PURLs

ILLUSTRATIVE CASE

Two weeks ago, you informed your patient—a 53-year-old man with a body mass index of 28.4—that he has type 2 diabetes. Since then, he has seen a nutritionist and begun exercising regularly. His hemoglobin A1c (HbA1c) is 7.7%. You recommend that he begin taking metformin. The patient is worried about the potential for oral antidiabetic agents to cause hypoglycemia. He’s aware that many patients with diabetes monitor their blood sugar levels at home and wants to know if he should, too. You wonder whether it’s necessary, or even advisable, to initiate self-monitoring at this time.

For patients with type 2 diabetes, self-monitoring of blood glucose makes intuitive sense. Theoretically, it reinforces self-management behaviors, promotes adherence to the prescribed medication regimen, and leads to better glucose control. It seems obvious, too, that patients taking medications intended to lower blood sugar need to be aware of their glucose levels so they can take action to reduce the risk of complications.

But things that make sense intuitively do not always stand up to scrutiny. New high-quality evidence suggests that for those with newly diagnosed diabetes, self-monitoring of blood glucose may do more harm than good.

More questions than answers

While it is generally accepted that glucose self-monitoring is useful for those with insulin-treated type 2 diabetes,^2-4 evidence supporting the practice for patients with diabetes who do not require insulin is limited. Two recent meta-analyses of RCTs^5,6 found that self-monitoring of blood glucose achieves a statistically significant reduction of 0.4% in HbA1c; the quality of the studies, however, was limited. A well-designed RCT was needed, the researchers concluded, to settle questions about the value of self-monitoring.

The most recent Cochrane review⁷ of self-monitoring reached a similar conclusion: The reviewers called for additional research into the benefits of self-monitoring for patients with diabetes who do not need insulin. The reviewers also emphasized the need for information on patient-related outcomes such as quality of life, well-being, and satisfaction.

Are recommendations out of step?

Despite the lack of definitive evidence, the Department of Health and Human Services calls on us to increase the proportion of patients with diabetes who monitor their blood sugar at least once daily to 60% as part of its Healthy People 2010 initiative.⁸ The American Diabetes Association states that self-monitoring of blood glucose may help patients taking oral antidiabetic agents achieve glycemic goals.⁹ And the International Diabetes Federation recommends that self-monitoring of blood glucose be offered to all people with type 2 diabetes taking insulin or oral agents—and be part of the patient education that is given to all those who are newly diagnosed.¹⁰

But all of these groups may need to rethink their recommendations in light of the latest findings from the O’Kane RCT.

STUDY SUMMARY: Self-monitoring has little effect on glycemic control

O’Kane and colleagues conducted a prospective RCT comparing self-monitoring versus no monitoring among 184 people with newly diagnosed type 2 diabetes.¹ Patients were randomized to the self-monitoring or control group for 1 year, with clinic visits at 3-month intervals. Those who were already taking insulin or had engaged in self-monitoring of blood glucose were excluded.

At baseline, there was no significant difference in HbA1c, age, or sex between the 2 groups. Participants in both groups underwent identical diabetes education programs throughout the study period and received dietary and medical management based on the same treatment algorithm. Patients whose baseline HbA1c was >7.5% received metformin, followed by the sulfonylurea gliclazide if they did not reach target at the maximum dose of metformin. There was no significant difference in medication use at baseline or at 12 months.

Patients in the self-monitoring group were given glucose monitors and asked to record 4 fasting and 4 postprandial capillary blood glucose measurements per week. They were also taught to monitor and interpret blood glucose readings, and to respond appropriately to high or low readings.

At each follow-up visit, patients underwent blood tests for HbA1c, lipids, and electrolyte levels and completed questionnaires about treatment satisfaction, attitudes about diabetes, and levels of depression, anxiety, and well-being. Adherence to self-monitoring was verified by downloading meter readings. The dropout rate was low (2.2%), and adherence in the self-monitoring group was high. Study results were assessed using intent-to-treat analysis.

HbA1c fell in both the self-monitoring and control groups, with no significant differences at any point. The mean (standard deviation) value at 12 months was 6.9% (0.8%) in the self-monitoring group, compared to 6.9% (1.2%) in the control group, with a 95% confidence interval for the change in HbA1c of –0.25% to 0.38%. Throughout the study period, there was no difference in use of oral hypoglycemic medications or reported hypoglycemia.

Self-monitoring linked to depression

Measures of depression and anxiety were scored on a 100-point scale and compared to baseline measurements. At 12 months, participants in the self-monitoring group were more depressed, scoring 6% higher, on average, on the depression subscale of the well-being questionnaire (P=.01) than those in the control group. There was a trend toward increased anxiety in the self-monitoring group, but no significant differences in well-being, energy, or any of the other diabetes attitude subscales.

WHAT’S NEW: Less may be better

Because we emphasize self-management skills when we counsel patients about diabetes, it is surprising to learn that knowledge about glycemic control and blood sugar levels does not lead to better glycemic control. This RCT provides strong evidence that more information is not necessarily desirable, at least for patients with newly diagnosed type 2 diabetes who do not need insulin.

Depression is a known complication of diabetes. It affects an estimated 10% to 30% of patients with diabetes, who have double the odds of depression compared to people without diabetes.^11,12 Patients with depression and diabetes have poorer glycemic control,^13,14 an increased risk of complications,^15-17 a decreased quality of life,¹⁸ an increased disability burden,^19,20 and increased health care use and costs.^18,21,22 In addition, they face a significantly higher risk of death from all causes, beyond the risks associated with depression or diabetes alone.²³

CAVEATS: Patients on sulfonylureas may be an exception

This study used metformin as the initial oral medication, with sulfonylureas reserved for those who did not reach target glycemic control with maximum metformin therapy. The number of patients taking sulfonylureas was 11 in the self-monitoring group and 6 in the control group. Because hypoglycemia is a concern in patients taking sulfonylureas, there may be a role for self-monitoring of blood glucose in these patients.

Also of note: This study does not provide definitive evidence that self-monitoring of blood glucose causes harm. Although self-monitoring was associated with a 6% higher score on a depression subscale and a trend toward increased anxiety, overall satisfaction with treatment was similar in both groups. Additional studies are needed to better understand the relationship between self-monitoring and depression.

Self-monitoring may still be a good idea for certain patients, regardless of their diabetic medication regimen. When evaluating the potential benefits of self-monitoring of blood glucose, physicians should consider the individual’s predisposition to depression, among other concerns.

CHALLENGES TO IMPLEMENTATION: Hard to forego a practice that everyone expects

Self-monitoring serves different purposes for different populations. Blood glucose levels, along with HbA1c, can guide clinicians in making treatment decisions. Knowing blood sugar levels may be educational or empowering to patients, and provides critical information if hypoglycemia is a concern. These considerations lead us to conclude that while self-monitoring is not indicated for all newly diagnosed diabetic patients, it should be considered in selected circumstances.

Because of the prevalence of self-monitoring of blood glucose, patients may see it as a key component of an optimal self-management regimen. It may be hard to convince patients with newly diagnosed diabetes otherwise—and to convince some clinicians that there is little benefit in recommending it. Again, clinical judgment is required. We suspect, however, that with the proper explanation, many patients will be relieved to learn that they will not have to prick their fingers regularly or record their blood glucose.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

Two weeks ago, you informed your patient—a 53-year-old man with a body mass index of 28.4—that he has type 2 diabetes. Since then, he has seen a nutritionist and begun exercising regularly. His hemoglobin A1c (HbA1c) is 7.7%. You recommend that he begin taking metformin. The patient is worried about the potential for oral antidiabetic agents to cause hypoglycemia. He’s aware that many patients with diabetes monitor their blood sugar levels at home and wants to know if he should, too. You wonder whether it’s necessary, or even advisable, to initiate self-monitoring at this time.

For patients with type 2 diabetes, self-monitoring of blood glucose makes intuitive sense. Theoretically, it reinforces self-management behaviors, promotes adherence to the prescribed medication regimen, and leads to better glucose control. It seems obvious, too, that patients taking medications intended to lower blood sugar need to be aware of their glucose levels so they can take action to reduce the risk of complications.

But things that make sense intuitively do not always stand up to scrutiny. New high-quality evidence suggests that for those with newly diagnosed diabetes, self-monitoring of blood glucose may do more harm than good.

More questions than answers

While it is generally accepted that glucose self-monitoring is useful for those with insulin-treated type 2 diabetes,^2-4 evidence supporting the practice for patients with diabetes who do not require insulin is limited. Two recent meta-analyses of RCTs^5,6 found that self-monitoring of blood glucose achieves a statistically significant reduction of 0.4% in HbA1c; the quality of the studies, however, was limited. A well-designed RCT was needed, the researchers concluded, to settle questions about the value of self-monitoring.

The most recent Cochrane review⁷ of self-monitoring reached a similar conclusion: The reviewers called for additional research into the benefits of self-monitoring for patients with diabetes who do not need insulin. The reviewers also emphasized the need for information on patient-related outcomes such as quality of life, well-being, and satisfaction.

Are recommendations out of step?

Despite the lack of definitive evidence, the Department of Health and Human Services calls on us to increase the proportion of patients with diabetes who monitor their blood sugar at least once daily to 60% as part of its Healthy People 2010 initiative.⁸ The American Diabetes Association states that self-monitoring of blood glucose may help patients taking oral antidiabetic agents achieve glycemic goals.⁹ And the International Diabetes Federation recommends that self-monitoring of blood glucose be offered to all people with type 2 diabetes taking insulin or oral agents—and be part of the patient education that is given to all those who are newly diagnosed.¹⁰

But all of these groups may need to rethink their recommendations in light of the latest findings from the O’Kane RCT.

STUDY SUMMARY: Self-monitoring has little effect on glycemic control

O’Kane and colleagues conducted a prospective RCT comparing self-monitoring versus no monitoring among 184 people with newly diagnosed type 2 diabetes.¹ Patients were randomized to the self-monitoring or control group for 1 year, with clinic visits at 3-month intervals. Those who were already taking insulin or had engaged in self-monitoring of blood glucose were excluded.

At baseline, there was no significant difference in HbA1c, age, or sex between the 2 groups. Participants in both groups underwent identical diabetes education programs throughout the study period and received dietary and medical management based on the same treatment algorithm. Patients whose baseline HbA1c was >7.5% received metformin, followed by the sulfonylurea gliclazide if they did not reach target at the maximum dose of metformin. There was no significant difference in medication use at baseline or at 12 months.

Patients in the self-monitoring group were given glucose monitors and asked to record 4 fasting and 4 postprandial capillary blood glucose measurements per week. They were also taught to monitor and interpret blood glucose readings, and to respond appropriately to high or low readings.

At each follow-up visit, patients underwent blood tests for HbA1c, lipids, and electrolyte levels and completed questionnaires about treatment satisfaction, attitudes about diabetes, and levels of depression, anxiety, and well-being. Adherence to self-monitoring was verified by downloading meter readings. The dropout rate was low (2.2%), and adherence in the self-monitoring group was high. Study results were assessed using intent-to-treat analysis.

HbA1c fell in both the self-monitoring and control groups, with no significant differences at any point. The mean (standard deviation) value at 12 months was 6.9% (0.8%) in the self-monitoring group, compared to 6.9% (1.2%) in the control group, with a 95% confidence interval for the change in HbA1c of –0.25% to 0.38%. Throughout the study period, there was no difference in use of oral hypoglycemic medications or reported hypoglycemia.

Self-monitoring linked to depression

Measures of depression and anxiety were scored on a 100-point scale and compared to baseline measurements. At 12 months, participants in the self-monitoring group were more depressed, scoring 6% higher, on average, on the depression subscale of the well-being questionnaire (P=.01) than those in the control group. There was a trend toward increased anxiety in the self-monitoring group, but no significant differences in well-being, energy, or any of the other diabetes attitude subscales.

WHAT’S NEW: Less may be better

Because we emphasize self-management skills when we counsel patients about diabetes, it is surprising to learn that knowledge about glycemic control and blood sugar levels does not lead to better glycemic control. This RCT provides strong evidence that more information is not necessarily desirable, at least for patients with newly diagnosed type 2 diabetes who do not need insulin.

Depression is a known complication of diabetes. It affects an estimated 10% to 30% of patients with diabetes, who have double the odds of depression compared to people without diabetes.^11,12 Patients with depression and diabetes have poorer glycemic control,^13,14 an increased risk of complications,^15-17 a decreased quality of life,¹⁸ an increased disability burden,^19,20 and increased health care use and costs.^18,21,22 In addition, they face a significantly higher risk of death from all causes, beyond the risks associated with depression or diabetes alone.²³

CAVEATS: Patients on sulfonylureas may be an exception

This study used metformin as the initial oral medication, with sulfonylureas reserved for those who did not reach target glycemic control with maximum metformin therapy. The number of patients taking sulfonylureas was 11 in the self-monitoring group and 6 in the control group. Because hypoglycemia is a concern in patients taking sulfonylureas, there may be a role for self-monitoring of blood glucose in these patients.

Also of note: This study does not provide definitive evidence that self-monitoring of blood glucose causes harm. Although self-monitoring was associated with a 6% higher score on a depression subscale and a trend toward increased anxiety, overall satisfaction with treatment was similar in both groups. Additional studies are needed to better understand the relationship between self-monitoring and depression.

Self-monitoring may still be a good idea for certain patients, regardless of their diabetic medication regimen. When evaluating the potential benefits of self-monitoring of blood glucose, physicians should consider the individual’s predisposition to depression, among other concerns.

CHALLENGES TO IMPLEMENTATION: Hard to forego a practice that everyone expects

Self-monitoring serves different purposes for different populations. Blood glucose levels, along with HbA1c, can guide clinicians in making treatment decisions. Knowing blood sugar levels may be educational or empowering to patients, and provides critical information if hypoglycemia is a concern. These considerations lead us to conclude that while self-monitoring is not indicated for all newly diagnosed diabetic patients, it should be considered in selected circumstances.

Because of the prevalence of self-monitoring of blood glucose, patients may see it as a key component of an optimal self-management regimen. It may be hard to convince patients with newly diagnosed diabetes otherwise—and to convince some clinicians that there is little benefit in recommending it. Again, clinical judgment is required. We suspect, however, that with the proper explanation, many patients will be relieved to learn that they will not have to prick their fingers regularly or record their blood glucose.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

Two weeks ago, you informed your patient—a 53-year-old man with a body mass index of 28.4—that he has type 2 diabetes. Since then, he has seen a nutritionist and begun exercising regularly. His hemoglobin A1c (HbA1c) is 7.7%. You recommend that he begin taking metformin. The patient is worried about the potential for oral antidiabetic agents to cause hypoglycemia. He’s aware that many patients with diabetes monitor their blood sugar levels at home and wants to know if he should, too. You wonder whether it’s necessary, or even advisable, to initiate self-monitoring at this time.

For patients with type 2 diabetes, self-monitoring of blood glucose makes intuitive sense. Theoretically, it reinforces self-management behaviors, promotes adherence to the prescribed medication regimen, and leads to better glucose control. It seems obvious, too, that patients taking medications intended to lower blood sugar need to be aware of their glucose levels so they can take action to reduce the risk of complications.

But things that make sense intuitively do not always stand up to scrutiny. New high-quality evidence suggests that for those with newly diagnosed diabetes, self-monitoring of blood glucose may do more harm than good.

More questions than answers

While it is generally accepted that glucose self-monitoring is useful for those with insulin-treated type 2 diabetes,^2-4 evidence supporting the practice for patients with diabetes who do not require insulin is limited. Two recent meta-analyses of RCTs^5,6 found that self-monitoring of blood glucose achieves a statistically significant reduction of 0.4% in HbA1c; the quality of the studies, however, was limited. A well-designed RCT was needed, the researchers concluded, to settle questions about the value of self-monitoring.

The most recent Cochrane review⁷ of self-monitoring reached a similar conclusion: The reviewers called for additional research into the benefits of self-monitoring for patients with diabetes who do not need insulin. The reviewers also emphasized the need for information on patient-related outcomes such as quality of life, well-being, and satisfaction.

Are recommendations out of step?

Despite the lack of definitive evidence, the Department of Health and Human Services calls on us to increase the proportion of patients with diabetes who monitor their blood sugar at least once daily to 60% as part of its Healthy People 2010 initiative.⁸ The American Diabetes Association states that self-monitoring of blood glucose may help patients taking oral antidiabetic agents achieve glycemic goals.⁹ And the International Diabetes Federation recommends that self-monitoring of blood glucose be offered to all people with type 2 diabetes taking insulin or oral agents—and be part of the patient education that is given to all those who are newly diagnosed.¹⁰

But all of these groups may need to rethink their recommendations in light of the latest findings from the O’Kane RCT.

STUDY SUMMARY: Self-monitoring has little effect on glycemic control

O’Kane and colleagues conducted a prospective RCT comparing self-monitoring versus no monitoring among 184 people with newly diagnosed type 2 diabetes.¹ Patients were randomized to the self-monitoring or control group for 1 year, with clinic visits at 3-month intervals. Those who were already taking insulin or had engaged in self-monitoring of blood glucose were excluded.

At baseline, there was no significant difference in HbA1c, age, or sex between the 2 groups. Participants in both groups underwent identical diabetes education programs throughout the study period and received dietary and medical management based on the same treatment algorithm. Patients whose baseline HbA1c was >7.5% received metformin, followed by the sulfonylurea gliclazide if they did not reach target at the maximum dose of metformin. There was no significant difference in medication use at baseline or at 12 months.

Patients in the self-monitoring group were given glucose monitors and asked to record 4 fasting and 4 postprandial capillary blood glucose measurements per week. They were also taught to monitor and interpret blood glucose readings, and to respond appropriately to high or low readings.

At each follow-up visit, patients underwent blood tests for HbA1c, lipids, and electrolyte levels and completed questionnaires about treatment satisfaction, attitudes about diabetes, and levels of depression, anxiety, and well-being. Adherence to self-monitoring was verified by downloading meter readings. The dropout rate was low (2.2%), and adherence in the self-monitoring group was high. Study results were assessed using intent-to-treat analysis.

