, is another matter, and has been the subject of confusion in the past.

Pain stops in a few weeks

Usually, the symptoms of calcaneal apophysitis resolve fairly quickly, and with relatively simple treatment. (The symptoms also disappear as the child gets older and the calcaneal apophysis amalgamates with the main body of the calcaneus.)

Physiotherapy, forced ankle dorsiflexion stretching, gastrocsoleus stretching, ice, heat, heel cups and pads,^1,10-13 and anti-inflammatories have all been used in the management of the condition.^3,8 Clinicians have also historically restricted the patients’ activity, but this is unnecessary.

Rx for relief: ⅝″ compression orthotic

An in-shoe soft orthotic is helpful in treating calcaneal apophysitis. The prescription that the lead author writes is for a ⅝″ compressible, sponge-filled leather orthotic that is made in the form of a heel wedge or heel pad. Pain relief is believed to occur as a result of relaxation of the tension on the gastrocsoleus complex inserting onto the calcaneal apophysis and by “cushioning” the impact of heel strike.³ The orthotic, which typically lasts for 3 to 6 months, generally abrogates the need for anti-inflammatories as a primary treatment. However, relief of discomfort during this period may include use of antiflammatories.

For many years, the lead author has utilized a simple in-shoe, wedge-shaped orthotic consisting of a sponge material covered by leather, and compressible down to ⅝″. It raises the heel and cushions the impact of weightbearing. It can be transferred from shoe to shoe, and the patient can resume full activities while wearing the orthotic. Pain relief is generally achieved within 6 weeks to 3 months. Recalcitrant cases may require a 4 to 6 week period of casting in a plantar flexed position. Surgery is not necessary, nor are there any surgical cases reported in the literature. Orthopaedic referral is indicated for recalcitrant cases.

Acknowledgments

The Audio-Visual Department, Children’s Hospital Medical Center, Akron and Adeline Weiner assisted in preparing this paper.

Correspondence
Dennis S. Weiner, MD, 300 Locust Street, Suite 160, Akron, OH 44302-1821. [email protected]

Two things about calcaneal “apophysitis” are a bit misleading. The first is its name. Although this common cause of heel pain in adolescents and teenagers was once considered a true osteochondritis, we now know that it’s actually a mechanical overuse pain syndrome with a self-limited, benign prognosis.^1-3 The second area of confusion is what you’ll see on x-ray: an increased density and irregular fragmentation that was once viewed with suspicion, but is actually a normal pattern of ossification for this particular apophysis.

Don’t let the x-ray fool you

Primary care physicians can properly manage this common pain condition, given an understanding of the features, natural history, and treatment principles presented here.

Orthopedic referral is indicated for only a few recalcitrant cases.

Shoes aren’t to blame, but activity level is

Adolescents with calcaneal apophysitis—also known as Sever’s disease—will typically come into the office complaining of pain, often in both heels, particularly with mechanical activities such as running, jumping, and long-distance walking. Patients may walk on tiptoe to avoid the pain.⁴

The condition is common in both boys and girls, although personal experience indicates it’s more common in boys. The typical age of the patient is 8 to 15 years. The condition is most commonly seen in patients who are engaged in athletic endeavors,^5,6 including soccer, basketball, and gymnastics,^7,8 though no specific athletic endeavor has been directly implicated in the pathogenesis. Likewise, no specific foot structure or type of shoe wear has been directly related to the symptomatology.

Should Johnny quit the track team?

An otherwise healthy boy, age 12, walks into your office—on tiptoe. His problem is pain in both heels, especially when running. It’s his first season on his school track team, and he says he’s been practicing hard for the 50-yard dash, “my best event.” his parents express to you their concern about possible sports-related injuries or underlying disease, and their son’s distress about the possibilty of “letting down the team” if he quits. You find no swelling, no skin changes, no erythema, and no other local abnormalities. Symptoms of marked pain are produced by medial and lateral compression (squeezing) of the heel at the site where the calcaneal apophysis attaches to the main body of the os calcis. There is no pain on plantar, posterior, or retrocalcaneal pressure, or adjacent to the Achilles tendon.

Exquisite heel pain produced by medial and lateral compression of the heel is the most distinguishing feature of calcaneal apophysitis

Is this x-ray normal? You order a lateral x-ray of the calcaneus to exclude other pathology. You observe a pattern of increased density and apparent irregular fragmentation on the x-ray. The radiologist reports no abnormal findings. The above x-ray typifies calcaneal apophysitis, an overuse syndrome often seen in children 8 to 15 years of age. The “dense” area is actually a secondary ossification center of the calcaneus, not an indication of pathology.