HbA1c fell in both the self-monitoring and control groups, with no significant differences at any point. The mean (standard deviation) value at 12 months was 6.9% (0.8%) in the self-monitoring group, compared to 6.9% (1.2%) in the control group, with a 95% confidence interval for the change in HbA1c of –0.25% to 0.38%. Throughout the study period, there was no difference in use of oral hypoglycemic medications or reported hypoglycemia.

Self-monitoring linked to depression

Measures of depression and anxiety were scored on a 100-point scale and compared to baseline measurements. At 12 months, participants in the self-monitoring group were more depressed, scoring 6% higher, on average, on the depression subscale of the well-being questionnaire (P=.01) than those in the control group. There was a trend toward increased anxiety in the self-monitoring group, but no significant differences in well-being, energy, or any of the other diabetes attitude subscales.

WHAT’S NEW: Less may be better

Because we emphasize self-management skills when we counsel patients about diabetes, it is surprising to learn that knowledge about glycemic control and blood sugar levels does not lead to better glycemic control. This RCT provides strong evidence that more information is not necessarily desirable, at least for patients with newly diagnosed type 2 diabetes who do not need insulin.

Depression is a known complication of diabetes. It affects an estimated 10% to 30% of patients with diabetes, who have double the odds of depression compared to people without diabetes.^11,12 Patients with depression and diabetes have poorer glycemic control,^13,14 an increased risk of complications,^15-17 a decreased quality of life,¹⁸ an increased disability burden,^19,20 and increased health care use and costs.^18,21,22 In addition, they face a significantly higher risk of death from all causes, beyond the risks associated with depression or diabetes alone.²³

CAVEATS: Patients on sulfonylureas may be an exception

This study used metformin as the initial oral medication, with sulfonylureas reserved for those who did not reach target glycemic control with maximum metformin therapy. The number of patients taking sulfonylureas was 11 in the self-monitoring group and 6 in the control group. Because hypoglycemia is a concern in patients taking sulfonylureas, there may be a role for self-monitoring of blood glucose in these patients.

Also of note: This study does not provide definitive evidence that self-monitoring of blood glucose causes harm. Although self-monitoring was associated with a 6% higher score on a depression subscale and a trend toward increased anxiety, overall satisfaction with treatment was similar in both groups. Additional studies are needed to better understand the relationship between self-monitoring and depression.

Self-monitoring may still be a good idea for certain patients, regardless of their diabetic medication regimen. When evaluating the potential benefits of self-monitoring of blood glucose, physicians should consider the individual’s predisposition to depression, among other concerns.

CHALLENGES TO IMPLEMENTATION: Hard to forego a practice that everyone expects

Self-monitoring serves different purposes for different populations. Blood glucose levels, along with HbA1c, can guide clinicians in making treatment decisions. Knowing blood sugar levels may be educational or empowering to patients, and provides critical information if hypoglycemia is a concern. These considerations lead us to conclude that while self-monitoring is not indicated for all newly diagnosed diabetic patients, it should be considered in selected circumstances.

Because of the prevalence of self-monitoring of blood glucose, patients may see it as a key component of an optimal self-management regimen. It may be hard to convince patients with newly diagnosed diabetes otherwise—and to convince some clinicians that there is little benefit in recommending it. Again, clinical judgment is required. We suspect, however, that with the proper explanation, many patients will be relieved to learn that they will not have to prick their fingers regularly or record their blood glucose.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 68-year-old man with a history of ulcer disease and mild renal insufficiency comes to your office complaining of severe pain in his right foot. You note swelling and redness around the base of the big toe and diagnose acute gout. Wishing to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine because of the patient’s medical history, you wonder what you can safely prescribe for pain relief.

NSAIDs have become the mainstay of treatment for acute gout,^3,4 replacing colchicine—widely used for gout pain relief since the early 19th century.⁵ Colchicine fell out of favor because it routinely causes diarrhea and requires caution in patients with renal insufficiency.⁶ Now, however, there is growing concern about the adverse effects of NSAIDs.

Comorbidities, age, mean fewer options

NSAIDs increase the risk of gastrointestinal (GI) bleeding, especially in the first week of use.⁷ Cyclooxygenase-2 (COX-2) inhibitors, considered as effective as NSAIDs in treating acute gout pain,⁸ are also associated with GI bleeds.⁹ In addition, NSAIDs and COX-2 inhibitors increase cardiovascular risks, prompting the American Heart Association to recommend restricted use of both.¹⁰ NSAIDs’ effect on renal function, fluid retention, and interactions with anticoagulants are additional concerns, because gout patients are generally older and often have comorbid renal and cardiovascular diseases.^3,11-13

In the United States, nearly 70% of patients who develop acute gout seek treatment from primary care physicians.¹² Family physicians need a safe alternative to NSAIDs to relieve the severe pain associated with this condition. Will oral corticosteroids fit the bill?

STUDY SUMMARIES: Oral steroids: A safe and effective alternative

Janssens et al¹ conducted a double-blind, randomized equivalence trial of 118 patients to compare the efficacy of prednisolone and naproxen for the treatment of monoarticular gout, confirmed by crystal analysis of synovial fluid. The study was conducted in the eastern Netherlands at a trial center patients were referred to by their family physicians. Those with major comorbidities, including a history of GI bleed or peptic ulcer, were excluded.

Participants were randomized to receive either prednisolone 35 mg* or naproxen 500 mg twice a day, with look-alike placebo tablets of the alternate drug, for 5 days. Pain, the primary outcome, was scored on a validated visual analog scale from 0 mm (no pain) to 100 mm (worst pain experienced).¹⁵ The reduction in the pain score at 90 hours was similar in both groups. Only a few minor side effects were reported in both groups, and all completely resolved in 3 weeks.

The study by Man et al² was a randomized trial that compared indomethacin with oral prednisolone in 90 patients presenting to an emergency department in Hong Kong. Diagnosis of gout was made by clinical impression. Participants in the indomethacin group also received an intramuscular (IM) injection of diclofenac 75 mg, and those in both groups were monitored for acetaminophen use as a secondary endpoint.

Pain reduction, the primary endpoint, was assessed with a 10-point visual analog score, and was slightly better statistically in the oral steroid group. The study was not designed to evaluate for safety, but the authors noted that patients in the indomethacin group experienced more adverse effects (number needed to harm [NNH] for any adverse event: 3; NNH for serious events: 6).

Short-term steroids have few side effects

In both studies, patients receiving oral steroids experienced no significant side effects. This finding is consistent with other studies that have investigated short-term oral steroid use in the treatment of both rheumatoid arthritis and asthma.^16,17

WHAT’S NEW?: Evidence supports use of steroids for acute gout

In the United States, prednisone is prescribed as treatment for acute gout only about 9% of the time.¹² These 2 studies—the first randomized trials comparing oral steroids with NSAIDs, the usual gout treatment—may lead to greater use of steroids for this painful condition.

Both studies were well designed and conducted in an outpatient (or emergency) setting. Both showed that a short course of oral steroids is as effective as NSAIDs, and without significant side effects.

Previous studies have compared IM steroids with NSAIDs, and IM steroids with IM adrenocorticotropic hormone (ACTH).^18,19 However, these studies were not blinded—just one of their methodological problems.⁴

CAVEATS: Joint aspiration is not the norm

In the Janssens study, participants were diagnosed with gout after monosodium urate crystals were found in joint aspirate.¹ This may not be the usual practice in primary care settings, where a clinical diagnosis of gout is typically made. The authors indicate that the failure to perform joint aspiration will lead to occasional cases of septic arthritis being treated with oral steroids. We recommend joint aspiration or a referral for such a procedure when clinical evidence (eg, fever and leukocytosis) is suggestive of septic arthritis.

Possible impact of acetaminophen

In the study by Man et al, acetaminophen was used by both groups as an adjunct for pain relief, and the amount used was higher (mean 10.3 g vs 6.4 g over 14 days) in the oral steroid group. It is possible that some of the pain relief experienced by those in the steroid group may have been from acetaminophen; however, a difference of 4 g over a 14-day period makes that unlikely. Even if additional acetaminophen is required, the advantages of oral steroids rather than NSAIDs or colchicine for patients with contraindications remain.

Also of note: These trials examined short-term treatment of acute gout. These findings cannot be extrapolated to the treatment of intercurrent gout or chronic gouty arthritis, since long-term steroid use has severe adverse effects.

CHALLENGES TO IMPLEMENTATION: No significant barriers

We found little to prevent physicians from adopting this practice changer. Oral steroids are readily available and inexpensive, and most primary care clinicians regularly prescribe them for other conditions. This practice change recommendation should be readily implemented.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

* Prednisone is the precursor of prednisolone and is activated in the liver. The activity of both drugs is comparable, and prednisone and prednisolone can be converted milligram to milligram. However, prednisolone may be preferred for patients with severe liver disease.¹⁴ (In the United States, prednisolone is available as a liquid and prednisone as a tablet.)

PURL METHODOLOGY
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 68-year-old man with a history of ulcer disease and mild renal insufficiency comes to your office complaining of severe pain in his right foot. You note swelling and redness around the base of the big toe and diagnose acute gout. Wishing to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine because of the patient’s medical history, you wonder what you can safely prescribe for pain relief.

NSAIDs have become the mainstay of treatment for acute gout,^3,4 replacing colchicine—widely used for gout pain relief since the early 19th century.⁵ Colchicine fell out of favor because it routinely causes diarrhea and requires caution in patients with renal insufficiency.⁶ Now, however, there is growing concern about the adverse effects of NSAIDs.

Comorbidities, age, mean fewer options

NSAIDs increase the risk of gastrointestinal (GI) bleeding, especially in the first week of use.⁷ Cyclooxygenase-2 (COX-2) inhibitors, considered as effective as NSAIDs in treating acute gout pain,⁸ are also associated with GI bleeds.⁹ In addition, NSAIDs and COX-2 inhibitors increase cardiovascular risks, prompting the American Heart Association to recommend restricted use of both.¹⁰ NSAIDs’ effect on renal function, fluid retention, and interactions with anticoagulants are additional concerns, because gout patients are generally older and often have comorbid renal and cardiovascular diseases.^3,11-13

In the United States, nearly 70% of patients who develop acute gout seek treatment from primary care physicians.¹² Family physicians need a safe alternative to NSAIDs to relieve the severe pain associated with this condition. Will oral corticosteroids fit the bill?

STUDY SUMMARIES: Oral steroids: A safe and effective alternative

Janssens et al¹ conducted a double-blind, randomized equivalence trial of 118 patients to compare the efficacy of prednisolone and naproxen for the treatment of monoarticular gout, confirmed by crystal analysis of synovial fluid. The study was conducted in the eastern Netherlands at a trial center patients were referred to by their family physicians. Those with major comorbidities, including a history of GI bleed or peptic ulcer, were excluded.

Participants were randomized to receive either prednisolone 35 mg* or naproxen 500 mg twice a day, with look-alike placebo tablets of the alternate drug, for 5 days. Pain, the primary outcome, was scored on a validated visual analog scale from 0 mm (no pain) to 100 mm (worst pain experienced).¹⁵ The reduction in the pain score at 90 hours was similar in both groups. Only a few minor side effects were reported in both groups, and all completely resolved in 3 weeks.

The study by Man et al² was a randomized trial that compared indomethacin with oral prednisolone in 90 patients presenting to an emergency department in Hong Kong. Diagnosis of gout was made by clinical impression. Participants in the indomethacin group also received an intramuscular (IM) injection of diclofenac 75 mg, and those in both groups were monitored for acetaminophen use as a secondary endpoint.

Pain reduction, the primary endpoint, was assessed with a 10-point visual analog score, and was slightly better statistically in the oral steroid group. The study was not designed to evaluate for safety, but the authors noted that patients in the indomethacin group experienced more adverse effects (number needed to harm [NNH] for any adverse event: 3; NNH for serious events: 6).

Short-term steroids have few side effects

In both studies, patients receiving oral steroids experienced no significant side effects. This finding is consistent with other studies that have investigated short-term oral steroid use in the treatment of both rheumatoid arthritis and asthma.^16,17

WHAT’S NEW?: Evidence supports use of steroids for acute gout

In the United States, prednisone is prescribed as treatment for acute gout only about 9% of the time.¹² These 2 studies—the first randomized trials comparing oral steroids with NSAIDs, the usual gout treatment—may lead to greater use of steroids for this painful condition.

Both studies were well designed and conducted in an outpatient (or emergency) setting. Both showed that a short course of oral steroids is as effective as NSAIDs, and without significant side effects.

Previous studies have compared IM steroids with NSAIDs, and IM steroids with IM adrenocorticotropic hormone (ACTH).^18,19 However, these studies were not blinded—just one of their methodological problems.⁴

CAVEATS: Joint aspiration is not the norm

In the Janssens study, participants were diagnosed with gout after monosodium urate crystals were found in joint aspirate.¹ This may not be the usual practice in primary care settings, where a clinical diagnosis of gout is typically made. The authors indicate that the failure to perform joint aspiration will lead to occasional cases of septic arthritis being treated with oral steroids. We recommend joint aspiration or a referral for such a procedure when clinical evidence (eg, fever and leukocytosis) is suggestive of septic arthritis.

Possible impact of acetaminophen

In the study by Man et al, acetaminophen was used by both groups as an adjunct for pain relief, and the amount used was higher (mean 10.3 g vs 6.4 g over 14 days) in the oral steroid group. It is possible that some of the pain relief experienced by those in the steroid group may have been from acetaminophen; however, a difference of 4 g over a 14-day period makes that unlikely. Even if additional acetaminophen is required, the advantages of oral steroids rather than NSAIDs or colchicine for patients with contraindications remain.

Also of note: These trials examined short-term treatment of acute gout. These findings cannot be extrapolated to the treatment of intercurrent gout or chronic gouty arthritis, since long-term steroid use has severe adverse effects.

CHALLENGES TO IMPLEMENTATION: No significant barriers

We found little to prevent physicians from adopting this practice changer. Oral steroids are readily available and inexpensive, and most primary care clinicians regularly prescribe them for other conditions. This practice change recommendation should be readily implemented.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

* Prednisone is the precursor of prednisolone and is activated in the liver. The activity of both drugs is comparable, and prednisone and prednisolone can be converted milligram to milligram. However, prednisolone may be preferred for patients with severe liver disease.¹⁴ (In the United States, prednisolone is available as a liquid and prednisone as a tablet.)

PURL METHODOLOGY
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 68-year-old man with a history of ulcer disease and mild renal insufficiency comes to your office complaining of severe pain in his right foot. You note swelling and redness around the base of the big toe and diagnose acute gout. Wishing to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine because of the patient’s medical history, you wonder what you can safely prescribe for pain relief.

NSAIDs have become the mainstay of treatment for acute gout,^3,4 replacing colchicine—widely used for gout pain relief since the early 19th century.⁵ Colchicine fell out of favor because it routinely causes diarrhea and requires caution in patients with renal insufficiency.⁶ Now, however, there is growing concern about the adverse effects of NSAIDs.

Comorbidities, age, mean fewer options

NSAIDs increase the risk of gastrointestinal (GI) bleeding, especially in the first week of use.⁷ Cyclooxygenase-2 (COX-2) inhibitors, considered as effective as NSAIDs in treating acute gout pain,⁸ are also associated with GI bleeds.⁹ In addition, NSAIDs and COX-2 inhibitors increase cardiovascular risks, prompting the American Heart Association to recommend restricted use of both.¹⁰ NSAIDs’ effect on renal function, fluid retention, and interactions with anticoagulants are additional concerns, because gout patients are generally older and often have comorbid renal and cardiovascular diseases.^3,11-13

In the United States, nearly 70% of patients who develop acute gout seek treatment from primary care physicians.¹² Family physicians need a safe alternative to NSAIDs to relieve the severe pain associated with this condition. Will oral corticosteroids fit the bill?

STUDY SUMMARIES: Oral steroids: A safe and effective alternative

Janssens et al¹ conducted a double-blind, randomized equivalence trial of 118 patients to compare the efficacy of prednisolone and naproxen for the treatment of monoarticular gout, confirmed by crystal analysis of synovial fluid. The study was conducted in the eastern Netherlands at a trial center patients were referred to by their family physicians. Those with major comorbidities, including a history of GI bleed or peptic ulcer, were excluded.

Participants were randomized to receive either prednisolone 35 mg* or naproxen 500 mg twice a day, with look-alike placebo tablets of the alternate drug, for 5 days. Pain, the primary outcome, was scored on a validated visual analog scale from 0 mm (no pain) to 100 mm (worst pain experienced).¹⁵ The reduction in the pain score at 90 hours was similar in both groups. Only a few minor side effects were reported in both groups, and all completely resolved in 3 weeks.

The study by Man et al² was a randomized trial that compared indomethacin with oral prednisolone in 90 patients presenting to an emergency department in Hong Kong. Diagnosis of gout was made by clinical impression. Participants in the indomethacin group also received an intramuscular (IM) injection of diclofenac 75 mg, and those in both groups were monitored for acetaminophen use as a secondary endpoint.

Pain reduction, the primary endpoint, was assessed with a 10-point visual analog score, and was slightly better statistically in the oral steroid group. The study was not designed to evaluate for safety, but the authors noted that patients in the indomethacin group experienced more adverse effects (number needed to harm [NNH] for any adverse event: 3; NNH for serious events: 6).

Short-term steroids have few side effects

In both studies, patients receiving oral steroids experienced no significant side effects. This finding is consistent with other studies that have investigated short-term oral steroid use in the treatment of both rheumatoid arthritis and asthma.^16,17

WHAT’S NEW?: Evidence supports use of steroids for acute gout

In the United States, prednisone is prescribed as treatment for acute gout only about 9% of the time.¹² These 2 studies—the first randomized trials comparing oral steroids with NSAIDs, the usual gout treatment—may lead to greater use of steroids for this painful condition.

Both studies were well designed and conducted in an outpatient (or emergency) setting. Both showed that a short course of oral steroids is as effective as NSAIDs, and without significant side effects.

Previous studies have compared IM steroids with NSAIDs, and IM steroids with IM adrenocorticotropic hormone (ACTH).^18,19 However, these studies were not blinded—just one of their methodological problems.⁴

CAVEATS: Joint aspiration is not the norm

In the Janssens study, participants were diagnosed with gout after monosodium urate crystals were found in joint aspirate.¹ This may not be the usual practice in primary care settings, where a clinical diagnosis of gout is typically made. The authors indicate that the failure to perform joint aspiration will lead to occasional cases of septic arthritis being treated with oral steroids. We recommend joint aspiration or a referral for such a procedure when clinical evidence (eg, fever and leukocytosis) is suggestive of septic arthritis.

Possible impact of acetaminophen

In the study by Man et al, acetaminophen was used by both groups as an adjunct for pain relief, and the amount used was higher (mean 10.3 g vs 6.4 g over 14 days) in the oral steroid group. It is possible that some of the pain relief experienced by those in the steroid group may have been from acetaminophen; however, a difference of 4 g over a 14-day period makes that unlikely. Even if additional acetaminophen is required, the advantages of oral steroids rather than NSAIDs or colchicine for patients with contraindications remain.

Also of note: These trials examined short-term treatment of acute gout. These findings cannot be extrapolated to the treatment of intercurrent gout or chronic gouty arthritis, since long-term steroid use has severe adverse effects.

CHALLENGES TO IMPLEMENTATION: No significant barriers

We found little to prevent physicians from adopting this practice changer. Oral steroids are readily available and inexpensive, and most primary care clinicians regularly prescribe them for other conditions. This practice change recommendation should be readily implemented.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

* Prednisone is the precursor of prednisolone and is activated in the liver. The activity of both drugs is comparable, and prednisone and prednisolone can be converted milligram to milligram. However, prednisolone may be preferred for patients with severe liver disease.¹⁴ (In the United States, prednisolone is available as a liquid and prednisone as a tablet.)

PURL METHODOLOGY
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 40-year-old woman with a peptic ulcer has been diagnosed with Helicobacter pylori infection, and schedules a visit to discuss treatment. You’re aware of the declining eradication rates associated with standard therapy, and have heard that sequential therapy may be a more effective option. Should you offer it to this patient?

An estimated 30% to 40% of the US population is infected with H pylori,² a bacterium that plays a crucial role in the pathogenesis of peptic ulcer disease, chronic gastritis, and gastric cancer.¹ The triple-drug regimen (a proton-pump inhibitor [PPI] and clarithromycin with amoxicillin, tinidazole, or another imidazole) is commonly used to treat H pylori in Europe and in the United States.³ Yet the eradication rate associated with this standard 3-drug regimen in this country is <80%, and appears to be on the decline. The likely problem: the increase in antibiotic-resistant strains of H pylori.²

Put amoxicillin first

In Italy, eradication rates of >90% have been reported with a sequential therapy: a PPI and amoxicillin for 5 days, followed by the PPI, clarithromycin, and tinidazole for an additional 5 days (FIGURE).⁴ (Because tinidazole is a relatively new drug in the United States and physicians may use other drugs in its class instead, we refer to the drug class—imidazoles—rather than a specific medication in the FIGURE and much of the text that follows.) Using amoxicillin before the other antibiotics weakens bacterial cell walls, preventing the formation of drug efflux channels that can inhibit clarithromycin and other antibiotics, according to 1 theory.¹ Thus, clarithromycin and an imidazole are more effective in the second phase of treatment.¹

Should US physicians adopt the Italian protocol and prescribe tinidazole? Would metronidazole or other imidazoles be equally effective?

FIGURE
Sequential vs standard therapy: A comparison

STUDY SUMMARY: Sequential therapy is better on all counts

This meta-analysis found 9 randomized controlled trials (RCTs) that compared H pylori eradication rates with standard 7- to 10-day triple-drug therapy to 10-day sequential therapy; an additional small study used a 5-day triple-drug comparison group. The authors performed a thorough search and used standard meta-analysis methods for data synthesis and analysis. The patients were all H pylori treatment naïve and had not used PPIs, histamine-2 receptor antagonists, or antibiotics in the month preceding the study. All patients (n=2747) had documented H pylori infection based on fecal antigen test, histologic evaluation, biopsy urease test, or urea breath test.

All the trials were conducted in Italy, although 2 of the studies included patients from the United States. Nine RCTs compared a triple-therapy regimen with PPI to sequential therapy, 1 RCT compared a triple-drug regimen with ranitidine to sequential therapy, and 1 included only pediatric patients. Pooled eradication rates were 93.4% (95% confidence interval [CI,] 91.3%-95.5%) for sequential therapy and 76.9% (CI, 71.0%-82.8%) for standard therapy, with a relative risk reduction of 71% (CI, 64%-77%).¹ The authors estimated that for every 6.3 patients (95% CI, 5.2-7.1) treated with sequential therapy, there would be 1 additional cure compared to standard therapy. Standard 7- to 10-day triple therapy remained inferior to sequential therapy in all subgroup analyses, including patients with risk factors for eradication failure.

Adherence rates were similar in both groups. Sequential therapy resulted in a median adherence rate of 97.4% (range, 90.0%-98.9%), with standard therapy at 96.8% (range, 93.0%-100%).¹ Reported side effects were also similar in both treatment groups.¹

WHAT’S NEW?: This meta-analysis reduces doubt

The latest American College of Gastroenterology guidelines on the management of H pylori infection acknowledge that sequential therapy has shown promise in Europe, but the organization has not supported a change from the standard regimen to sequential therapy as first-line treatment. The standard triple-therapy regimen is approved by the US Food and Drug Administration, and is the most commonly used H pylori treatment in the United States.¹ This is the first meta-analysis based solely on RCTs, and it clearly demonstrates that sequential therapy increased eradication rates.

PATIENT HANDOUT: How to take your medicine for H pylori infection

Helicobacter pylori (called H pylori for short) is a type of bacteria that can cause an ulcer (sore) to develop within the lining of your stomach and intestines. Ulcers can cause pain and bleeding, so it is important to get rid of this bacteria. To do this, you will need to take 4 different medicines over the next 10 days. They must be taken in a certain order, exactly as your doctor has prescribed.

One of the drugs you will be taking (for the entire 10-day period) is a proton pump inhibitor (called a PPI), a medicine that helps reduce the amount of acid in your stomach. ______________ is the name of the PPI your doctor has ordered. Take it twice a day, once in the morning and once in the evening, for 10 days.

You will also take 3 different kinds of antibiotics to eliminate the H pylori bacteria. For the first 5 days, you will take amoxicillin twice a day (2 pills in the morning and 2 in the evening), along with the PPI.

After 5 days, all the amoxicillin pills should be gone, and you will switch to 2 other antibiotics: clarithromycin AND ______________. For the next 5 days, you will take 1 PPI plus 1 clarithromycin and 1 ______________ every morning AND every night.

These medications may cause nausea, diarrhea, and a bad taste in your mouth. These side effects are usually not serious, but if they bother you so much that you cannot continue to take the medicine, it is important to call our office right away.

To remember to take each of the medicines in the morning AND evening on the correct day, use this chart to follow along. Put a check mark in the morning box or the evening box every time you take your medicine.

 

 

 

CAVEATS: Drug resistance, previous Tx could skew results

This meta-analysis only included studies performed in Italy, although 2 of the trials did include US recruits. Drug resistance patterns may be different in this country, which could alter sequential therapy’s eradication rates.

Because 3 antibiotics are used in sequential therapy, we may have fewer remaining options for patients who do not respond to this regimen, and we do not have information about patients with previous treatment failures. In addition, this meta-analysis only evaluated H pylori eradication rates in treatment-naïve patients, so we have no information about the effectiveness of this regimen in patients with previous treatment failures.

Would other sequential regimens—or drugs—work?

Patients who are allergic to amoxicillin would not be candidates for this sequential therapy protocol. While sequential therapy was compared with 7- to 10-day standard triple therapy, this study did not compare it with other regimens—eg, quadruple therapy or a 14-day course of standard triple-drug therapy.

Other drugs may also affect outcomes. The sequential therapy studies all used tinidazole, a relatively new agent in the United States; we don’t know whether metronidazole or other imidazoles are as effective.

The authors of this meta-analysis also noted the possibility of publication bias, but we doubt that there are enough unpublished data to invalidate the findings. Also, the selected RCTs only addressed eradication rates and not patient-oriented outcomes. However, most patient-oriented outcomes, including cancer and ulcers, can take years, even decades, to develop.

CHALLENGES TO IMPLEMENTATION: Sequential therapy may be confusing

While adherence rates were similar in the standard and sequential treatment groups in the meta-analysis, sequential therapy—which requires switching medications midway through treatment—might be more confusing for patients in actual practice. This has the potential to negatively affect adherence to the sequential regimen.

It will be important for physicians who prescribe sequential therapy to counsel patients on the importance of completing the treatment regimen exactly as prescribed and to provide clear instructions for doing so, ideally in the form of a patient handout like the one on page 653. Cost is not a problem; the price of sequential therapy is about equal to, or possibly less than, that of standard therapy.⁵

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 40-year-old woman with a peptic ulcer has been diagnosed with Helicobacter pylori infection, and schedules a visit to discuss treatment. You’re aware of the declining eradication rates associated with standard therapy, and have heard that sequential therapy may be a more effective option. Should you offer it to this patient?

An estimated 30% to 40% of the US population is infected with H pylori,² a bacterium that plays a crucial role in the pathogenesis of peptic ulcer disease, chronic gastritis, and gastric cancer.¹ The triple-drug regimen (a proton-pump inhibitor [PPI] and clarithromycin with amoxicillin, tinidazole, or another imidazole) is commonly used to treat H pylori in Europe and in the United States.³ Yet the eradication rate associated with this standard 3-drug regimen in this country is <80%, and appears to be on the decline. The likely problem: the increase in antibiotic-resistant strains of H pylori.²

Put amoxicillin first

In Italy, eradication rates of >90% have been reported with a sequential therapy: a PPI and amoxicillin for 5 days, followed by the PPI, clarithromycin, and tinidazole for an additional 5 days (FIGURE).⁴ (Because tinidazole is a relatively new drug in the United States and physicians may use other drugs in its class instead, we refer to the drug class—imidazoles—rather than a specific medication in the FIGURE and much of the text that follows.) Using amoxicillin before the other antibiotics weakens bacterial cell walls, preventing the formation of drug efflux channels that can inhibit clarithromycin and other antibiotics, according to 1 theory.¹ Thus, clarithromycin and an imidazole are more effective in the second phase of treatment.¹

Should US physicians adopt the Italian protocol and prescribe tinidazole? Would metronidazole or other imidazoles be equally effective?

FIGURE
Sequential vs standard therapy: A comparison

STUDY SUMMARY: Sequential therapy is better on all counts

This meta-analysis found 9 randomized controlled trials (RCTs) that compared H pylori eradication rates with standard 7- to 10-day triple-drug therapy to 10-day sequential therapy; an additional small study used a 5-day triple-drug comparison group. The authors performed a thorough search and used standard meta-analysis methods for data synthesis and analysis. The patients were all H pylori treatment naïve and had not used PPIs, histamine-2 receptor antagonists, or antibiotics in the month preceding the study. All patients (n=2747) had documented H pylori infection based on fecal antigen test, histologic evaluation, biopsy urease test, or urea breath test.

All the trials were conducted in Italy, although 2 of the studies included patients from the United States. Nine RCTs compared a triple-therapy regimen with PPI to sequential therapy, 1 RCT compared a triple-drug regimen with ranitidine to sequential therapy, and 1 included only pediatric patients. Pooled eradication rates were 93.4% (95% confidence interval [CI,] 91.3%-95.5%) for sequential therapy and 76.9% (CI, 71.0%-82.8%) for standard therapy, with a relative risk reduction of 71% (CI, 64%-77%).¹ The authors estimated that for every 6.3 patients (95% CI, 5.2-7.1) treated with sequential therapy, there would be 1 additional cure compared to standard therapy. Standard 7- to 10-day triple therapy remained inferior to sequential therapy in all subgroup analyses, including patients with risk factors for eradication failure.

Adherence rates were similar in both groups. Sequential therapy resulted in a median adherence rate of 97.4% (range, 90.0%-98.9%), with standard therapy at 96.8% (range, 93.0%-100%).¹ Reported side effects were also similar in both treatment groups.¹

WHAT’S NEW?: This meta-analysis reduces doubt

The latest American College of Gastroenterology guidelines on the management of H pylori infection acknowledge that sequential therapy has shown promise in Europe, but the organization has not supported a change from the standard regimen to sequential therapy as first-line treatment. The standard triple-therapy regimen is approved by the US Food and Drug Administration, and is the most commonly used H pylori treatment in the United States.¹ This is the first meta-analysis based solely on RCTs, and it clearly demonstrates that sequential therapy increased eradication rates.

PATIENT HANDOUT: How to take your medicine for H pylori infection

Helicobacter pylori (called H pylori for short) is a type of bacteria that can cause an ulcer (sore) to develop within the lining of your stomach and intestines. Ulcers can cause pain and bleeding, so it is important to get rid of this bacteria. To do this, you will need to take 4 different medicines over the next 10 days. They must be taken in a certain order, exactly as your doctor has prescribed.

One of the drugs you will be taking (for the entire 10-day period) is a proton pump inhibitor (called a PPI), a medicine that helps reduce the amount of acid in your stomach. ______________ is the name of the PPI your doctor has ordered. Take it twice a day, once in the morning and once in the evening, for 10 days.

You will also take 3 different kinds of antibiotics to eliminate the H pylori bacteria. For the first 5 days, you will take amoxicillin twice a day (2 pills in the morning and 2 in the evening), along with the PPI.

After 5 days, all the amoxicillin pills should be gone, and you will switch to 2 other antibiotics: clarithromycin AND ______________. For the next 5 days, you will take 1 PPI plus 1 clarithromycin and 1 ______________ every morning AND every night.

These medications may cause nausea, diarrhea, and a bad taste in your mouth. These side effects are usually not serious, but if they bother you so much that you cannot continue to take the medicine, it is important to call our office right away.

To remember to take each of the medicines in the morning AND evening on the correct day, use this chart to follow along. Put a check mark in the morning box or the evening box every time you take your medicine.

 

 

 

CAVEATS: Drug resistance, previous Tx could skew results

This meta-analysis only included studies performed in Italy, although 2 of the trials did include US recruits. Drug resistance patterns may be different in this country, which could alter sequential therapy’s eradication rates.

Because 3 antibiotics are used in sequential therapy, we may have fewer remaining options for patients who do not respond to this regimen, and we do not have information about patients with previous treatment failures. In addition, this meta-analysis only evaluated H pylori eradication rates in treatment-naïve patients, so we have no information about the effectiveness of this regimen in patients with previous treatment failures.

Would other sequential regimens—or drugs—work?

Patients who are allergic to amoxicillin would not be candidates for this sequential therapy protocol. While sequential therapy was compared with 7- to 10-day standard triple therapy, this study did not compare it with other regimens—eg, quadruple therapy or a 14-day course of standard triple-drug therapy.

Other drugs may also affect outcomes. The sequential therapy studies all used tinidazole, a relatively new agent in the United States; we don’t know whether metronidazole or other imidazoles are as effective.

The authors of this meta-analysis also noted the possibility of publication bias, but we doubt that there are enough unpublished data to invalidate the findings. Also, the selected RCTs only addressed eradication rates and not patient-oriented outcomes. However, most patient-oriented outcomes, including cancer and ulcers, can take years, even decades, to develop.

CHALLENGES TO IMPLEMENTATION: Sequential therapy may be confusing

While adherence rates were similar in the standard and sequential treatment groups in the meta-analysis, sequential therapy—which requires switching medications midway through treatment—might be more confusing for patients in actual practice. This has the potential to negatively affect adherence to the sequential regimen.

It will be important for physicians who prescribe sequential therapy to counsel patients on the importance of completing the treatment regimen exactly as prescribed and to provide clear instructions for doing so, ideally in the form of a patient handout like the one on page 653. Cost is not a problem; the price of sequential therapy is about equal to, or possibly less than, that of standard therapy.⁵

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 40-year-old woman with a peptic ulcer has been diagnosed with Helicobacter pylori infection, and schedules a visit to discuss treatment. You’re aware of the declining eradication rates associated with standard therapy, and have heard that sequential therapy may be a more effective option. Should you offer it to this patient?

An estimated 30% to 40% of the US population is infected with H pylori,² a bacterium that plays a crucial role in the pathogenesis of peptic ulcer disease, chronic gastritis, and gastric cancer.¹ The triple-drug regimen (a proton-pump inhibitor [PPI] and clarithromycin with amoxicillin, tinidazole, or another imidazole) is commonly used to treat H pylori in Europe and in the United States.³ Yet the eradication rate associated with this standard 3-drug regimen in this country is <80%, and appears to be on the decline. The likely problem: the increase in antibiotic-resistant strains of H pylori.²

Put amoxicillin first

In Italy, eradication rates of >90% have been reported with a sequential therapy: a PPI and amoxicillin for 5 days, followed by the PPI, clarithromycin, and tinidazole for an additional 5 days (FIGURE).⁴ (Because tinidazole is a relatively new drug in the United States and physicians may use other drugs in its class instead, we refer to the drug class—imidazoles—rather than a specific medication in the FIGURE and much of the text that follows.) Using amoxicillin before the other antibiotics weakens bacterial cell walls, preventing the formation of drug efflux channels that can inhibit clarithromycin and other antibiotics, according to 1 theory.¹ Thus, clarithromycin and an imidazole are more effective in the second phase of treatment.¹

Should US physicians adopt the Italian protocol and prescribe tinidazole? Would metronidazole or other imidazoles be equally effective?

FIGURE
Sequential vs standard therapy: A comparison

STUDY SUMMARY: Sequential therapy is better on all counts

This meta-analysis found 9 randomized controlled trials (RCTs) that compared H pylori eradication rates with standard 7- to 10-day triple-drug therapy to 10-day sequential therapy; an additional small study used a 5-day triple-drug comparison group. The authors performed a thorough search and used standard meta-analysis methods for data synthesis and analysis. The patients were all H pylori treatment naïve and had not used PPIs, histamine-2 receptor antagonists, or antibiotics in the month preceding the study. All patients (n=2747) had documented H pylori infection based on fecal antigen test, histologic evaluation, biopsy urease test, or urea breath test.