The ossification of the calcaneus is different from that of the tarsal bones, which are each ossified from a single center. In the case of the calcaneus, a secondary center of ossification typically appears in girls by age 6, and in boys by age 8.^14,15 During adolescence, a C-shaped cartilage develops between the metaphyseal bone of the body of the calcaneus and the secondary center (or centers) of ossification. Then, at around age 10 or 11, a more superior tertiary ossification center appears in the apophysis of the calcaneus.

As the calcaneal apophysis progressively ossifies, it presents as a very dense radiographic pattern in an adolescent. For years, this was thought to represent a form of osteochondritis.¹⁶ In fact, this is a normal pattern of ossification for this particular apophysis.^17-22

What do you tell the patient and parents? You advise an in-shoe orthotic, no limits on physical activity, and no surgery. You explain that the pain is due to recurrent impact (overuse), and that the orthotic will “unload” the heel and permit symtoms to resolve, typically within 60 days. If asked about discomfort, you may advise anti-inflammatories and ice/heat.

Patients typically have no swelling, skin changes, erythema, or other local abnormalities.⁸ The most characteristic distinguishing feature on physical examination is exquisite pain produced on medial and lateral compression (“squeezing”) of the heel at the site where the calcaneal apophysis attaches to the main body of the os calcis. The pain is not on plantar pressure (as you would see with plantar fasciitis), or posterior, retrocalcaneal, or adjacent to the Achilles tendon (as you would see on Achilles tendinitis), but on medial and lateral compression.³

Researchers found microfractures. Magnetic resonance imaging (MRI) evidence suggests that the true pathogenesis of calcaneal apophysitis is a stress microfracture related to chronic repetitive microtrauma.⁹ In addition, MRI evidence suggests that the location of the stress microfractures is in the metaphysis of the body of the calcaneus adjacent to—but not directly involving—the apophysis.^1,7 This more recent evidence replaces the historical hypotheses that the condition is primarily an inflammatory process. As a consequence of the microtrauma, however, it’s possible that an inflammatory process may occur secondarily.

Should you order x-rays? X-rays are not essential to the diagnosis, though they may be used to rule out other conditions, such as fracture, infection, or a bone cyst. Keep in mind, though, that patients with calcaneal pain will have a normal x-ray.⁷ What is normal, however, is another matter, and has been the subject of confusion in the past.

Pain stops in a few weeks

Usually, the symptoms of calcaneal apophysitis resolve fairly quickly, and with relatively simple treatment. (The symptoms also disappear as the child gets older and the calcaneal apophysis amalgamates with the main body of the calcaneus.)

Physiotherapy, forced ankle dorsiflexion stretching, gastrocsoleus stretching, ice, heat, heel cups and pads,^1,10-13 and anti-inflammatories have all been used in the management of the condition.^3,8 Clinicians have also historically restricted the patients’ activity, but this is unnecessary.

Rx for relief: ⅝″ compression orthotic

An in-shoe soft orthotic is helpful in treating calcaneal apophysitis. The prescription that the lead author writes is for a ⅝″ compressible, sponge-filled leather orthotic that is made in the form of a heel wedge or heel pad. Pain relief is believed to occur as a result of relaxation of the tension on the gastrocsoleus complex inserting onto the calcaneal apophysis and by “cushioning” the impact of heel strike.³ The orthotic, which typically lasts for 3 to 6 months, generally abrogates the need for anti-inflammatories as a primary treatment. However, relief of discomfort during this period may include use of antiflammatories.

For many years, the lead author has utilized a simple in-shoe, wedge-shaped orthotic consisting of a sponge material covered by leather, and compressible down to ⅝″. It raises the heel and cushions the impact of weightbearing. It can be transferred from shoe to shoe, and the patient can resume full activities while wearing the orthotic. Pain relief is generally achieved within 6 weeks to 3 months. Recalcitrant cases may require a 4 to 6 week period of casting in a plantar flexed position. Surgery is not necessary, nor are there any surgical cases reported in the literature. Orthopaedic referral is indicated for recalcitrant cases.

Acknowledgments

The Audio-Visual Department, Children’s Hospital Medical Center, Akron and Adeline Weiner assisted in preparing this paper.

Correspondence
Dennis S. Weiner, MD, 300 Locust Street, Suite 160, Akron, OH 44302-1821. [email protected]

Are you a wise “consumer” of stress tests? That is: Do you consider your patient’s CAD probability score before ordering an exercise treadmill test or pharmacologic stress myocardial imaging (PSMI)? Are you as well-versed as you’d like to be on the predictive value of things like the Duke Treadmill Score?

If your answer is No to either question, this review may help guide your use of stress tests, based on evidence.

What is the pretest probability of CAD?