All the trials were conducted in Italy, although 2 of the studies included patients from the United States. Nine RCTs compared a triple-therapy regimen with PPI to sequential therapy, 1 RCT compared a triple-drug regimen with ranitidine to sequential therapy, and 1 included only pediatric patients. Pooled eradication rates were 93.4% (95% confidence interval [CI,] 91.3%-95.5%) for sequential therapy and 76.9% (CI, 71.0%-82.8%) for standard therapy, with a relative risk reduction of 71% (CI, 64%-77%).¹ The authors estimated that for every 6.3 patients (95% CI, 5.2-7.1) treated with sequential therapy, there would be 1 additional cure compared to standard therapy. Standard 7- to 10-day triple therapy remained inferior to sequential therapy in all subgroup analyses, including patients with risk factors for eradication failure.

Adherence rates were similar in both groups. Sequential therapy resulted in a median adherence rate of 97.4% (range, 90.0%-98.9%), with standard therapy at 96.8% (range, 93.0%-100%).¹ Reported side effects were also similar in both treatment groups.¹

WHAT’S NEW?: This meta-analysis reduces doubt

The latest American College of Gastroenterology guidelines on the management of H pylori infection acknowledge that sequential therapy has shown promise in Europe, but the organization has not supported a change from the standard regimen to sequential therapy as first-line treatment. The standard triple-therapy regimen is approved by the US Food and Drug Administration, and is the most commonly used H pylori treatment in the United States.¹ This is the first meta-analysis based solely on RCTs, and it clearly demonstrates that sequential therapy increased eradication rates.

PATIENT HANDOUT: How to take your medicine for H pylori infection

Helicobacter pylori (called H pylori for short) is a type of bacteria that can cause an ulcer (sore) to develop within the lining of your stomach and intestines. Ulcers can cause pain and bleeding, so it is important to get rid of this bacteria. To do this, you will need to take 4 different medicines over the next 10 days. They must be taken in a certain order, exactly as your doctor has prescribed.

One of the drugs you will be taking (for the entire 10-day period) is a proton pump inhibitor (called a PPI), a medicine that helps reduce the amount of acid in your stomach. ______________ is the name of the PPI your doctor has ordered. Take it twice a day, once in the morning and once in the evening, for 10 days.

You will also take 3 different kinds of antibiotics to eliminate the H pylori bacteria. For the first 5 days, you will take amoxicillin twice a day (2 pills in the morning and 2 in the evening), along with the PPI.

After 5 days, all the amoxicillin pills should be gone, and you will switch to 2 other antibiotics: clarithromycin AND ______________. For the next 5 days, you will take 1 PPI plus 1 clarithromycin and 1 ______________ every morning AND every night.

These medications may cause nausea, diarrhea, and a bad taste in your mouth. These side effects are usually not serious, but if they bother you so much that you cannot continue to take the medicine, it is important to call our office right away.

To remember to take each of the medicines in the morning AND evening on the correct day, use this chart to follow along. Put a check mark in the morning box or the evening box every time you take your medicine.

 

 

 

CAVEATS: Drug resistance, previous Tx could skew results

This meta-analysis only included studies performed in Italy, although 2 of the trials did include US recruits. Drug resistance patterns may be different in this country, which could alter sequential therapy’s eradication rates.

Because 3 antibiotics are used in sequential therapy, we may have fewer remaining options for patients who do not respond to this regimen, and we do not have information about patients with previous treatment failures. In addition, this meta-analysis only evaluated H pylori eradication rates in treatment-naïve patients, so we have no information about the effectiveness of this regimen in patients with previous treatment failures.

Would other sequential regimens—or drugs—work?

Patients who are allergic to amoxicillin would not be candidates for this sequential therapy protocol. While sequential therapy was compared with 7- to 10-day standard triple therapy, this study did not compare it with other regimens—eg, quadruple therapy or a 14-day course of standard triple-drug therapy.

Other drugs may also affect outcomes. The sequential therapy studies all used tinidazole, a relatively new agent in the United States; we don’t know whether metronidazole or other imidazoles are as effective.

The authors of this meta-analysis also noted the possibility of publication bias, but we doubt that there are enough unpublished data to invalidate the findings. Also, the selected RCTs only addressed eradication rates and not patient-oriented outcomes. However, most patient-oriented outcomes, including cancer and ulcers, can take years, even decades, to develop.

CHALLENGES TO IMPLEMENTATION: Sequential therapy may be confusing

While adherence rates were similar in the standard and sequential treatment groups in the meta-analysis, sequential therapy—which requires switching medications midway through treatment—might be more confusing for patients in actual practice. This has the potential to negatively affect adherence to the sequential regimen.

It will be important for physicians who prescribe sequential therapy to counsel patients on the importance of completing the treatment regimen exactly as prescribed and to provide clear instructions for doing so, ideally in the form of a patient handout like the one on page 653. Cost is not a problem; the price of sequential therapy is about equal to, or possibly less than, that of standard therapy.⁵

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Lack of evidence for weight loss drugs

The most recent guideline on this topic does not recommend any medication, citing a lack of evidence. In its 2003 consensus statement, a panel representing the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity³ recommends:

• That patients taking second-generation antipsychotics have the following assessments at baseline and regular intervals: weight, height, waist circumference, blood pressure, fasting plasma glucose, and fasting lipids.
• Providing nutrition and exercise counseling to all patients who are over-weight or obese at baseline.
• Initiating treatment with one of the second-generation antipsychotics with a lower risk of weight gain for patients at high risk of diabetes (ie, family history) and for patients who gain 5% or more of their initial weight or develop worsening hyperglycemia or dyslipidemia during treatment.

This guideline does not recommend metformin to reduce weight gain.

A 2007 Cochrane review of interventions to reduce weight gain in patients with schizophrenia included 23 randomized controlled trials of a variety of weight loss interventions, including cognitive/behavioral interventions and a variety of medications, including sibutramine, orlistat, fluoxetine, topiramate, and metformin. The authors highlighted the limited number of studies of short duration and with small sample sizes and concluded that the evidence was insufficient for the use of pharmacologic interventions to prevent or treat weight gain.⁵

STUDY SUMMARY: Lifestyle changes and metformin compared

This randomized controlled trial was conducted in China and included 128 adults aged 18 to 45 with a first psychotic episode of schizophrenia. All patients had to have gained more than 10% of their pretreatment body weight during the first year of treatment with an antipsychotic medication (clozapine, olanzapine, risperidone, or sulpiride [not approved for use in the United States]). All study participants had to be under the care of an adult caregiver who monitored and recorded food intake, exercise, and medication intake. Patients with diabetes, cardiovascular disease, liver or renal dysfunction, substance abuse, or psychiatric diagnoses other than schizophrenia were excluded.

Patients were randomized to 1 of 4 groups for the 12 weeks of the study:

• Metformin alone, 250 mg 3 times daily
• Placebo alone
• Lifestyle intervention plus metformin
• Lifestyle intervention plus placebo

The lifestyle intervention included 3 components: (1) education: monthly programs on nutrition and physical activity; (2) diet: the American Heart Association step 2 diet (<30% calories from fat, 55% carbohydrates, >15% protein, with at least 15 g fiber per 1000 kcal); and (3) exercise: 1 week of sessions with an exercise physiologist followed by an individualized home-based exercise program.

Primary outcomes included changes in weight, body mass index (BMI), waist circumference, and fasting glucose ( TABLE 2 ). Ten of the 128 randomized patients either discontinued the study or were lost to follow up, but all 128 patients were included in the analysis.

TABLE 2
Mean difference between baseline and endpoint (week 12) of treatment outcomes (95% confidence intervals)¹

Best result: Lifestyle changes plus metformin

Compared with baseline, weight decreased by 7.3% in the lifestyle plus metformin group, by 4.9% in the metformin-only group, and by 2.2% in the lifestyle-only group; in the placebo group, weight increased by 4.8%.

Participants in all 3 intervention groups also showed significant decreases in the mean fasting glucose, insulin levels, and insulin resistance index (IRI). The insulin levels and the IRI increased in the placebo group.

No significant differences in adverse effects were noted among the 4 treatment groups.¹

WHAT’S NEW: Convincing evidence

This is the first randomized controlled trial to show convincingly that metformin alone or in combination with lifestyle changes is superior to lifestyle changes alone or placebo for reducing weight gain and other adverse metabolic outcomes induced by second-generation antipsychotics.

Intensive lifestyle interventions

Prior studies found that intensive lifestyle interventions can help reduce antipsychotic-related weight gain. A 3-month randomized controlled trial compared an early behavioral intervention (dietary counseling, an exercise program, and behavior therapy) with routine care in 61 patients with first-episode psychosis who were taking risperidone, olanzapine, or haloperidol;⁶ significantly fewer patients assigned to behavioral intervention had an increased initial body weight of more than 7%: 39% in the behavioral intervention group vs 79% in the routine care group (P<.002).

Small samples, small effect sizes

Past studies of metformin for antipsychotic-associated weight gain have generally shown a small benefit, though small sample sizes and small effect sizes prohibited definitive conclusions. Unlike the study by Wu and colleagues,¹ none of these past studies were designed to compare the combination of metformin and lifestyle intervention with metformin alone, lifestyle intervention alone, or placebo alone.

Klein et al conducted a randomized placebo-controlled trial of metformin in 39 children ages 10 to 17 whose weight had increased more than 10% on atypical antipsychotic therapy.⁷ The children treated with placebo gained a mean of 4 kg and increased their mean BMI by 1.12 kg/m² during 16 weeks of treatment, while those in the metformin group did not gain weight and decreased their mean BMI by 0.43 kg/m².

Baptista et al randomized 40 in-patients with schizophrenia, who were being switched from conventional antipsychotics to olanzapine, to either metformin (850-1750 mg/d) or placebo. Both groups gained a similar amount of weight after the 14-week study (5.5 vs 6.3 kg, metformin vs placebo). Three patients who started with high fasting glucose had decreases while taking metformin, and 3 patients given placebo developed elevated fasting glucose during the study.⁸

In another randomized controlled trial of metformin vs placebo in 80 patients who had been taking olanzapine for at least 4 months, Baptista et al found only a small, insignificant difference in weight loss after 12 weeks of treatment (metformin group lost 1.4 kg, placebo group lost 0.18 kg, P=.09). They reported that both groups were highly motivated to lose weight and were compliant with the healthy lifestyle recommendations.⁹

An adequately powered study

The trial¹ highlighted in this PURL had an adequate sample size to compare metformin plus a lifestyle intervention with either treatment alone or placebo. It showed a clinically important effect of metformin both by itself and in conjunction with the lifestyle intervention.

CAVEATS: Consider switching drugs

Before adding metformin to help with weight loss, primary care clinicians should contact the patient’s psychiatrist to discuss the option of switching antipsychotic medications. Switching from a medication with a higher risk for weight gain, such as olanzapine, to one with a lower risk, such as aripiprazole or ziprasidone, can lead to significant weight loss.¹⁰

Not an option for some

However, some patients, especially those taking clozapine, may have already tried multiple antipsychotic agents without success, and switching is not an option for them.

Prescribing metformin

CHALLENGES TO IMPLEMENTATION: Adherence

These study participants were under the care of an adult caregiver who monitored and recorded food and medication intake and exercise level. The lifestyle intervention was thorough and structured and this kind of program is often not available to us for our patients. As a consequence, we may not obtain the same results as in this study. However, even the metformin-alone group showed improvements, and if our patients can reliably take their second-generation antipsychotic, they should also be able to take metformin reliably.

Patient resistance

Some patients may resist taking an additional medication to treat the side effects of their antipsychotic medication. Taking the time to educate them about the increased risk of diabetes and cardiovascular disease related to weight gain may help convince them to do so. Warn them about possible gastrointestinal adverse effects of metformin, which tend to lessen or disappear with time.

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Lack of evidence for weight loss drugs

The most recent guideline on this topic does not recommend any medication, citing a lack of evidence. In its 2003 consensus statement, a panel representing the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity³ recommends:

• That patients taking second-generation antipsychotics have the following assessments at baseline and regular intervals: weight, height, waist circumference, blood pressure, fasting plasma glucose, and fasting lipids.
• Providing nutrition and exercise counseling to all patients who are over-weight or obese at baseline.
• Initiating treatment with one of the second-generation antipsychotics with a lower risk of weight gain for patients at high risk of diabetes (ie, family history) and for patients who gain 5% or more of their initial weight or develop worsening hyperglycemia or dyslipidemia during treatment.

This guideline does not recommend metformin to reduce weight gain.

A 2007 Cochrane review of interventions to reduce weight gain in patients with schizophrenia included 23 randomized controlled trials of a variety of weight loss interventions, including cognitive/behavioral interventions and a variety of medications, including sibutramine, orlistat, fluoxetine, topiramate, and metformin. The authors highlighted the limited number of studies of short duration and with small sample sizes and concluded that the evidence was insufficient for the use of pharmacologic interventions to prevent or treat weight gain.⁵

STUDY SUMMARY: Lifestyle changes and metformin compared

This randomized controlled trial was conducted in China and included 128 adults aged 18 to 45 with a first psychotic episode of schizophrenia. All patients had to have gained more than 10% of their pretreatment body weight during the first year of treatment with an antipsychotic medication (clozapine, olanzapine, risperidone, or sulpiride [not approved for use in the United States]). All study participants had to be under the care of an adult caregiver who monitored and recorded food intake, exercise, and medication intake. Patients with diabetes, cardiovascular disease, liver or renal dysfunction, substance abuse, or psychiatric diagnoses other than schizophrenia were excluded.

Patients were randomized to 1 of 4 groups for the 12 weeks of the study:

• Metformin alone, 250 mg 3 times daily
• Placebo alone
• Lifestyle intervention plus metformin
• Lifestyle intervention plus placebo

The lifestyle intervention included 3 components: (1) education: monthly programs on nutrition and physical activity; (2) diet: the American Heart Association step 2 diet (<30% calories from fat, 55% carbohydrates, >15% protein, with at least 15 g fiber per 1000 kcal); and (3) exercise: 1 week of sessions with an exercise physiologist followed by an individualized home-based exercise program.

Primary outcomes included changes in weight, body mass index (BMI), waist circumference, and fasting glucose ( TABLE 2 ). Ten of the 128 randomized patients either discontinued the study or were lost to follow up, but all 128 patients were included in the analysis.

TABLE 2
Mean difference between baseline and endpoint (week 12) of treatment outcomes (95% confidence intervals)¹

Best result: Lifestyle changes plus metformin

Compared with baseline, weight decreased by 7.3% in the lifestyle plus metformin group, by 4.9% in the metformin-only group, and by 2.2% in the lifestyle-only group; in the placebo group, weight increased by 4.8%.

Participants in all 3 intervention groups also showed significant decreases in the mean fasting glucose, insulin levels, and insulin resistance index (IRI). The insulin levels and the IRI increased in the placebo group.

No significant differences in adverse effects were noted among the 4 treatment groups.¹

WHAT’S NEW: Convincing evidence

This is the first randomized controlled trial to show convincingly that metformin alone or in combination with lifestyle changes is superior to lifestyle changes alone or placebo for reducing weight gain and other adverse metabolic outcomes induced by second-generation antipsychotics.

Intensive lifestyle interventions

Prior studies found that intensive lifestyle interventions can help reduce antipsychotic-related weight gain. A 3-month randomized controlled trial compared an early behavioral intervention (dietary counseling, an exercise program, and behavior therapy) with routine care in 61 patients with first-episode psychosis who were taking risperidone, olanzapine, or haloperidol;⁶ significantly fewer patients assigned to behavioral intervention had an increased initial body weight of more than 7%: 39% in the behavioral intervention group vs 79% in the routine care group (P<.002).

Small samples, small effect sizes

Past studies of metformin for antipsychotic-associated weight gain have generally shown a small benefit, though small sample sizes and small effect sizes prohibited definitive conclusions. Unlike the study by Wu and colleagues,¹ none of these past studies were designed to compare the combination of metformin and lifestyle intervention with metformin alone, lifestyle intervention alone, or placebo alone.

Klein et al conducted a randomized placebo-controlled trial of metformin in 39 children ages 10 to 17 whose weight had increased more than 10% on atypical antipsychotic therapy.⁷ The children treated with placebo gained a mean of 4 kg and increased their mean BMI by 1.12 kg/m² during 16 weeks of treatment, while those in the metformin group did not gain weight and decreased their mean BMI by 0.43 kg/m².

Baptista et al randomized 40 in-patients with schizophrenia, who were being switched from conventional antipsychotics to olanzapine, to either metformin (850-1750 mg/d) or placebo. Both groups gained a similar amount of weight after the 14-week study (5.5 vs 6.3 kg, metformin vs placebo). Three patients who started with high fasting glucose had decreases while taking metformin, and 3 patients given placebo developed elevated fasting glucose during the study.⁸

In another randomized controlled trial of metformin vs placebo in 80 patients who had been taking olanzapine for at least 4 months, Baptista et al found only a small, insignificant difference in weight loss after 12 weeks of treatment (metformin group lost 1.4 kg, placebo group lost 0.18 kg, P=.09). They reported that both groups were highly motivated to lose weight and were compliant with the healthy lifestyle recommendations.⁹

An adequately powered study

The trial¹ highlighted in this PURL had an adequate sample size to compare metformin plus a lifestyle intervention with either treatment alone or placebo. It showed a clinically important effect of metformin both by itself and in conjunction with the lifestyle intervention.

CAVEATS: Consider switching drugs

Before adding metformin to help with weight loss, primary care clinicians should contact the patient’s psychiatrist to discuss the option of switching antipsychotic medications. Switching from a medication with a higher risk for weight gain, such as olanzapine, to one with a lower risk, such as aripiprazole or ziprasidone, can lead to significant weight loss.¹⁰

Not an option for some

However, some patients, especially those taking clozapine, may have already tried multiple antipsychotic agents without success, and switching is not an option for them.

Prescribing metformin

CHALLENGES TO IMPLEMENTATION: Adherence

These study participants were under the care of an adult caregiver who monitored and recorded food and medication intake and exercise level. The lifestyle intervention was thorough and structured and this kind of program is often not available to us for our patients. As a consequence, we may not obtain the same results as in this study. However, even the metformin-alone group showed improvements, and if our patients can reliably take their second-generation antipsychotic, they should also be able to take metformin reliably.

Patient resistance

Some patients may resist taking an additional medication to treat the side effects of their antipsychotic medication. Taking the time to educate them about the increased risk of diabetes and cardiovascular disease related to weight gain may help convince them to do so. Warn them about possible gastrointestinal adverse effects of metformin, which tend to lessen or disappear with time.

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Lack of evidence for weight loss drugs

The most recent guideline on this topic does not recommend any medication, citing a lack of evidence. In its 2003 consensus statement, a panel representing the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity³ recommends:

• That patients taking second-generation antipsychotics have the following assessments at baseline and regular intervals: weight, height, waist circumference, blood pressure, fasting plasma glucose, and fasting lipids.
• Providing nutrition and exercise counseling to all patients who are over-weight or obese at baseline.
• Initiating treatment with one of the second-generation antipsychotics with a lower risk of weight gain for patients at high risk of diabetes (ie, family history) and for patients who gain 5% or more of their initial weight or develop worsening hyperglycemia or dyslipidemia during treatment.

This guideline does not recommend metformin to reduce weight gain.

A 2007 Cochrane review of interventions to reduce weight gain in patients with schizophrenia included 23 randomized controlled trials of a variety of weight loss interventions, including cognitive/behavioral interventions and a variety of medications, including sibutramine, orlistat, fluoxetine, topiramate, and metformin. The authors highlighted the limited number of studies of short duration and with small sample sizes and concluded that the evidence was insufficient for the use of pharmacologic interventions to prevent or treat weight gain.⁵

STUDY SUMMARY: Lifestyle changes and metformin compared

This randomized controlled trial was conducted in China and included 128 adults aged 18 to 45 with a first psychotic episode of schizophrenia. All patients had to have gained more than 10% of their pretreatment body weight during the first year of treatment with an antipsychotic medication (clozapine, olanzapine, risperidone, or sulpiride [not approved for use in the United States]). All study participants had to be under the care of an adult caregiver who monitored and recorded food intake, exercise, and medication intake. Patients with diabetes, cardiovascular disease, liver or renal dysfunction, substance abuse, or psychiatric diagnoses other than schizophrenia were excluded.

Patients were randomized to 1 of 4 groups for the 12 weeks of the study:

• Metformin alone, 250 mg 3 times daily
• Placebo alone
• Lifestyle intervention plus metformin
• Lifestyle intervention plus placebo

The lifestyle intervention included 3 components: (1) education: monthly programs on nutrition and physical activity; (2) diet: the American Heart Association step 2 diet (<30% calories from fat, 55% carbohydrates, >15% protein, with at least 15 g fiber per 1000 kcal); and (3) exercise: 1 week of sessions with an exercise physiologist followed by an individualized home-based exercise program.

Primary outcomes included changes in weight, body mass index (BMI), waist circumference, and fasting glucose ( TABLE 2 ). Ten of the 128 randomized patients either discontinued the study or were lost to follow up, but all 128 patients were included in the analysis.

TABLE 2
Mean difference between baseline and endpoint (week 12) of treatment outcomes (95% confidence intervals)¹

Best result: Lifestyle changes plus metformin

Compared with baseline, weight decreased by 7.3% in the lifestyle plus metformin group, by 4.9% in the metformin-only group, and by 2.2% in the lifestyle-only group; in the placebo group, weight increased by 4.8%.

Participants in all 3 intervention groups also showed significant decreases in the mean fasting glucose, insulin levels, and insulin resistance index (IRI). The insulin levels and the IRI increased in the placebo group.

No significant differences in adverse effects were noted among the 4 treatment groups.¹

WHAT’S NEW: Convincing evidence

This is the first randomized controlled trial to show convincingly that metformin alone or in combination with lifestyle changes is superior to lifestyle changes alone or placebo for reducing weight gain and other adverse metabolic outcomes induced by second-generation antipsychotics.

Intensive lifestyle interventions

Prior studies found that intensive lifestyle interventions can help reduce antipsychotic-related weight gain. A 3-month randomized controlled trial compared an early behavioral intervention (dietary counseling, an exercise program, and behavior therapy) with routine care in 61 patients with first-episode psychosis who were taking risperidone, olanzapine, or haloperidol;⁶ significantly fewer patients assigned to behavioral intervention had an increased initial body weight of more than 7%: 39% in the behavioral intervention group vs 79% in the routine care group (P<.002).

Small samples, small effect sizes

Past studies of metformin for antipsychotic-associated weight gain have generally shown a small benefit, though small sample sizes and small effect sizes prohibited definitive conclusions. Unlike the study by Wu and colleagues,¹ none of these past studies were designed to compare the combination of metformin and lifestyle intervention with metformin alone, lifestyle intervention alone, or placebo alone.

Klein et al conducted a randomized placebo-controlled trial of metformin in 39 children ages 10 to 17 whose weight had increased more than 10% on atypical antipsychotic therapy.⁷ The children treated with placebo gained a mean of 4 kg and increased their mean BMI by 1.12 kg/m² during 16 weeks of treatment, while those in the metformin group did not gain weight and decreased their mean BMI by 0.43 kg/m².

Baptista et al randomized 40 in-patients with schizophrenia, who were being switched from conventional antipsychotics to olanzapine, to either metformin (850-1750 mg/d) or placebo. Both groups gained a similar amount of weight after the 14-week study (5.5 vs 6.3 kg, metformin vs placebo). Three patients who started with high fasting glucose had decreases while taking metformin, and 3 patients given placebo developed elevated fasting glucose during the study.⁸

In another randomized controlled trial of metformin vs placebo in 80 patients who had been taking olanzapine for at least 4 months, Baptista et al found only a small, insignificant difference in weight loss after 12 weeks of treatment (metformin group lost 1.4 kg, placebo group lost 0.18 kg, P=.09). They reported that both groups were highly motivated to lose weight and were compliant with the healthy lifestyle recommendations.⁹

An adequately powered study

The trial¹ highlighted in this PURL had an adequate sample size to compare metformin plus a lifestyle intervention with either treatment alone or placebo. It showed a clinically important effect of metformin both by itself and in conjunction with the lifestyle intervention.

CAVEATS: Consider switching drugs

Before adding metformin to help with weight loss, primary care clinicians should contact the patient’s psychiatrist to discuss the option of switching antipsychotic medications. Switching from a medication with a higher risk for weight gain, such as olanzapine, to one with a lower risk, such as aripiprazole or ziprasidone, can lead to significant weight loss.¹⁰

Not an option for some

However, some patients, especially those taking clozapine, may have already tried multiple antipsychotic agents without success, and switching is not an option for them.

Prescribing metformin

CHALLENGES TO IMPLEMENTATION: Adherence

These study participants were under the care of an adult caregiver who monitored and recorded food and medication intake and exercise level. The lifestyle intervention was thorough and structured and this kind of program is often not available to us for our patients. As a consequence, we may not obtain the same results as in this study. However, even the metformin-alone group showed improvements, and if our patients can reliably take their second-generation antipsychotic, they should also be able to take metformin reliably.

Patient resistance

Some patients may resist taking an additional medication to treat the side effects of their antipsychotic medication. Taking the time to educate them about the increased risk of diabetes and cardiovascular disease related to weight gain may help convince them to do so. Warn them about possible gastrointestinal adverse effects of metformin, which tend to lessen or disappear with time.

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 23-year-old woman presents to your office with a 1-week history of cough, purulent nasal discharge, and unilateral facial pain. You diagnose acute sinusitis.

Should you prescribe an antibiotic?

No. Yet it’s no wonder that most adults treated for acute sinusitis leave the doctor’s office with a prescription for antibiotics. Until the publication of the meta-analysis by Young and colleagues¹ featured in this PURL, we have lacked A-level evidence from studies conducted in realistic settings—like your practice and ours.

Review of serial data from the National Ambulatory Medical Care Surveys (NAMCS) from 1999 through 2005 does show a slight downward trend in antibiotic prescribing for acute sinusitis: 1999-2002 data showed that 83% of cases of acute sinusitis were treated with an antibiotic.² Data from the 2004 and 2005 NAMCS reveal that family physicians prescribed antibiotics for 80% of patients with acute sinusitis in 2004 and 76% of patients in 2005 (S. Medvedev, unpublished data, NAMCS database, March 2008).

Is this continued high rate of antibiotic prescribing justified?

Do antibiotics improve symptoms and shorten the duration of illness or not?

These questions are important, obviously, not only because of the high rate of prescribing but also because sinusitis is one of the most common diagnoses: approximately 20 million cases annually in the United States, or about 21% of all outpatient antibiotic prescriptions for adults.²

Which patients might benefit from antibiotics?

Common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom treatment is clearly justified, given the cost, adverse events, and bacterial resistance associated with antibiotic use

• Severity of symptoms is important only in that signs suggestive of a serious complication are the sole reason for immediate antibiotic treatment
• Purulent discharge noted in the pharynx on exam was associated with a higher likelihood of benefit from antibiotics, but NNT was 8
• Antibiotics are not justified even if a patient reports having symptoms for longer than 7-10 days

Source: Young et al.¹

A diagnostic dilemma

Before we discuss the evidence that is summarized in the excellent meta-analysis by Young and colleagues,¹ let’s acknowledge that acute sinusitis is undeniably a diagnostic dilemma. Distinguishing bacterial from viral infection is nearly impossible on clinical grounds because the symptoms are so similar. A litany of identical upper respiratory symptoms accompanies both viral and bacterial sinus infections. Purulent nasal secretions, maxillary facial pain (especially with unilateral predominance), maxillary tooth pain (which is uncommon with sinus infection), altered sense of smell, and worsening illness after improvement constitute the short list of signs and symptoms that has some predictive value, but even the presence of all of these is not a terrific predictor of bacterial sinus infection. Plain x-rays have low accuracy in distinguishing viral from bacterial infection. Computed tomography (CT) sinus scans are better but far from perfect, are not readily available in practice, and are expensive.

Sinusitis in the real world

How effective are antibiotics for patients diagnosed not by sinus x-rays or CTs, but by signs and symptoms—as we typically do in daily practice?

A meta-analysis³ of 13 randomized controlled trials (RCTs) found that sinusitis improved without antibiotics, but it included trials in which patients were recruited based on results of imaging studies and cultures, which are not normally used in primary care clinical practice. That study compared antibiotic treatment to placebo for acute uncomplicated sinusitis; 35% of placebo-treated patients were clinically cured by 7 to 12 days and 73% were improved after 7 days. Antibiotic therapy increased cure rates by 15% and improvement rates by 14%, yielding a number needed to treat of 7 to achieve 1 additional positive outcome at 7 days.

STUDY SUMMARY: Meta-analysis of primary care trials

Young and colleagues¹ aggregated and analyzed individual patient-level data from all known placebo-controlled, randomized, antibiotic treatment trials of adults with clinical symptoms of acute sinusitis that were conducted in primary care settings. They excluded trials that used imaging or bacterial culture as part of patient recruitment.

Studies were included that allowed the use of concomitant medication such as nonsteroidal anti-inflammatory drugs, decongestants, or nasal steroids, as long as patients in both groups had access to the same medications. All trials excluded patients with severe symptoms such as high fever, periorbital swelling or erythema, or intense facial pain, important exclusions that we will discuss below.

They identified 10 such studies and completed an intent-to-treat analysis of the 9 double-blind trials for which patient level data were available. Using individual data from 2547 patients, the odds ratio for an overall antibiotic treatment effect was 1.37 (95% confidence interval, 1.13-1.66), with a number needed to treat (NNT) of 15.

This finding means that 15 patients needed to be given an antibiotic for 1 additional patient to be cured at 8 to 15 days after treatment commenced. Using statistical modeling, they determined that 64% of patients treated with placebo were cured at 14 days compared with 70% given an antibiotic. One patient out of 1381 treated with placebo experienced a serious complication, a brain abscess.

Do antibiotics benefit any subgroups?

The investigators also analyzed the prognostic value of specific signs and symptoms to answer the question: Is there any subgroup of patients who might benefit more from antibiotic treatment?

Duration. Patients with a longer duration of symptoms, more severe symptoms, or increased age took longer to cure, but were no more likely to benefit from antibiotic treatment than other patients.

Symptoms, such as a previous common cold, pain on bending, unilateral facial pain, tooth pain, and purulent nasal discharge did not have any prognostic value.

Only one sign—purulent discharge noted in the pharynx on examination—was associated with a higher likelihood of benefit from treatment with antibiotics, but the NNT was still 8 in this group. Patients with symptoms for 7 days or longer were no more likely to respond to antibiotics than those with symptoms for fewer than 7 days.¹

WHAT’S NEW: Realistic evidence from realistic settings

We believe this meta-analysis provides a high level of evidence against routine treatment of sinusitis with antibiotics in primary care practice. Treating 15 patients with an antibiotic to possibly benefit 1 patient 2 weeks after treatment commences does not seem like a good idea when one considers the cost and complications of antibiotic use. Diarrhea and other adverse outcomes are 80% more common among patients with sinusitis who are treated with an antibiotic compared with placebo.³ As noted above, prior meta-analyses of antibiotic treatment for acute sinusitis have been more encouraging than this meta-analysis, with a number needed to treat of 7, but those meta-analyses are clearly overly optimistic for the results one will achieve in primary care practice using clinical signs and symptoms to diagnose acute sinusitis.^3,4 Unlike the Young study, they included trials in specialty clinics with CT scans and sinus puncture and culture used for the diagnostic standard.

Symptoms >1 week are not a reason to prescribe

One very important new finding in this meta-analysis that should change practice is that the duration of illness did not predict a positive response to antibiotics.

Current national recommendations are to use an antibiotic for patients with a duration of illness longer than 1 week, as these patients are presumably more likely to have a bacterial infection.^5-7 However, that recommendation had been based on expert opinion, not on data from clinical trials. A longer duration of symptoms should not be a reason to prescribe an antibiotic for sinusitis symptoms.

How can you help your patient?

What to do, then, for patients with acute sinusitis? Treat the symptoms, which means recommending pain medication for facial pain or headache and saline nasal spray for the nasal discharge, not antibiotics or nasal corticosteroids. Side effects will be fewer and costs will be lower.

• Saline irrigation. A 2007 Cochrane review of 8 chronic and recurrent sinusitis trials showed that nasal saline irrigation is effective for reducing symptoms of chronic and recurrent sinusitis.⁸ Although we do not have high-quality RCT data on saline nasal irrigation for treatment of acute sinusitis, nasal saline irrigation is harmless and inexpensive.
• What about nasal steroids? The evidence is equivocal, and the most recent high-quality RCT of nasal steroids showed no effect.⁹

CAVEATS: Refer seriously ill patients and complicated cases

A very important caveat to our recommendation is that seriously ill patients must be managed differently. Very infrequently a patient develops a serious complication of acute sinusitis such as brain abscess, periorbital cellulitis, or meningitis. Therefore, seriously ill patients with signs and symptoms of acute bacterial sinusitis, such as high fever, periorbital erythema or edema, severe headache, or intense facial pain must be carefully evaluated and treated with great caution and close follow-up. These patients should be referred immediately for consultation with an otolaryngologist.

Of course, mildly ill patients today may become quite ill tomorrow, so always provide advice to patients to return if they are getting worse, a good clinical practice for any condition that is usually benign but occasionally serious.

Patients who have prolonged or recurrent sinusitis symptoms need further evaluation for other diagnoses such as allergies, cystic fibrosis, fungal sinus infection, and other illnesses associated with immune compromise. These complicated patients benefit from consultation with an otolaryngologist who has a specific interest in chronic and recurrent sinusitis, and perhaps consultation from an infectious disease specialist as well.

CHALLENGES TO IMPLEMENTATION: The patient who wants a pill

Some patients may be accustomed to receiving an antibiotic prescription for their “sinus infections” and may resist conservative management. It may be difficult to convince them that antibiotics won’t make a difference when they attribute past resolution of symptoms to antibiotics.

Take enough time to educate your patients on the natural course of illness, the positive benefits of nasal saline, and the reasons not to use unnecessary antibiotics (eg, they are not effective, have potential adverse effects, and can contribute to future antibiotic resistance); this effort will save you time in future visits.¹⁰ A “just in case you don’t get better” prescription to be filled only if the patient is not improving in the next few days is about 50% effective in reducing antibiotic usage for upper respiratory infections.¹¹

Acknowledgement

We acknowledge Sofia Medvedev of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 23-year-old woman presents to your office with a 1-week history of cough, purulent nasal discharge, and unilateral facial pain. You diagnose acute sinusitis.

Should you prescribe an antibiotic?

No. Yet it’s no wonder that most adults treated for acute sinusitis leave the doctor’s office with a prescription for antibiotics. Until the publication of the meta-analysis by Young and colleagues¹ featured in this PURL, we have lacked A-level evidence from studies conducted in realistic settings—like your practice and ours.

Review of serial data from the National Ambulatory Medical Care Surveys (NAMCS) from 1999 through 2005 does show a slight downward trend in antibiotic prescribing for acute sinusitis: 1999-2002 data showed that 83% of cases of acute sinusitis were treated with an antibiotic.² Data from the 2004 and 2005 NAMCS reveal that family physicians prescribed antibiotics for 80% of patients with acute sinusitis in 2004 and 76% of patients in 2005 (S. Medvedev, unpublished data, NAMCS database, March 2008).

Is this continued high rate of antibiotic prescribing justified?

Do antibiotics improve symptoms and shorten the duration of illness or not?

These questions are important, obviously, not only because of the high rate of prescribing but also because sinusitis is one of the most common diagnoses: approximately 20 million cases annually in the United States, or about 21% of all outpatient antibiotic prescriptions for adults.²

Which patients might benefit from antibiotics?

Common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom treatment is clearly justified, given the cost, adverse events, and bacterial resistance associated with antibiotic use

• Severity of symptoms is important only in that signs suggestive of a serious complication are the sole reason for immediate antibiotic treatment
• Purulent discharge noted in the pharynx on exam was associated with a higher likelihood of benefit from antibiotics, but NNT was 8
• Antibiotics are not justified even if a patient reports having symptoms for longer than 7-10 days

Source: Young et al.¹

A diagnostic dilemma

Before we discuss the evidence that is summarized in the excellent meta-analysis by Young and colleagues,¹ let’s acknowledge that acute sinusitis is undeniably a diagnostic dilemma. Distinguishing bacterial from viral infection is nearly impossible on clinical grounds because the symptoms are so similar. A litany of identical upper respiratory symptoms accompanies both viral and bacterial sinus infections. Purulent nasal secretions, maxillary facial pain (especially with unilateral predominance), maxillary tooth pain (which is uncommon with sinus infection), altered sense of smell, and worsening illness after improvement constitute the short list of signs and symptoms that has some predictive value, but even the presence of all of these is not a terrific predictor of bacterial sinus infection. Plain x-rays have low accuracy in distinguishing viral from bacterial infection. Computed tomography (CT) sinus scans are better but far from perfect, are not readily available in practice, and are expensive.