The decision to order an exercise stress test or a PSMI should be based on history, physical examination, and pretest probability for CAD. You can estimate the pretest probability for CAD in a chest pain patient based on the patient’s age, sex, and pain characteristics.¹

Determine whether symptoms are typical, atypical, or nonanginal, based on whether the chest pain is substernal, brought on by exertion, or relieved by rest or nitroglycerin.²

To recap:

• Typical angina requires all 3 pain characteristics
• Atypical angina, only 2
• Nonanginal chest pain, 1.²

Use this information (along with the patient’s age) to determine whether he has a high, intermediate, low, or very low likelihood of CAD (TABLE 1). From the low, to the intermediate, to the high pretest probability levels, the positive predictive value increases progressively (21%, 62%, and 92%) and the negative predictive value decreases progressively (94%, 72%, and 28%).³ (These values are based on a review of symptomatic patients who had angiography following stress testing.)

TABLE 1
How to determine pretest probability of coronary artery disease

Your patients’ score dictates whether testing is required, and if so what kind.

Very low pretest probability patients should not have an exercise test, since they have a high risk of false-positive results. Evaluate and treat them for noncardiac causes of chest pain and begin primary prevention of CAD.

Low pretest probability patients should undergo exercise treadmill testing alone since negative results carry a high negative predictive value in both men and women, but positive test results may be false and can be evaluated by more studies.³

Intermediate pretest probability patients, including those with complete right bundle branch block or less than 1 mm ST depression at rest should have an exercise treadmill test without imaging modality.^3-5 However, intermediate pretest probability patients with baseline ECG abnormalities such as electronically paced ventricular rhythm or left bundle-branch block will require myocardial perfusion imaging.⁵

High pretest probability patients should have coronary angiography as an initial strategy for diagnosis of CAD.³

History, exam, and ECG determine test suitability

Can your patient take an exercise stress test, or will he need a pharmacologic stress test instead? (See “A guide to sensitivity, specificity, and likelihood ratios for stress tests.”) Can he pedal a bicycle, walk, or exercise for 6 minutes? On physical examination, take note of his gait, mobility, and limb strength.

What medications is the patient taking? Digoxin may cause false ST changes, beta-blockers may prevent attaining maximum heart rate, and antihypertensive agents and vasodilators may alter the blood pressure response, producing a false negative result. Nitrates attenuate angina and the associated ST depression of ischemia.⁶ In addition, metabolic abnormalities and cocaine or alcohol use may affect heart rate, metabolic oxygen demand and the ability to perform the exercise treadmill testing.

On examination, document murmurs, rhythm abnormalities, vascular bruits, and abnormal pulses. Limit laboratory studies to recent cardiac damage screening if indicated. Screen with a resting ECG for arrhythmias, conduction abnormalities or preexisting cardiac damage. ST-segment (≥1 mm) and T-wave changes such as inversions secondary to strain or old injury or conduction abnormalities such as bundle branch blocks and prolonged QT interval may obscure exercise treadmill testing findings. Consider spirometry for patients with asthma or chronic lung disease.

The decisive factors

Absolute contraindications to exercise treadmill testing include recent MI; significant aortic stenosis,⁷ and weight exceeding equipment capacity. Relative contraindications to exercise treadmill testing (which can be superseded if the benefits of exercise outweigh the risks) include: hypertension (systolic >200 mm Hg/diastolic >110 mm Hg),⁵ left main coronary stenosis and stenotic valvular disease. (For more on “Contraindications to exercise testing,” see TABLE 2.)

The role of imaging: Important, yes—routine, no

An important element of stress testing is, of course, the imaging method(s) that will be used. The options include myocardial perfusion imaging with thallium Tl 201 or technetium Tc 99m, and echocardiography.

Indications for myocardial perfusion imaging with exercise treadmill testing are a high pretest probability for CAD, an abnormal baseline ECG such as left bundle branch block, previous myocardial damage or coronary revascularization, or a previous equivocal or unexpected exercise ECG result. In women with an intermediate pretest probability for CAD, the sensitivity and specificity of an exercise treadmill testing is less than in men, which suggests that nuclear imaging would improve this test.⁸ There is, however, insufficient data to justify initial routine stress imaging tests in women.¹

TABLE 2
Contraindications to exercise testing

Of the 2 agents used for myocardial perfusion imaging, technetium Tc 99m has more favorable imaging characteristics.⁹ It has a shorter half-life (6 hours) than thallium Tl 201 (73 hours), and larger doses of technetium Tc99m may be used, permitting the assessment of ventricular function.¹⁰

Echocardiography may also be done with either exercise treadmill testing or PSMI to evaluate relative myocardial perfusion. While radionuclide technique assesses relative myocardial perfusion, echocardiography also evaluates global and regional function. Indications for echocardiography are similar to myocardial perfusion imaging but also include the need for prognostic information after MI, and to assess physiologic significance of a lesion or to determine the success of an intervention.