Sinusitis in the real world

How effective are antibiotics for patients diagnosed not by sinus x-rays or CTs, but by signs and symptoms—as we typically do in daily practice?

A meta-analysis³ of 13 randomized controlled trials (RCTs) found that sinusitis improved without antibiotics, but it included trials in which patients were recruited based on results of imaging studies and cultures, which are not normally used in primary care clinical practice. That study compared antibiotic treatment to placebo for acute uncomplicated sinusitis; 35% of placebo-treated patients were clinically cured by 7 to 12 days and 73% were improved after 7 days. Antibiotic therapy increased cure rates by 15% and improvement rates by 14%, yielding a number needed to treat of 7 to achieve 1 additional positive outcome at 7 days.

STUDY SUMMARY: Meta-analysis of primary care trials

Young and colleagues¹ aggregated and analyzed individual patient-level data from all known placebo-controlled, randomized, antibiotic treatment trials of adults with clinical symptoms of acute sinusitis that were conducted in primary care settings. They excluded trials that used imaging or bacterial culture as part of patient recruitment.

Studies were included that allowed the use of concomitant medication such as nonsteroidal anti-inflammatory drugs, decongestants, or nasal steroids, as long as patients in both groups had access to the same medications. All trials excluded patients with severe symptoms such as high fever, periorbital swelling or erythema, or intense facial pain, important exclusions that we will discuss below.

They identified 10 such studies and completed an intent-to-treat analysis of the 9 double-blind trials for which patient level data were available. Using individual data from 2547 patients, the odds ratio for an overall antibiotic treatment effect was 1.37 (95% confidence interval, 1.13-1.66), with a number needed to treat (NNT) of 15.

This finding means that 15 patients needed to be given an antibiotic for 1 additional patient to be cured at 8 to 15 days after treatment commenced. Using statistical modeling, they determined that 64% of patients treated with placebo were cured at 14 days compared with 70% given an antibiotic. One patient out of 1381 treated with placebo experienced a serious complication, a brain abscess.

Do antibiotics benefit any subgroups?

The investigators also analyzed the prognostic value of specific signs and symptoms to answer the question: Is there any subgroup of patients who might benefit more from antibiotic treatment?

Duration. Patients with a longer duration of symptoms, more severe symptoms, or increased age took longer to cure, but were no more likely to benefit from antibiotic treatment than other patients.

Symptoms, such as a previous common cold, pain on bending, unilateral facial pain, tooth pain, and purulent nasal discharge did not have any prognostic value.

Only one sign—purulent discharge noted in the pharynx on examination—was associated with a higher likelihood of benefit from treatment with antibiotics, but the NNT was still 8 in this group. Patients with symptoms for 7 days or longer were no more likely to respond to antibiotics than those with symptoms for fewer than 7 days.¹

WHAT’S NEW: Realistic evidence from realistic settings

We believe this meta-analysis provides a high level of evidence against routine treatment of sinusitis with antibiotics in primary care practice. Treating 15 patients with an antibiotic to possibly benefit 1 patient 2 weeks after treatment commences does not seem like a good idea when one considers the cost and complications of antibiotic use. Diarrhea and other adverse outcomes are 80% more common among patients with sinusitis who are treated with an antibiotic compared with placebo.³ As noted above, prior meta-analyses of antibiotic treatment for acute sinusitis have been more encouraging than this meta-analysis, with a number needed to treat of 7, but those meta-analyses are clearly overly optimistic for the results one will achieve in primary care practice using clinical signs and symptoms to diagnose acute sinusitis.^3,4 Unlike the Young study, they included trials in specialty clinics with CT scans and sinus puncture and culture used for the diagnostic standard.

Symptoms >1 week are not a reason to prescribe

One very important new finding in this meta-analysis that should change practice is that the duration of illness did not predict a positive response to antibiotics.

Current national recommendations are to use an antibiotic for patients with a duration of illness longer than 1 week, as these patients are presumably more likely to have a bacterial infection.^5-7 However, that recommendation had been based on expert opinion, not on data from clinical trials. A longer duration of symptoms should not be a reason to prescribe an antibiotic for sinusitis symptoms.

How can you help your patient?

What to do, then, for patients with acute sinusitis? Treat the symptoms, which means recommending pain medication for facial pain or headache and saline nasal spray for the nasal discharge, not antibiotics or nasal corticosteroids. Side effects will be fewer and costs will be lower.

• Saline irrigation. A 2007 Cochrane review of 8 chronic and recurrent sinusitis trials showed that nasal saline irrigation is effective for reducing symptoms of chronic and recurrent sinusitis.⁸ Although we do not have high-quality RCT data on saline nasal irrigation for treatment of acute sinusitis, nasal saline irrigation is harmless and inexpensive.
• What about nasal steroids? The evidence is equivocal, and the most recent high-quality RCT of nasal steroids showed no effect.⁹

CAVEATS: Refer seriously ill patients and complicated cases

A very important caveat to our recommendation is that seriously ill patients must be managed differently. Very infrequently a patient develops a serious complication of acute sinusitis such as brain abscess, periorbital cellulitis, or meningitis. Therefore, seriously ill patients with signs and symptoms of acute bacterial sinusitis, such as high fever, periorbital erythema or edema, severe headache, or intense facial pain must be carefully evaluated and treated with great caution and close follow-up. These patients should be referred immediately for consultation with an otolaryngologist.

Of course, mildly ill patients today may become quite ill tomorrow, so always provide advice to patients to return if they are getting worse, a good clinical practice for any condition that is usually benign but occasionally serious.

Patients who have prolonged or recurrent sinusitis symptoms need further evaluation for other diagnoses such as allergies, cystic fibrosis, fungal sinus infection, and other illnesses associated with immune compromise. These complicated patients benefit from consultation with an otolaryngologist who has a specific interest in chronic and recurrent sinusitis, and perhaps consultation from an infectious disease specialist as well.

CHALLENGES TO IMPLEMENTATION: The patient who wants a pill

Some patients may be accustomed to receiving an antibiotic prescription for their “sinus infections” and may resist conservative management. It may be difficult to convince them that antibiotics won’t make a difference when they attribute past resolution of symptoms to antibiotics.

Take enough time to educate your patients on the natural course of illness, the positive benefits of nasal saline, and the reasons not to use unnecessary antibiotics (eg, they are not effective, have potential adverse effects, and can contribute to future antibiotic resistance); this effort will save you time in future visits.¹⁰ A “just in case you don’t get better” prescription to be filled only if the patient is not improving in the next few days is about 50% effective in reducing antibiotic usage for upper respiratory infections.¹¹

Acknowledgement

We acknowledge Sofia Medvedev of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 23-year-old woman presents to your office with a 1-week history of cough, purulent nasal discharge, and unilateral facial pain. You diagnose acute sinusitis.

Should you prescribe an antibiotic?

No. Yet it’s no wonder that most adults treated for acute sinusitis leave the doctor’s office with a prescription for antibiotics. Until the publication of the meta-analysis by Young and colleagues¹ featured in this PURL, we have lacked A-level evidence from studies conducted in realistic settings—like your practice and ours.

Review of serial data from the National Ambulatory Medical Care Surveys (NAMCS) from 1999 through 2005 does show a slight downward trend in antibiotic prescribing for acute sinusitis: 1999-2002 data showed that 83% of cases of acute sinusitis were treated with an antibiotic.² Data from the 2004 and 2005 NAMCS reveal that family physicians prescribed antibiotics for 80% of patients with acute sinusitis in 2004 and 76% of patients in 2005 (S. Medvedev, unpublished data, NAMCS database, March 2008).

Is this continued high rate of antibiotic prescribing justified?

Do antibiotics improve symptoms and shorten the duration of illness or not?

These questions are important, obviously, not only because of the high rate of prescribing but also because sinusitis is one of the most common diagnoses: approximately 20 million cases annually in the United States, or about 21% of all outpatient antibiotic prescriptions for adults.²

Which patients might benefit from antibiotics?

Common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom treatment is clearly justified, given the cost, adverse events, and bacterial resistance associated with antibiotic use

• Severity of symptoms is important only in that signs suggestive of a serious complication are the sole reason for immediate antibiotic treatment
• Purulent discharge noted in the pharynx on exam was associated with a higher likelihood of benefit from antibiotics, but NNT was 8
• Antibiotics are not justified even if a patient reports having symptoms for longer than 7-10 days

Source: Young et al.¹

A diagnostic dilemma

Before we discuss the evidence that is summarized in the excellent meta-analysis by Young and colleagues,¹ let’s acknowledge that acute sinusitis is undeniably a diagnostic dilemma. Distinguishing bacterial from viral infection is nearly impossible on clinical grounds because the symptoms are so similar. A litany of identical upper respiratory symptoms accompanies both viral and bacterial sinus infections. Purulent nasal secretions, maxillary facial pain (especially with unilateral predominance), maxillary tooth pain (which is uncommon with sinus infection), altered sense of smell, and worsening illness after improvement constitute the short list of signs and symptoms that has some predictive value, but even the presence of all of these is not a terrific predictor of bacterial sinus infection. Plain x-rays have low accuracy in distinguishing viral from bacterial infection. Computed tomography (CT) sinus scans are better but far from perfect, are not readily available in practice, and are expensive.

Sinusitis in the real world

How effective are antibiotics for patients diagnosed not by sinus x-rays or CTs, but by signs and symptoms—as we typically do in daily practice?

A meta-analysis³ of 13 randomized controlled trials (RCTs) found that sinusitis improved without antibiotics, but it included trials in which patients were recruited based on results of imaging studies and cultures, which are not normally used in primary care clinical practice. That study compared antibiotic treatment to placebo for acute uncomplicated sinusitis; 35% of placebo-treated patients were clinically cured by 7 to 12 days and 73% were improved after 7 days. Antibiotic therapy increased cure rates by 15% and improvement rates by 14%, yielding a number needed to treat of 7 to achieve 1 additional positive outcome at 7 days.

STUDY SUMMARY: Meta-analysis of primary care trials

Young and colleagues¹ aggregated and analyzed individual patient-level data from all known placebo-controlled, randomized, antibiotic treatment trials of adults with clinical symptoms of acute sinusitis that were conducted in primary care settings. They excluded trials that used imaging or bacterial culture as part of patient recruitment.

Studies were included that allowed the use of concomitant medication such as nonsteroidal anti-inflammatory drugs, decongestants, or nasal steroids, as long as patients in both groups had access to the same medications. All trials excluded patients with severe symptoms such as high fever, periorbital swelling or erythema, or intense facial pain, important exclusions that we will discuss below.

They identified 10 such studies and completed an intent-to-treat analysis of the 9 double-blind trials for which patient level data were available. Using individual data from 2547 patients, the odds ratio for an overall antibiotic treatment effect was 1.37 (95% confidence interval, 1.13-1.66), with a number needed to treat (NNT) of 15.

This finding means that 15 patients needed to be given an antibiotic for 1 additional patient to be cured at 8 to 15 days after treatment commenced. Using statistical modeling, they determined that 64% of patients treated with placebo were cured at 14 days compared with 70% given an antibiotic. One patient out of 1381 treated with placebo experienced a serious complication, a brain abscess.

Do antibiotics benefit any subgroups?

The investigators also analyzed the prognostic value of specific signs and symptoms to answer the question: Is there any subgroup of patients who might benefit more from antibiotic treatment?

Duration. Patients with a longer duration of symptoms, more severe symptoms, or increased age took longer to cure, but were no more likely to benefit from antibiotic treatment than other patients.

Symptoms, such as a previous common cold, pain on bending, unilateral facial pain, tooth pain, and purulent nasal discharge did not have any prognostic value.

Only one sign—purulent discharge noted in the pharynx on examination—was associated with a higher likelihood of benefit from treatment with antibiotics, but the NNT was still 8 in this group. Patients with symptoms for 7 days or longer were no more likely to respond to antibiotics than those with symptoms for fewer than 7 days.¹

WHAT’S NEW: Realistic evidence from realistic settings

We believe this meta-analysis provides a high level of evidence against routine treatment of sinusitis with antibiotics in primary care practice. Treating 15 patients with an antibiotic to possibly benefit 1 patient 2 weeks after treatment commences does not seem like a good idea when one considers the cost and complications of antibiotic use. Diarrhea and other adverse outcomes are 80% more common among patients with sinusitis who are treated with an antibiotic compared with placebo.³ As noted above, prior meta-analyses of antibiotic treatment for acute sinusitis have been more encouraging than this meta-analysis, with a number needed to treat of 7, but those meta-analyses are clearly overly optimistic for the results one will achieve in primary care practice using clinical signs and symptoms to diagnose acute sinusitis.^3,4 Unlike the Young study, they included trials in specialty clinics with CT scans and sinus puncture and culture used for the diagnostic standard.

Symptoms >1 week are not a reason to prescribe

One very important new finding in this meta-analysis that should change practice is that the duration of illness did not predict a positive response to antibiotics.

Current national recommendations are to use an antibiotic for patients with a duration of illness longer than 1 week, as these patients are presumably more likely to have a bacterial infection.^5-7 However, that recommendation had been based on expert opinion, not on data from clinical trials. A longer duration of symptoms should not be a reason to prescribe an antibiotic for sinusitis symptoms.

How can you help your patient?

What to do, then, for patients with acute sinusitis? Treat the symptoms, which means recommending pain medication for facial pain or headache and saline nasal spray for the nasal discharge, not antibiotics or nasal corticosteroids. Side effects will be fewer and costs will be lower.

• Saline irrigation. A 2007 Cochrane review of 8 chronic and recurrent sinusitis trials showed that nasal saline irrigation is effective for reducing symptoms of chronic and recurrent sinusitis.⁸ Although we do not have high-quality RCT data on saline nasal irrigation for treatment of acute sinusitis, nasal saline irrigation is harmless and inexpensive.
• What about nasal steroids? The evidence is equivocal, and the most recent high-quality RCT of nasal steroids showed no effect.⁹

CAVEATS: Refer seriously ill patients and complicated cases

A very important caveat to our recommendation is that seriously ill patients must be managed differently. Very infrequently a patient develops a serious complication of acute sinusitis such as brain abscess, periorbital cellulitis, or meningitis. Therefore, seriously ill patients with signs and symptoms of acute bacterial sinusitis, such as high fever, periorbital erythema or edema, severe headache, or intense facial pain must be carefully evaluated and treated with great caution and close follow-up. These patients should be referred immediately for consultation with an otolaryngologist.

Of course, mildly ill patients today may become quite ill tomorrow, so always provide advice to patients to return if they are getting worse, a good clinical practice for any condition that is usually benign but occasionally serious.

Patients who have prolonged or recurrent sinusitis symptoms need further evaluation for other diagnoses such as allergies, cystic fibrosis, fungal sinus infection, and other illnesses associated with immune compromise. These complicated patients benefit from consultation with an otolaryngologist who has a specific interest in chronic and recurrent sinusitis, and perhaps consultation from an infectious disease specialist as well.

CHALLENGES TO IMPLEMENTATION: The patient who wants a pill

Some patients may be accustomed to receiving an antibiotic prescription for their “sinus infections” and may resist conservative management. It may be difficult to convince them that antibiotics won’t make a difference when they attribute past resolution of symptoms to antibiotics.

Take enough time to educate your patients on the natural course of illness, the positive benefits of nasal saline, and the reasons not to use unnecessary antibiotics (eg, they are not effective, have potential adverse effects, and can contribute to future antibiotic resistance); this effort will save you time in future visits.¹⁰ A “just in case you don’t get better” prescription to be filled only if the patient is not improving in the next few days is about 50% effective in reducing antibiotic usage for upper respiratory infections.¹¹

Acknowledgement

We acknowledge Sofia Medvedev of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A mother brings her 3-year-old son to your office first thing in the morning. The boy has fever and right ear pain. You see that the tympanic membrane is dull, red, and bulging. The mother has been up most of the night with her child. She implores you to “do something.” She is exhausted and her son is crying and holding his right ear. You know that antibiotics will not provide immediate pain relief and oral analgesics will take a while to help. What can you offer that will help right away?

Until this study, we’ve had only 1 placebo-controlled trial to guide how we manage a big problem. Big in terms of distress to parents and children, and in sheer numbers—acute otitis media (AOM) is extremely common in children.^2,3

Routine antibiotics: Woeful lack of evidence

Even when antibiotics are indicated, pain relief is minimal and takes several days.^4-8 Despite “a woeful lack of substantial evidence on the question of antibiotic therapy” for AOM, it is the most common reason for the prescription of antibiotics in children.^4,6 A Cochrane review showed that antibiotics have no effect on recurrence of AOM or complications, including hearing impairment.⁵ The same review showed no pain reduction in 24 hours and only 30% pain reduction in 2 to 7 days with antibiotic use.⁵ Antibiotics clearly have a minimal role in providing pain relief for AOM.

Oral analgesics too slow

Oral analgesic use in AOM has been studied and has shown good results. We calculated the number needed to treat (1.0 divided by the absolute risk reduction) for both ibuprofen (number needed to treat [NNT]=5) and acetaminophen (NNT=6) from data in the 1996 trial by Bertin et al.⁹

It is a common practice in the United States to treat AOM with oral analgesics. However, the onset of pain relief with oral medications can be slow and the relief is generally not complete, so oral medications are not immediately helpful to meet the needs of our crying 3-year-old patient and his exhausted mother.

Topical anesthetics

To our knowledge, prior evidence on the efficacy of topical anesthetics is limited to 1 placebo-controlled trial. A randomized trial by Hoberman et al,¹⁰ with 54 subjects, showed a statistically significant 25% reduction in pain with the analgesic drops Auralgan (containing antipyrine, benzocaine, and glycerine) at 30 minutes when compared with olive oil. A 2006 Cochrane review¹¹ did not include the Bolt et al trial¹ described in this PURL, but did include the Hoberman trial¹⁰ and 3 trials that compared a topical anesthetic with naturopathic herbal ear drops for AOM pain, and the review concluded that evidence was insufficient.