Time for the test: Selecting the protocol

While the Bruce exercise treadmill testing protocol is the most commonly used (82% of tests)¹¹ in healthy adults, it may not be appropriate for women or the elderly as most protocols were developed for the evaluation of men.¹² A ramp method with gradual increase in grade each minute is preferred by some clinicians when patients are unable to perform a standard Bruce protocol. Another option, the Modified Bruce protocol, which is more gradual than the standard Bruce protocol; it has two 3-minute warm-up stages.¹²

The 3 PSMI protocols include adenosine, dipyridamole, and dobutamine. Each has a different administration routine,⁹ though ECG, blood pressure and pulse are taken every minute for all 3.

• Adenosine is infused with a pump over 6 minutes and technetium Tc99m is injected 3 minutes into the infusion.
• Dipyridamole is infused over 4 minutes and technetium Tc99m is injected 2 to no more than 5 minutes after the infusion. Theophylline is injected, after dipyridamole if necessary, no earlier than 1 minute after technetium Tc99m is administered to avoid interference with the uptake.
• Dobutamine is titrated with a dose increase every 3 minutes. Tc99m is injected after the first minute at the highest concentration. (Typically dobutamine is used with echocardiography.⁶)

Ideal endpoints and the realities that may creep in

The ideal endpoint in an exercise treadmill testing is 100% of the age-predicted maximum heart rate (220–age). Eighty-five percent of maximum heart rate is the minimum for an acceptable test.

Absolute contraindications

Absolute indicators for stopping an exercise treadmill test are either a 10 mm Hg systolic drop in blood pressure from standing baseline, moderate to severe angina symptoms, feelings of syncope, skin color changes suggestive of hypoxia or hypotension, ischemic ST changes, or the patient’s desire to stop.

Relative contraindications

Relative indicators to stop include fatigue, shortness of breath, leg pain, increased arrhythmias—particularly PVCs that increase with the exercise level—and blood pressure ≥250 systolic or 115 diastolic.⁶

Ideally, PSMI evaluations are terminated according to the prescribed length of infusions. They will also be terminated if a patient develops wheezing, severe or increasing chest pain or hypotension, neurological symptoms, ST-segment elevation abnormalities, or arrhythmias. To reverse the side effects of adenosine or dipyridamole, aminophylline IV will be administered (1–2 mg/kg slowly, up to 250 mg).

Heart of the matter: What a report should cover

Assuming you have ordered the stress test (and not done it yourself), a complete report should include

• ST changes
• symptoms during testing
• reason for ending the test
• estimation of exercise capacity
• blood pressure response
• the presence and frequency of arrhythmias or ectopy.

Abnormal. ST segment change is the most important ECG finding in a positive test; it’s defined as >1 mm horizontal or down sloping depression or elevation, at least 60 to 80 milliseconds after the end of the QRS complex and should prompt further workup to confirm CAD.⁵ An abnormal ECG during a PSMI test indicates an elevated risk of multivessel CAD and should prompt further evaluation regardless of normal myocardial perfusion imaging.¹³

Equivocal. Reports that come back as equivocal will have ECG changes nondiagnostic of ischemia such as alterations in P- or T-wave morphology and nondiagnostic changes in AV conduction, particularly if changes revert to baseline during the rest period. Unifocal PACs or PVCs (<5/min) are not specific indicators for CAD and the development of bundle branch blocks are nondiagnostic findings. Equivocal results need additional testing such as myocardial perfusion imaging or angiography to document ischemia if the pretest probability is high.

Incomplete or failure. If your patient’s test involves equipment failure or if he (or the operator) was unable to complete the test, you should get a report to that effect. Depending on the nature of the failure, you may need to repeat the test, consider PSMI, or make a cardiology referral.

Duke Treadmill Score

A helpful calculation following treadmill testing

If your patient had a positive or negative exercise treadmill test, consider calculating his Duke Treadmill Score (DTS), which is predictive of 5-year survival and significant severe CAD for patients who are younger than 75 years.^4,14

DTS helps you to exclude low-risk patients from further invasive testing and ensure high-risk patients receive further evaluation and appropriate treatment. DTS appears to be more useful in women with an intermediate pretest score but not with a low pretest score.¹⁵

The DTS score typically ranges from –25 to +15.⁵ Patients at low risk will have a score of > +5), moderate risk will have scores ranging from –10 to +4, and those at high risk will have a score of ≤–11.⁴

A modified DTS is used for patients older than 65 years who may have a limited exercise capacity, controlled asymptomatic congestive heart failure, or be on digoxin, which may affect their ability to perform a maximal exercise treadmill test.⁵ The values for the Elderly Alternative Treadmill Score are as follows: low risk (< –2); moderate risk (–2 to 2); and high risk (>2). (See “The calculations behind the scores.”)

Bottom line

DTS scores, Elderly Alternative Treadmill Scores, and pre–stress test CAD probability scores are all extremely useful. Integrating them into your practice can ensure that patients get the prompt care they may need, while sparing them unnecessary tests along the way.

FIGURE
Template for dictating noninvasive cardiac tests

Correspondence
Dennis P. Breen, MD, Eau Claire Family Medicine Clinic, 617 Clairemont Avenue, Eau Claire, WI 54701. [email protected]

Are you a wise “consumer” of stress tests? That is: Do you consider your patient’s CAD probability score before ordering an exercise treadmill test or pharmacologic stress myocardial imaging (PSMI)? Are you as well-versed as you’d like to be on the predictive value of things like the Duke Treadmill Score?

If your answer is No to either question, this review may help guide your use of stress tests, based on evidence.

What is the pretest probability of CAD?

The decision to order an exercise stress test or a PSMI should be based on history, physical examination, and pretest probability for CAD. You can estimate the pretest probability for CAD in a chest pain patient based on the patient’s age, sex, and pain characteristics.¹

Determine whether symptoms are typical, atypical, or nonanginal, based on whether the chest pain is substernal, brought on by exertion, or relieved by rest or nitroglycerin.²

To recap:

• Typical angina requires all 3 pain characteristics
• Atypical angina, only 2
• Nonanginal chest pain, 1.²

Use this information (along with the patient’s age) to determine whether he has a high, intermediate, low, or very low likelihood of CAD (TABLE 1). From the low, to the intermediate, to the high pretest probability levels, the positive predictive value increases progressively (21%, 62%, and 92%) and the negative predictive value decreases progressively (94%, 72%, and 28%).³ (These values are based on a review of symptomatic patients who had angiography following stress testing.)

TABLE 1
How to determine pretest probability of coronary artery disease

Your patients’ score dictates whether testing is required, and if so what kind.

Very low pretest probability patients should not have an exercise test, since they have a high risk of false-positive results. Evaluate and treat them for noncardiac causes of chest pain and begin primary prevention of CAD.

Low pretest probability patients should undergo exercise treadmill testing alone since negative results carry a high negative predictive value in both men and women, but positive test results may be false and can be evaluated by more studies.³

Intermediate pretest probability patients, including those with complete right bundle branch block or less than 1 mm ST depression at rest should have an exercise treadmill test without imaging modality.^3-5 However, intermediate pretest probability patients with baseline ECG abnormalities such as electronically paced ventricular rhythm or left bundle-branch block will require myocardial perfusion imaging.⁵

High pretest probability patients should have coronary angiography as an initial strategy for diagnosis of CAD.³

History, exam, and ECG determine test suitability

Can your patient take an exercise stress test, or will he need a pharmacologic stress test instead? (See “A guide to sensitivity, specificity, and likelihood ratios for stress tests.”) Can he pedal a bicycle, walk, or exercise for 6 minutes? On physical examination, take note of his gait, mobility, and limb strength.

What medications is the patient taking? Digoxin may cause false ST changes, beta-blockers may prevent attaining maximum heart rate, and antihypertensive agents and vasodilators may alter the blood pressure response, producing a false negative result. Nitrates attenuate angina and the associated ST depression of ischemia.⁶ In addition, metabolic abnormalities and cocaine or alcohol use may affect heart rate, metabolic oxygen demand and the ability to perform the exercise treadmill testing.

On examination, document murmurs, rhythm abnormalities, vascular bruits, and abnormal pulses. Limit laboratory studies to recent cardiac damage screening if indicated. Screen with a resting ECG for arrhythmias, conduction abnormalities or preexisting cardiac damage. ST-segment (≥1 mm) and T-wave changes such as inversions secondary to strain or old injury or conduction abnormalities such as bundle branch blocks and prolonged QT interval may obscure exercise treadmill testing findings. Consider spirometry for patients with asthma or chronic lung disease.

The decisive factors

Absolute contraindications to exercise treadmill testing include recent MI; significant aortic stenosis,⁷ and weight exceeding equipment capacity. Relative contraindications to exercise treadmill testing (which can be superseded if the benefits of exercise outweigh the risks) include: hypertension (systolic >200 mm Hg/diastolic >110 mm Hg),⁵ left main coronary stenosis and stenotic valvular disease. (For more on “Contraindications to exercise testing,” see TABLE 2.)

The role of imaging: Important, yes—routine, no

An important element of stress testing is, of course, the imaging method(s) that will be used. The options include myocardial perfusion imaging with thallium Tl 201 or technetium Tc 99m, and echocardiography.