Topical anesthetic plus oraI analgesia for earache relief

STUDY SUMMARY: Pain measured by visual analogue, Bieri faces scales

This double-blind, randomized, placebo-controlled trial¹ compared aqueous lidocaine 2% drops with saline drops in the ear, for reducing pain due to AOM in patients 3 to 17 years of age. The trial was conducted at an Australian children’s hospital emergency room. The study evaluated “lignocaine,” the name for lidocaine in Australia.

Emergency physicians instilled 3 drops of either lidocaine or saline into the affected ear in the 2 groups (n=31 in the study group and n=32 in the placebo group). Patients, parents, treating physicians, and staff administering ear drops and assessing pain were blinded to group assignment. Doctors measured pain at baseline and after 30 minutes and patients measured pain at baseline, 10, 20, and 30 minutes after the drops were instilled, using the Bieri faces pain scale and a visual analogue scale.¹²

Lidocaine reduced pain scores by 50% from baseline at 10 and 30 minutes compared with saline. No serious side effects were noted at 30 minutes, although 3 patients in the lidocaine group complained of mild dizziness the next day. The treating physician prescribed paracetamol (equivalent to acetaminophen) for participants in both the lidocaine and the placebo group at their discretion. The proportion given paracetamol was similar in both groups.

WHAT’S NEW: Pain relief is immediate

Family physicians have used topical anethestics for otitis externa for decades. This RCT adds evidence that topical anesthetics are useful for providing immediate pain relief from AOM, as well. The 2004 guidelines from the American Academy of Pediatrics and the American Academy of Family Physicians indicate that management of AOM should include the assessment and treatment of pain.

We think that topical agents such as lidocaine and benzocaine are useful adjuncts to oral analgesics in providing immediate pain relief, especially in the face of evidence showing that antibiotics do not offer significant pain relief.

Previous studies have shown that aqueous lidocaine is ineffective on uninflamed tympanic membrane.¹³ The results of this study are consistent with increased uptake of the drug through the inflamed tympanic membrane.

CAVEATS: Children >3 years studied

This trial included only children older than 3 years, so the results may not apply to younger children and infants.

This essentially was a study of ear pain treatment, which, in our view, does not detract from the clinical usefulness of the findings. Topical anesthetics seem to be useful for ear pain in general.

Concurrent analgesics

Some variability existed in the oral analgesics the children received, as these agents were given at the discretion of the parents and treating physicians. We think that this does not detract from the study findings, as it represents a practical, real-world setting, which is desirable in an effectiveness RCT. Moreover, the extent of pain reduction was over and above that conferred by analgesic administration.

CHALLENGES TO IMPLEMENTATION: Lidocaine is not sold in a dropper

Aqueous lidocaine is not sold in a bottle with a dropper: our search on www.drugstore.com and www.drugs.com did not yield an otic preparation with only aqueous lidocaine. However, 2% injectable lidocaine, which is readily available, can be used with a dropper. Aqueous lidocaine can be compounded at a compounding pharmacy and placed in a bottle with a dropper.

Benzocaine might be a suitable substitute

In preparing this PURL, we learned from several colleagues that they always keep a bottle of benzocaine in their pocket and they apply the drops to the ears of their pediatric patients with AOM when they see them in their offices or in the emergency department.

Benzocaine is available in various brand names (eg, Auralgan, Americaine, A/B otic drops, among others). These are oil suspensions and not an aqueous solution as used in this study, so it would be important not to use these preparations in the presence of a ruptured tympanic membrane because the oil suspension may not be absorbed. The aqueous solution will be absorbed so it can be used even if a ruptured tympanic membrane is suspected.

In most situations rupture of the tympanic membrane gives immediate pain relief. However, in some, the pain persists and it may be difficult to tell if the tympanic membrane has ruptured or the debris and pus is from otitis externa. In those situations, the aqueous lidocaine solution might be preferred.

Should parents give drops at home?

This study does not address home use of these drops. However, benzocaine preparations have been used safely for many years for otitis externa at home, and we cannot think of any reason why drops could not be prescribed for home use in acute otitis media.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A mother brings her 3-year-old son to your office first thing in the morning. The boy has fever and right ear pain. You see that the tympanic membrane is dull, red, and bulging. The mother has been up most of the night with her child. She implores you to “do something.” She is exhausted and her son is crying and holding his right ear. You know that antibiotics will not provide immediate pain relief and oral analgesics will take a while to help. What can you offer that will help right away?

Until this study, we’ve had only 1 placebo-controlled trial to guide how we manage a big problem. Big in terms of distress to parents and children, and in sheer numbers—acute otitis media (AOM) is extremely common in children.^2,3

Routine antibiotics: Woeful lack of evidence

Even when antibiotics are indicated, pain relief is minimal and takes several days.^4-8 Despite “a woeful lack of substantial evidence on the question of antibiotic therapy” for AOM, it is the most common reason for the prescription of antibiotics in children.^4,6 A Cochrane review showed that antibiotics have no effect on recurrence of AOM or complications, including hearing impairment.⁵ The same review showed no pain reduction in 24 hours and only 30% pain reduction in 2 to 7 days with antibiotic use.⁵ Antibiotics clearly have a minimal role in providing pain relief for AOM.

Oral analgesics too slow

Oral analgesic use in AOM has been studied and has shown good results. We calculated the number needed to treat (1.0 divided by the absolute risk reduction) for both ibuprofen (number needed to treat [NNT]=5) and acetaminophen (NNT=6) from data in the 1996 trial by Bertin et al.⁹

It is a common practice in the United States to treat AOM with oral analgesics. However, the onset of pain relief with oral medications can be slow and the relief is generally not complete, so oral medications are not immediately helpful to meet the needs of our crying 3-year-old patient and his exhausted mother.

Topical anesthetics

To our knowledge, prior evidence on the efficacy of topical anesthetics is limited to 1 placebo-controlled trial. A randomized trial by Hoberman et al,¹⁰ with 54 subjects, showed a statistically significant 25% reduction in pain with the analgesic drops Auralgan (containing antipyrine, benzocaine, and glycerine) at 30 minutes when compared with olive oil. A 2006 Cochrane review¹¹ did not include the Bolt et al trial¹ described in this PURL, but did include the Hoberman trial¹⁰ and 3 trials that compared a topical anesthetic with naturopathic herbal ear drops for AOM pain, and the review concluded that evidence was insufficient.

Topical anesthetic plus oraI analgesia for earache relief

STUDY SUMMARY: Pain measured by visual analogue, Bieri faces scales

This double-blind, randomized, placebo-controlled trial¹ compared aqueous lidocaine 2% drops with saline drops in the ear, for reducing pain due to AOM in patients 3 to 17 years of age. The trial was conducted at an Australian children’s hospital emergency room. The study evaluated “lignocaine,” the name for lidocaine in Australia.

Emergency physicians instilled 3 drops of either lidocaine or saline into the affected ear in the 2 groups (n=31 in the study group and n=32 in the placebo group). Patients, parents, treating physicians, and staff administering ear drops and assessing pain were blinded to group assignment. Doctors measured pain at baseline and after 30 minutes and patients measured pain at baseline, 10, 20, and 30 minutes after the drops were instilled, using the Bieri faces pain scale and a visual analogue scale.¹²

Lidocaine reduced pain scores by 50% from baseline at 10 and 30 minutes compared with saline. No serious side effects were noted at 30 minutes, although 3 patients in the lidocaine group complained of mild dizziness the next day. The treating physician prescribed paracetamol (equivalent to acetaminophen) for participants in both the lidocaine and the placebo group at their discretion. The proportion given paracetamol was similar in both groups.

WHAT’S NEW: Pain relief is immediate

Family physicians have used topical anethestics for otitis externa for decades. This RCT adds evidence that topical anesthetics are useful for providing immediate pain relief from AOM, as well. The 2004 guidelines from the American Academy of Pediatrics and the American Academy of Family Physicians indicate that management of AOM should include the assessment and treatment of pain.

We think that topical agents such as lidocaine and benzocaine are useful adjuncts to oral analgesics in providing immediate pain relief, especially in the face of evidence showing that antibiotics do not offer significant pain relief.

Previous studies have shown that aqueous lidocaine is ineffective on uninflamed tympanic membrane.¹³ The results of this study are consistent with increased uptake of the drug through the inflamed tympanic membrane.

CAVEATS: Children >3 years studied

This trial included only children older than 3 years, so the results may not apply to younger children and infants.

This essentially was a study of ear pain treatment, which, in our view, does not detract from the clinical usefulness of the findings. Topical anesthetics seem to be useful for ear pain in general.

Concurrent analgesics

Some variability existed in the oral analgesics the children received, as these agents were given at the discretion of the parents and treating physicians. We think that this does not detract from the study findings, as it represents a practical, real-world setting, which is desirable in an effectiveness RCT. Moreover, the extent of pain reduction was over and above that conferred by analgesic administration.

CHALLENGES TO IMPLEMENTATION: Lidocaine is not sold in a dropper

Aqueous lidocaine is not sold in a bottle with a dropper: our search on www.drugstore.com and www.drugs.com did not yield an otic preparation with only aqueous lidocaine. However, 2% injectable lidocaine, which is readily available, can be used with a dropper. Aqueous lidocaine can be compounded at a compounding pharmacy and placed in a bottle with a dropper.

Benzocaine might be a suitable substitute

In preparing this PURL, we learned from several colleagues that they always keep a bottle of benzocaine in their pocket and they apply the drops to the ears of their pediatric patients with AOM when they see them in their offices or in the emergency department.

Benzocaine is available in various brand names (eg, Auralgan, Americaine, A/B otic drops, among others). These are oil suspensions and not an aqueous solution as used in this study, so it would be important not to use these preparations in the presence of a ruptured tympanic membrane because the oil suspension may not be absorbed. The aqueous solution will be absorbed so it can be used even if a ruptured tympanic membrane is suspected.

In most situations rupture of the tympanic membrane gives immediate pain relief. However, in some, the pain persists and it may be difficult to tell if the tympanic membrane has ruptured or the debris and pus is from otitis externa. In those situations, the aqueous lidocaine solution might be preferred.

Should parents give drops at home?

This study does not address home use of these drops. However, benzocaine preparations have been used safely for many years for otitis externa at home, and we cannot think of any reason why drops could not be prescribed for home use in acute otitis media.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A mother brings her 3-year-old son to your office first thing in the morning. The boy has fever and right ear pain. You see that the tympanic membrane is dull, red, and bulging. The mother has been up most of the night with her child. She implores you to “do something.” She is exhausted and her son is crying and holding his right ear. You know that antibiotics will not provide immediate pain relief and oral analgesics will take a while to help. What can you offer that will help right away?

Until this study, we’ve had only 1 placebo-controlled trial to guide how we manage a big problem. Big in terms of distress to parents and children, and in sheer numbers—acute otitis media (AOM) is extremely common in children.^2,3

Routine antibiotics: Woeful lack of evidence

Even when antibiotics are indicated, pain relief is minimal and takes several days.^4-8 Despite “a woeful lack of substantial evidence on the question of antibiotic therapy” for AOM, it is the most common reason for the prescription of antibiotics in children.^4,6 A Cochrane review showed that antibiotics have no effect on recurrence of AOM or complications, including hearing impairment.⁵ The same review showed no pain reduction in 24 hours and only 30% pain reduction in 2 to 7 days with antibiotic use.⁵ Antibiotics clearly have a minimal role in providing pain relief for AOM.

Oral analgesics too slow

Oral analgesic use in AOM has been studied and has shown good results. We calculated the number needed to treat (1.0 divided by the absolute risk reduction) for both ibuprofen (number needed to treat [NNT]=5) and acetaminophen (NNT=6) from data in the 1996 trial by Bertin et al.⁹

It is a common practice in the United States to treat AOM with oral analgesics. However, the onset of pain relief with oral medications can be slow and the relief is generally not complete, so oral medications are not immediately helpful to meet the needs of our crying 3-year-old patient and his exhausted mother.

Topical anesthetics

To our knowledge, prior evidence on the efficacy of topical anesthetics is limited to 1 placebo-controlled trial. A randomized trial by Hoberman et al,¹⁰ with 54 subjects, showed a statistically significant 25% reduction in pain with the analgesic drops Auralgan (containing antipyrine, benzocaine, and glycerine) at 30 minutes when compared with olive oil. A 2006 Cochrane review¹¹ did not include the Bolt et al trial¹ described in this PURL, but did include the Hoberman trial¹⁰ and 3 trials that compared a topical anesthetic with naturopathic herbal ear drops for AOM pain, and the review concluded that evidence was insufficient.

Topical anesthetic plus oraI analgesia for earache relief

STUDY SUMMARY: Pain measured by visual analogue, Bieri faces scales

This double-blind, randomized, placebo-controlled trial¹ compared aqueous lidocaine 2% drops with saline drops in the ear, for reducing pain due to AOM in patients 3 to 17 years of age. The trial was conducted at an Australian children’s hospital emergency room. The study evaluated “lignocaine,” the name for lidocaine in Australia.

Emergency physicians instilled 3 drops of either lidocaine or saline into the affected ear in the 2 groups (n=31 in the study group and n=32 in the placebo group). Patients, parents, treating physicians, and staff administering ear drops and assessing pain were blinded to group assignment. Doctors measured pain at baseline and after 30 minutes and patients measured pain at baseline, 10, 20, and 30 minutes after the drops were instilled, using the Bieri faces pain scale and a visual analogue scale.¹²

Lidocaine reduced pain scores by 50% from baseline at 10 and 30 minutes compared with saline. No serious side effects were noted at 30 minutes, although 3 patients in the lidocaine group complained of mild dizziness the next day. The treating physician prescribed paracetamol (equivalent to acetaminophen) for participants in both the lidocaine and the placebo group at their discretion. The proportion given paracetamol was similar in both groups.

WHAT’S NEW: Pain relief is immediate

Family physicians have used topical anethestics for otitis externa for decades. This RCT adds evidence that topical anesthetics are useful for providing immediate pain relief from AOM, as well. The 2004 guidelines from the American Academy of Pediatrics and the American Academy of Family Physicians indicate that management of AOM should include the assessment and treatment of pain.

We think that topical agents such as lidocaine and benzocaine are useful adjuncts to oral analgesics in providing immediate pain relief, especially in the face of evidence showing that antibiotics do not offer significant pain relief.

Previous studies have shown that aqueous lidocaine is ineffective on uninflamed tympanic membrane.¹³ The results of this study are consistent with increased uptake of the drug through the inflamed tympanic membrane.

CAVEATS: Children >3 years studied

This trial included only children older than 3 years, so the results may not apply to younger children and infants.

This essentially was a study of ear pain treatment, which, in our view, does not detract from the clinical usefulness of the findings. Topical anesthetics seem to be useful for ear pain in general.

Concurrent analgesics

Some variability existed in the oral analgesics the children received, as these agents were given at the discretion of the parents and treating physicians. We think that this does not detract from the study findings, as it represents a practical, real-world setting, which is desirable in an effectiveness RCT. Moreover, the extent of pain reduction was over and above that conferred by analgesic administration.

CHALLENGES TO IMPLEMENTATION: Lidocaine is not sold in a dropper

Aqueous lidocaine is not sold in a bottle with a dropper: our search on www.drugstore.com and www.drugs.com did not yield an otic preparation with only aqueous lidocaine. However, 2% injectable lidocaine, which is readily available, can be used with a dropper. Aqueous lidocaine can be compounded at a compounding pharmacy and placed in a bottle with a dropper.

Benzocaine might be a suitable substitute

In preparing this PURL, we learned from several colleagues that they always keep a bottle of benzocaine in their pocket and they apply the drops to the ears of their pediatric patients with AOM when they see them in their offices or in the emergency department.

Benzocaine is available in various brand names (eg, Auralgan, Americaine, A/B otic drops, among others). These are oil suspensions and not an aqueous solution as used in this study, so it would be important not to use these preparations in the presence of a ruptured tympanic membrane because the oil suspension may not be absorbed. The aqueous solution will be absorbed so it can be used even if a ruptured tympanic membrane is suspected.

In most situations rupture of the tympanic membrane gives immediate pain relief. However, in some, the pain persists and it may be difficult to tell if the tympanic membrane has ruptured or the debris and pus is from otitis externa. In those situations, the aqueous lidocaine solution might be preferred.

Should parents give drops at home?

This study does not address home use of these drops. However, benzocaine preparations have been used safely for many years for otitis externa at home, and we cannot think of any reason why drops could not be prescribed for home use in acute otitis media.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

Your new patient is a 57-year-old African American man. His blood pressure is 150/95 mm Hg, fasting glucose 115 mg/dL, body mass index 32, and triglycerides 155 mg/dL; he is on no prior medications. During the course of his care you diagnose hypertension with metabolic syndrome and decide to recommend an antihypertensive. Thiazide-type diuretics are your standard initial therapy, but this patient has metabolic syndrome, and you know that certain antihypertensive agents have a more favorable metabolic profile than thiazide diuretics. Furthermore, metabolic differences among races have been touted as reason to use other agents in black patients. Should you recommend a thiazide diuretic, or another agent?

Until now, we’ve had no simple approach to treating hypertension in patients with metabolic syndrome—and half or more of our hypertensive patients over the age of 55 have this disorder.

Now, however, we can base decisions on clinical outcomes data from a subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).¹ This new subgroup analysis supports use of thiazide-type diuretics in these patients—particularly in black patients—despite the more favorable metabolic profile of calcium channel blockers, alpha-blockers, and angiotensin-converting enzyme (ACE) inhibitors.

Cost is no longer as big a factor as it once was, now that ACE inhibitors and alpha-blockers, as well as thiazide diuretics, are available generically.

Does a better metabolic profile improve outcomes?

We have had reason to be concerned about the metabolic adverse effects of thiazide-type diuretics in the past. Studies published before this ALLHAT subgroup analysis showed that hydrochlorothiazide for essential hypertension had adverse effects on potassium, glucose, and lipid metabolism. Some speculated that these changes aggravate the metabolic changes in early diabetes^2-4 and may contribute to increased coronary heart disease risk.^5,6

FIGURE
Outcomes favor thiazides

We know many physicians who have adopted thiazide-type diuretics as the first-line treatment for hypertension in metabolic syndrome, but until now, data have been inadequate to support this decision.