Indications for myocardial perfusion imaging with exercise treadmill testing are a high pretest probability for CAD, an abnormal baseline ECG such as left bundle branch block, previous myocardial damage or coronary revascularization, or a previous equivocal or unexpected exercise ECG result. In women with an intermediate pretest probability for CAD, the sensitivity and specificity of an exercise treadmill testing is less than in men, which suggests that nuclear imaging would improve this test.⁸ There is, however, insufficient data to justify initial routine stress imaging tests in women.¹

TABLE 2
Contraindications to exercise testing

Of the 2 agents used for myocardial perfusion imaging, technetium Tc 99m has more favorable imaging characteristics.⁹ It has a shorter half-life (6 hours) than thallium Tl 201 (73 hours), and larger doses of technetium Tc99m may be used, permitting the assessment of ventricular function.¹⁰

Echocardiography may also be done with either exercise treadmill testing or PSMI to evaluate relative myocardial perfusion. While radionuclide technique assesses relative myocardial perfusion, echocardiography also evaluates global and regional function. Indications for echocardiography are similar to myocardial perfusion imaging but also include the need for prognostic information after MI, and to assess physiologic significance of a lesion or to determine the success of an intervention.

Time for the test: Selecting the protocol

While the Bruce exercise treadmill testing protocol is the most commonly used (82% of tests)¹¹ in healthy adults, it may not be appropriate for women or the elderly as most protocols were developed for the evaluation of men.¹² A ramp method with gradual increase in grade each minute is preferred by some clinicians when patients are unable to perform a standard Bruce protocol. Another option, the Modified Bruce protocol, which is more gradual than the standard Bruce protocol; it has two 3-minute warm-up stages.¹²

The 3 PSMI protocols include adenosine, dipyridamole, and dobutamine. Each has a different administration routine,⁹ though ECG, blood pressure and pulse are taken every minute for all 3.

• Adenosine is infused with a pump over 6 minutes and technetium Tc99m is injected 3 minutes into the infusion.
• Dipyridamole is infused over 4 minutes and technetium Tc99m is injected 2 to no more than 5 minutes after the infusion. Theophylline is injected, after dipyridamole if necessary, no earlier than 1 minute after technetium Tc99m is administered to avoid interference with the uptake.
• Dobutamine is titrated with a dose increase every 3 minutes. Tc99m is injected after the first minute at the highest concentration. (Typically dobutamine is used with echocardiography.⁶)

Ideal endpoints and the realities that may creep in

The ideal endpoint in an exercise treadmill testing is 100% of the age-predicted maximum heart rate (220–age). Eighty-five percent of maximum heart rate is the minimum for an acceptable test.

Absolute contraindications

Absolute indicators for stopping an exercise treadmill test are either a 10 mm Hg systolic drop in blood pressure from standing baseline, moderate to severe angina symptoms, feelings of syncope, skin color changes suggestive of hypoxia or hypotension, ischemic ST changes, or the patient’s desire to stop.

Relative contraindications

Relative indicators to stop include fatigue, shortness of breath, leg pain, increased arrhythmias—particularly PVCs that increase with the exercise level—and blood pressure ≥250 systolic or 115 diastolic.⁶

Ideally, PSMI evaluations are terminated according to the prescribed length of infusions. They will also be terminated if a patient develops wheezing, severe or increasing chest pain or hypotension, neurological symptoms, ST-segment elevation abnormalities, or arrhythmias. To reverse the side effects of adenosine or dipyridamole, aminophylline IV will be administered (1–2 mg/kg slowly, up to 250 mg).

Heart of the matter: What a report should cover

Assuming you have ordered the stress test (and not done it yourself), a complete report should include

• ST changes
• symptoms during testing
• reason for ending the test
• estimation of exercise capacity
• blood pressure response
• the presence and frequency of arrhythmias or ectopy.

Abnormal. ST segment change is the most important ECG finding in a positive test; it’s defined as >1 mm horizontal or down sloping depression or elevation, at least 60 to 80 milliseconds after the end of the QRS complex and should prompt further workup to confirm CAD.⁵ An abnormal ECG during a PSMI test indicates an elevated risk of multivessel CAD and should prompt further evaluation regardless of normal myocardial perfusion imaging.¹³

Equivocal. Reports that come back as equivocal will have ECG changes nondiagnostic of ischemia such as alterations in P- or T-wave morphology and nondiagnostic changes in AV conduction, particularly if changes revert to baseline during the rest period. Unifocal PACs or PVCs (<5/min) are not specific indicators for CAD and the development of bundle branch blocks are nondiagnostic findings. Equivocal results need additional testing such as myocardial perfusion imaging or angiography to document ischemia if the pretest probability is high.

Incomplete or failure. If your patient’s test involves equipment failure or if he (or the operator) was unable to complete the test, you should get a report to that effect. Depending on the nature of the failure, you may need to repeat the test, consider PSMI, or make a cardiology referral.

Duke Treadmill Score

A helpful calculation following treadmill testing

If your patient had a positive or negative exercise treadmill test, consider calculating his Duke Treadmill Score (DTS), which is predictive of 5-year survival and significant severe CAD for patients who are younger than 75 years.^4,14

DTS helps you to exclude low-risk patients from further invasive testing and ensure high-risk patients receive further evaluation and appropriate treatment. DTS appears to be more useful in women with an intermediate pretest score but not with a low pretest score.¹⁵

The DTS score typically ranges from –25 to +15.⁵ Patients at low risk will have a score of > +5), moderate risk will have scores ranging from –10 to +4, and those at high risk will have a score of ≤–11.⁴

A modified DTS is used for patients older than 65 years who may have a limited exercise capacity, controlled asymptomatic congestive heart failure, or be on digoxin, which may affect their ability to perform a maximal exercise treadmill test.⁵ The values for the Elderly Alternative Treadmill Score are as follows: low risk (< –2); moderate risk (–2 to 2); and high risk (>2). (See “The calculations behind the scores.”)

Bottom line

DTS scores, Elderly Alternative Treadmill Scores, and pre–stress test CAD probability scores are all extremely useful. Integrating them into your practice can ensure that patients get the prompt care they may need, while sparing them unnecessary tests along the way.

FIGURE
Template for dictating noninvasive cardiac tests

Correspondence
Dennis P. Breen, MD, Eau Claire Family Medicine Clinic, 617 Clairemont Avenue, Eau Claire, WI 54701. [email protected]

Are you a wise “consumer” of stress tests? That is: Do you consider your patient’s CAD probability score before ordering an exercise treadmill test or pharmacologic stress myocardial imaging (PSMI)? Are you as well-versed as you’d like to be on the predictive value of things like the Duke Treadmill Score?

If your answer is No to either question, this review may help guide your use of stress tests, based on evidence.

What is the pretest probability of CAD?

The decision to order an exercise stress test or a PSMI should be based on history, physical examination, and pretest probability for CAD. You can estimate the pretest probability for CAD in a chest pain patient based on the patient’s age, sex, and pain characteristics.¹

Determine whether symptoms are typical, atypical, or nonanginal, based on whether the chest pain is substernal, brought on by exertion, or relieved by rest or nitroglycerin.²

To recap:

• Typical angina requires all 3 pain characteristics
• Atypical angina, only 2
• Nonanginal chest pain, 1.²

Use this information (along with the patient’s age) to determine whether he has a high, intermediate, low, or very low likelihood of CAD (TABLE 1). From the low, to the intermediate, to the high pretest probability levels, the positive predictive value increases progressively (21%, 62%, and 92%) and the negative predictive value decreases progressively (94%, 72%, and 28%).³ (These values are based on a review of symptomatic patients who had angiography following stress testing.)

TABLE 1
How to determine pretest probability of coronary artery disease

Your patients’ score dictates whether testing is required, and if so what kind.

Very low pretest probability patients should not have an exercise test, since they have a high risk of false-positive results. Evaluate and treat them for noncardiac causes of chest pain and begin primary prevention of CAD.

Low pretest probability patients should undergo exercise treadmill testing alone since negative results carry a high negative predictive value in both men and women, but positive test results may be false and can be evaluated by more studies.³

Intermediate pretest probability patients, including those with complete right bundle branch block or less than 1 mm ST depression at rest should have an exercise treadmill test without imaging modality.^3-5 However, intermediate pretest probability patients with baseline ECG abnormalities such as electronically paced ventricular rhythm or left bundle-branch block will require myocardial perfusion imaging.⁵

High pretest probability patients should have coronary angiography as an initial strategy for diagnosis of CAD.³

History, exam, and ECG determine test suitability

Can your patient take an exercise stress test, or will he need a pharmacologic stress test instead? (See “A guide to sensitivity, specificity, and likelihood ratios for stress tests.”) Can he pedal a bicycle, walk, or exercise for 6 minutes? On physical examination, take note of his gait, mobility, and limb strength.

What medications is the patient taking? Digoxin may cause false ST changes, beta-blockers may prevent attaining maximum heart rate, and antihypertensive agents and vasodilators may alter the blood pressure response, producing a false negative result. Nitrates attenuate angina and the associated ST depression of ischemia.⁶ In addition, metabolic abnormalities and cocaine or alcohol use may affect heart rate, metabolic oxygen demand and the ability to perform the exercise treadmill testing.

On examination, document murmurs, rhythm abnormalities, vascular bruits, and abnormal pulses. Limit laboratory studies to recent cardiac damage screening if indicated. Screen with a resting ECG for arrhythmias, conduction abnormalities or preexisting cardiac damage. ST-segment (≥1 mm) and T-wave changes such as inversions secondary to strain or old injury or conduction abnormalities such as bundle branch blocks and prolonged QT interval may obscure exercise treadmill testing findings. Consider spirometry for patients with asthma or chronic lung disease.

The decisive factors

Absolute contraindications to exercise treadmill testing include recent MI; significant aortic stenosis,⁷ and weight exceeding equipment capacity. Relative contraindications to exercise treadmill testing (which can be superseded if the benefits of exercise outweigh the risks) include: hypertension (systolic >200 mm Hg/diastolic >110 mm Hg),⁵ left main coronary stenosis and stenotic valvular disease. (For more on “Contraindications to exercise testing,” see TABLE 2.)

The role of imaging: Important, yes—routine, no

An important element of stress testing is, of course, the imaging method(s) that will be used. The options include myocardial perfusion imaging with thallium Tl 201 or technetium Tc 99m, and echocardiography.

Indications for myocardial perfusion imaging with exercise treadmill testing are a high pretest probability for CAD, an abnormal baseline ECG such as left bundle branch block, previous myocardial damage or coronary revascularization, or a previous equivocal or unexpected exercise ECG result. In women with an intermediate pretest probability for CAD, the sensitivity and specificity of an exercise treadmill testing is less than in men, which suggests that nuclear imaging would improve this test.⁸ There is, however, insufficient data to justify initial routine stress imaging tests in women.¹

TABLE 2
Contraindications to exercise testing

Of the 2 agents used for myocardial perfusion imaging, technetium Tc 99m has more favorable imaging characteristics.⁹ It has a shorter half-life (6 hours) than thallium Tl 201 (73 hours), and larger doses of technetium Tc99m may be used, permitting the assessment of ventricular function.¹⁰

Echocardiography may also be done with either exercise treadmill testing or PSMI to evaluate relative myocardial perfusion. While radionuclide technique assesses relative myocardial perfusion, echocardiography also evaluates global and regional function. Indications for echocardiography are similar to myocardial perfusion imaging but also include the need for prognostic information after MI, and to assess physiologic significance of a lesion or to determine the success of an intervention.

Time for the test: Selecting the protocol

While the Bruce exercise treadmill testing protocol is the most commonly used (82% of tests)¹¹ in healthy adults, it may not be appropriate for women or the elderly as most protocols were developed for the evaluation of men.¹² A ramp method with gradual increase in grade each minute is preferred by some clinicians when patients are unable to perform a standard Bruce protocol. Another option, the Modified Bruce protocol, which is more gradual than the standard Bruce protocol; it has two 3-minute warm-up stages.¹²

The 3 PSMI protocols include adenosine, dipyridamole, and dobutamine. Each has a different administration routine,⁹ though ECG, blood pressure and pulse are taken every minute for all 3.

• Adenosine is infused with a pump over 6 minutes and technetium Tc99m is injected 3 minutes into the infusion.
• Dipyridamole is infused over 4 minutes and technetium Tc99m is injected 2 to no more than 5 minutes after the infusion. Theophylline is injected, after dipyridamole if necessary, no earlier than 1 minute after technetium Tc99m is administered to avoid interference with the uptake.
• Dobutamine is titrated with a dose increase every 3 minutes. Tc99m is injected after the first minute at the highest concentration. (Typically dobutamine is used with echocardiography.⁶)

Ideal endpoints and the realities that may creep in

The ideal endpoint in an exercise treadmill testing is 100% of the age-predicted maximum heart rate (220–age). Eighty-five percent of maximum heart rate is the minimum for an acceptable test.

Absolute contraindications

Absolute indicators for stopping an exercise treadmill test are either a 10 mm Hg systolic drop in blood pressure from standing baseline, moderate to severe angina symptoms, feelings of syncope, skin color changes suggestive of hypoxia or hypotension, ischemic ST changes, or the patient’s desire to stop.

Relative contraindications

Relative indicators to stop include fatigue, shortness of breath, leg pain, increased arrhythmias—particularly PVCs that increase with the exercise level—and blood pressure ≥250 systolic or 115 diastolic.⁶

Ideally, PSMI evaluations are terminated according to the prescribed length of infusions. They will also be terminated if a patient develops wheezing, severe or increasing chest pain or hypotension, neurological symptoms, ST-segment elevation abnormalities, or arrhythmias. To reverse the side effects of adenosine or dipyridamole, aminophylline IV will be administered (1–2 mg/kg slowly, up to 250 mg).

Heart of the matter: What a report should cover

Assuming you have ordered the stress test (and not done it yourself), a complete report should include

• ST changes
• symptoms during testing
• reason for ending the test
• estimation of exercise capacity
• blood pressure response
• the presence and frequency of arrhythmias or ectopy.

Abnormal. ST segment change is the most important ECG finding in a positive test; it’s defined as >1 mm horizontal or down sloping depression or elevation, at least 60 to 80 milliseconds after the end of the QRS complex and should prompt further workup to confirm CAD.⁵ An abnormal ECG during a PSMI test indicates an elevated risk of multivessel CAD and should prompt further evaluation regardless of normal myocardial perfusion imaging.¹³