A subgroup analysis from the ALLHAT¹ concludes: “The ALLHAT findings fail to support the preference for calcium channel blockers, alpha-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the metabolic syndrome, despite their more favorable metabolic profiles. This was particularly true for black participants.”

ACE inhibitors and ARBs

The metabolic benefits of ACE inhibitors and angiotensin-receptor blockers (ARBs) are widely known. In comparative studies prior to this ALLHAT subgroup analysis, ACE inhibitors were thought to be preferable to thiazide diuretics and beta-blockers for patients with obesity⁷ or the metabolic syndrome.⁸ These agents also protect against diabetic nephropathy.⁹ Other studies attribute additional vascular benefits to ACE inhibitors,¹⁰ beyond that of lowering blood pressure.

A 2005 meta-analysis by Abuissa et al¹¹ showed that ACE inhibitors and ARBs were associated with significant reductions in the incidence of newly diagnosed diabetes, which, in turn, might lead to reduced heart disease. That report concluded that use of ACE inhibitors or ARBs should be considered in patients with prediabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease.

Calcium-channel blockers and alpha-blockers

Calcium-channel blockers and alpha-blockers also do not appear to have the adverse metabolic effects of thiazides, and have also been advocated over beta-blockers and thiazides for hypertensive patients with metabolic syndrome.^12-15

Racial differences

In a consensus statement developed before the findings from the ALLHAT subgroup analysis were available, it was noted that racial differences in metabolic syndrome may make the selection of antihypertensive agents particularly important in African American patients.¹⁶

ALLHAT and JNC7 recommendations

The 2002 ALLHAT demonstrated that chlorthalidone (a thiazide-type diuretic) is superior to lisinopril, amlodipine, and doxazosin in preventing 1 or more major forms of cardiovascular disease. No difference was observed, however, for fatal coronary heart disease, nonfatal myocardial infarction, or all-cause mortality.¹⁷ These findings persisted in sub-group analyses stratified by race, diabetic status, and level of renal function, but ALLHAT did not identify patients with metabolic syndrome a priori.

The ALLHAT influenced the 2003 Joint National Commission VII (JNC7) Report, which recommends thiazide diuretics for first-line treatment of hypertension in the absence of compelling indications to begin an alternative antihypertensive agent.¹⁸

Special consideration, but no recommendation. The JNC7 Report mentions the metabolic syndrome as a special consideration, but does not explicitly recommend a first-line therapy other than thiazides.

Anecdotally, we know many physicians who have adopted thiazide-type diuretics as the first-line treatment for hypertension in metabolic syndrome, but until now, data have been inadequate to support this decision.

STUDY SUMMARY: Chlorthalidone outcomes were equivalent or better

Wright and colleagues analyzed a sub-group¹ of the ALLHAT cohort, which consisted of 42,418 participants, aged ≥55, with hypertension and at least 1 other cardiovascular risk factor ( FIGURE ).

Patients were randomly assigned to therapy with chlorthalidone, amlodipine, lisinopril, or doxazosin. After randomization, if patients failed to reach the target blood pressure (<140/90 mm Hg) with their assigned therapy, they were started on atenolol, clonidine, or reserpine. If they required a third agent, they received hydralazine. The doxazosin arm was stopped early due to increased stroke and heart failure risk.

The ALLHAT was well done and designed for adequate power to evaluate clinical outcomes in racial subgroups, as well as the general population.

Outcomes were compared by race in hypertensive patients with and without metabolic syndrome.

A total of 23,077 (54%) patients met all criteria; 12,818 were black, 7327 (57%) of whom had metabolic syndrome.

Not surprisingly in a study of this size, the expected metabolic effects of all 4 antihypertensive agents were detected. Patients taking chlorthalidone had higher glucose levels (1–4 mg/dL) and higher levels of cholesterol, although these higher glucose and cholesterol levels were not statistically significant for all comparisons over time and between different drugs.

Outcomes in the chlorthalidone group were equivalent or superior to the 3 other therapies, generally. This pattern held true regardless of race ( TABLE ):

Heart failure rates were significantly higher in patients with metabolic syndrome across all treatments compared with chlorthalidone.

Combined cardiovascular disease rates were higher with lisinopril and doxazosin compared with chlorthalidone.

Stroke rates were higher among black participants only in the lisinopril group.

TABLE
Number needed to treat to prevent blood pressure-related adverse outcomes in patients with hypertension and metabolic syndrome

WHAT’S NEW: Most effective, least expensive

First-line use of thiazide diuretics for hypertension gained major support from the findings of the first ALLHAT report, published in 2002. A year later, JNC7 supported the practice. Yet questions have persisted about whether the choice of initial antihypertensive agent in patients with metabolic syndrome warrants special consideration.

The difference for one patient is small, but when you consider the high prevalence of hypertension, the cumulative benefit at a population level is significant. This subgroup analysis confirms that there is no harm, and potentially a small benefit, in using chlorthalidone as a first-line agent for treating hypertension in patients with metabolic syndrome, regardless of race—despite the measurable and presumably adverse effects of diuretic agents on metabolic measurements.

How large is the benefit of first-line thiazides, overall?

Although, statistically, the relative risks (RR) are not large, the sheer number of patients means that there is significant benefit to the selection of thiazides as first-line treatment in most patients.

CAVEATS: Is stroke a concern? Was follow-up sufficient?

In this study, the only finding of harm in the diuretic group was an increased risk for stroke compared with amlodipine among non-black patients with metabolic syndrome. While this finding does raise some uncertainty, we still think that, on balance, thiazides are the most beneficial, even in this subgroup, as there was a larger benefit in preventing heart failure.

Another theoretical possibility is that follow-up was too short to demonstrate harm from the metabolic effects of thiazides. However, the metabolic effects of thiazides are very small and we believe that the evidence of benefit shown during this study period easily outweighs any such theoretical harms.

We also assume that hydrochlorothiazide, a commonly prescribed thiazide, has the same benefits as chlorthalidone, the medication studied.

Most ALLHAT participants with metabolic syndrome already had diabetes: 67.6% of black participants and 51.8% of non-black participants. Another sub-group analysis of the ALLHAT studied patients with metabolic syndrome without diabetes, and found similar results.¹⁹

Of note, lisinopril reduced the onset of diabetes over 5 years (number needed to treat [NNT]=22.2), at the cost of increased heart failure (RR=1.31; 95% confidence interval [CI], 1.04-1.64) and combined cardiovascular disease (RR=1.19; 95% CI, 1.07-1.32). This potentially confounds the claim that thiazides are effective in preventing diabetes, since so many people had it to begin with.

The criteria for metabolic syndrome did not include waist circumference, which is the National Cholesterol Education Program definition. The World Health Organization definition, however, does allow substitution of BMI. Purists would have you believe waist circumference is necessary. In practice, we have come to use BMI as an adequate surrogate. Some say it has, in fact, replaced waist circumference.

CHALLENGES TO IMPLEMENTATION: Inertia

Few interventions are as simple as this. Thiazide diuretics are well tolerated, need to be taken only once daily, and are inexpensive. Because generics are available, little to no pharmaceutical marketing is done to promote their use. The major barriers to implementing this practice may be overcoming clinical inertia, and the message of pharmaceutical marketing on behalf of the more expensive alternatives.

Acknowledgement

We acknowledge Sofia Medvedev, PhD, University HealthSystem Consortium, Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at here.

ILLUSTRATIVE CASE

Your new patient is a 57-year-old African American man. His blood pressure is 150/95 mm Hg, fasting glucose 115 mg/dL, body mass index 32, and triglycerides 155 mg/dL; he is on no prior medications. During the course of his care you diagnose hypertension with metabolic syndrome and decide to recommend an antihypertensive. Thiazide-type diuretics are your standard initial therapy, but this patient has metabolic syndrome, and you know that certain antihypertensive agents have a more favorable metabolic profile than thiazide diuretics. Furthermore, metabolic differences among races have been touted as reason to use other agents in black patients. Should you recommend a thiazide diuretic, or another agent?

Until now, we’ve had no simple approach to treating hypertension in patients with metabolic syndrome—and half or more of our hypertensive patients over the age of 55 have this disorder.

Now, however, we can base decisions on clinical outcomes data from a subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).¹ This new subgroup analysis supports use of thiazide-type diuretics in these patients—particularly in black patients—despite the more favorable metabolic profile of calcium channel blockers, alpha-blockers, and angiotensin-converting enzyme (ACE) inhibitors.

Cost is no longer as big a factor as it once was, now that ACE inhibitors and alpha-blockers, as well as thiazide diuretics, are available generically.

Does a better metabolic profile improve outcomes?

We have had reason to be concerned about the metabolic adverse effects of thiazide-type diuretics in the past. Studies published before this ALLHAT subgroup analysis showed that hydrochlorothiazide for essential hypertension had adverse effects on potassium, glucose, and lipid metabolism. Some speculated that these changes aggravate the metabolic changes in early diabetes^2-4 and may contribute to increased coronary heart disease risk.^5,6

FIGURE
Outcomes favor thiazides

We know many physicians who have adopted thiazide-type diuretics as the first-line treatment for hypertension in metabolic syndrome, but until now, data have been inadequate to support this decision.

A subgroup analysis from the ALLHAT¹ concludes: “The ALLHAT findings fail to support the preference for calcium channel blockers, alpha-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the metabolic syndrome, despite their more favorable metabolic profiles. This was particularly true for black participants.”

ACE inhibitors and ARBs

The metabolic benefits of ACE inhibitors and angiotensin-receptor blockers (ARBs) are widely known. In comparative studies prior to this ALLHAT subgroup analysis, ACE inhibitors were thought to be preferable to thiazide diuretics and beta-blockers for patients with obesity⁷ or the metabolic syndrome.⁸ These agents also protect against diabetic nephropathy.⁹ Other studies attribute additional vascular benefits to ACE inhibitors,¹⁰ beyond that of lowering blood pressure.

A 2005 meta-analysis by Abuissa et al¹¹ showed that ACE inhibitors and ARBs were associated with significant reductions in the incidence of newly diagnosed diabetes, which, in turn, might lead to reduced heart disease. That report concluded that use of ACE inhibitors or ARBs should be considered in patients with prediabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease.

Calcium-channel blockers and alpha-blockers

Calcium-channel blockers and alpha-blockers also do not appear to have the adverse metabolic effects of thiazides, and have also been advocated over beta-blockers and thiazides for hypertensive patients with metabolic syndrome.^12-15

Racial differences

In a consensus statement developed before the findings from the ALLHAT subgroup analysis were available, it was noted that racial differences in metabolic syndrome may make the selection of antihypertensive agents particularly important in African American patients.¹⁶

ALLHAT and JNC7 recommendations

The 2002 ALLHAT demonstrated that chlorthalidone (a thiazide-type diuretic) is superior to lisinopril, amlodipine, and doxazosin in preventing 1 or more major forms of cardiovascular disease. No difference was observed, however, for fatal coronary heart disease, nonfatal myocardial infarction, or all-cause mortality.¹⁷ These findings persisted in sub-group analyses stratified by race, diabetic status, and level of renal function, but ALLHAT did not identify patients with metabolic syndrome a priori.

The ALLHAT influenced the 2003 Joint National Commission VII (JNC7) Report, which recommends thiazide diuretics for first-line treatment of hypertension in the absence of compelling indications to begin an alternative antihypertensive agent.¹⁸

Special consideration, but no recommendation. The JNC7 Report mentions the metabolic syndrome as a special consideration, but does not explicitly recommend a first-line therapy other than thiazides.

Anecdotally, we know many physicians who have adopted thiazide-type diuretics as the first-line treatment for hypertension in metabolic syndrome, but until now, data have been inadequate to support this decision.

STUDY SUMMARY: Chlorthalidone outcomes were equivalent or better

Wright and colleagues analyzed a sub-group¹ of the ALLHAT cohort, which consisted of 42,418 participants, aged ≥55, with hypertension and at least 1 other cardiovascular risk factor ( FIGURE ).

Patients were randomly assigned to therapy with chlorthalidone, amlodipine, lisinopril, or doxazosin. After randomization, if patients failed to reach the target blood pressure (<140/90 mm Hg) with their assigned therapy, they were started on atenolol, clonidine, or reserpine. If they required a third agent, they received hydralazine. The doxazosin arm was stopped early due to increased stroke and heart failure risk.

The ALLHAT was well done and designed for adequate power to evaluate clinical outcomes in racial subgroups, as well as the general population.

Outcomes were compared by race in hypertensive patients with and without metabolic syndrome.

A total of 23,077 (54%) patients met all criteria; 12,818 were black, 7327 (57%) of whom had metabolic syndrome.

Not surprisingly in a study of this size, the expected metabolic effects of all 4 antihypertensive agents were detected. Patients taking chlorthalidone had higher glucose levels (1–4 mg/dL) and higher levels of cholesterol, although these higher glucose and cholesterol levels were not statistically significant for all comparisons over time and between different drugs.

Outcomes in the chlorthalidone group were equivalent or superior to the 3 other therapies, generally. This pattern held true regardless of race ( TABLE ):

Heart failure rates were significantly higher in patients with metabolic syndrome across all treatments compared with chlorthalidone.

Combined cardiovascular disease rates were higher with lisinopril and doxazosin compared with chlorthalidone.

Stroke rates were higher among black participants only in the lisinopril group.

TABLE
Number needed to treat to prevent blood pressure-related adverse outcomes in patients with hypertension and metabolic syndrome

WHAT’S NEW: Most effective, least expensive

First-line use of thiazide diuretics for hypertension gained major support from the findings of the first ALLHAT report, published in 2002. A year later, JNC7 supported the practice. Yet questions have persisted about whether the choice of initial antihypertensive agent in patients with metabolic syndrome warrants special consideration.

The difference for one patient is small, but when you consider the high prevalence of hypertension, the cumulative benefit at a population level is significant. This subgroup analysis confirms that there is no harm, and potentially a small benefit, in using chlorthalidone as a first-line agent for treating hypertension in patients with metabolic syndrome, regardless of race—despite the measurable and presumably adverse effects of diuretic agents on metabolic measurements.

How large is the benefit of first-line thiazides, overall?

Although, statistically, the relative risks (RR) are not large, the sheer number of patients means that there is significant benefit to the selection of thiazides as first-line treatment in most patients.

CAVEATS: Is stroke a concern? Was follow-up sufficient?

In this study, the only finding of harm in the diuretic group was an increased risk for stroke compared with amlodipine among non-black patients with metabolic syndrome. While this finding does raise some uncertainty, we still think that, on balance, thiazides are the most beneficial, even in this subgroup, as there was a larger benefit in preventing heart failure.

Another theoretical possibility is that follow-up was too short to demonstrate harm from the metabolic effects of thiazides. However, the metabolic effects of thiazides are very small and we believe that the evidence of benefit shown during this study period easily outweighs any such theoretical harms.

We also assume that hydrochlorothiazide, a commonly prescribed thiazide, has the same benefits as chlorthalidone, the medication studied.

Most ALLHAT participants with metabolic syndrome already had diabetes: 67.6% of black participants and 51.8% of non-black participants. Another sub-group analysis of the ALLHAT studied patients with metabolic syndrome without diabetes, and found similar results.¹⁹

Of note, lisinopril reduced the onset of diabetes over 5 years (number needed to treat [NNT]=22.2), at the cost of increased heart failure (RR=1.31; 95% confidence interval [CI], 1.04-1.64) and combined cardiovascular disease (RR=1.19; 95% CI, 1.07-1.32). This potentially confounds the claim that thiazides are effective in preventing diabetes, since so many people had it to begin with.

The criteria for metabolic syndrome did not include waist circumference, which is the National Cholesterol Education Program definition. The World Health Organization definition, however, does allow substitution of BMI. Purists would have you believe waist circumference is necessary. In practice, we have come to use BMI as an adequate surrogate. Some say it has, in fact, replaced waist circumference.

CHALLENGES TO IMPLEMENTATION: Inertia

Few interventions are as simple as this. Thiazide diuretics are well tolerated, need to be taken only once daily, and are inexpensive. Because generics are available, little to no pharmaceutical marketing is done to promote their use. The major barriers to implementing this practice may be overcoming clinical inertia, and the message of pharmaceutical marketing on behalf of the more expensive alternatives.

Acknowledgement

We acknowledge Sofia Medvedev, PhD, University HealthSystem Consortium, Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at here.

ILLUSTRATIVE CASE

Your new patient is a 57-year-old African American man. His blood pressure is 150/95 mm Hg, fasting glucose 115 mg/dL, body mass index 32, and triglycerides 155 mg/dL; he is on no prior medications. During the course of his care you diagnose hypertension with metabolic syndrome and decide to recommend an antihypertensive. Thiazide-type diuretics are your standard initial therapy, but this patient has metabolic syndrome, and you know that certain antihypertensive agents have a more favorable metabolic profile than thiazide diuretics. Furthermore, metabolic differences among races have been touted as reason to use other agents in black patients. Should you recommend a thiazide diuretic, or another agent?

Until now, we’ve had no simple approach to treating hypertension in patients with metabolic syndrome—and half or more of our hypertensive patients over the age of 55 have this disorder.

Now, however, we can base decisions on clinical outcomes data from a subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).¹ This new subgroup analysis supports use of thiazide-type diuretics in these patients—particularly in black patients—despite the more favorable metabolic profile of calcium channel blockers, alpha-blockers, and angiotensin-converting enzyme (ACE) inhibitors.

Cost is no longer as big a factor as it once was, now that ACE inhibitors and alpha-blockers, as well as thiazide diuretics, are available generically.

Does a better metabolic profile improve outcomes?

We have had reason to be concerned about the metabolic adverse effects of thiazide-type diuretics in the past. Studies published before this ALLHAT subgroup analysis showed that hydrochlorothiazide for essential hypertension had adverse effects on potassium, glucose, and lipid metabolism. Some speculated that these changes aggravate the metabolic changes in early diabetes^2-4 and may contribute to increased coronary heart disease risk.^5,6

FIGURE
Outcomes favor thiazides

We know many physicians who have adopted thiazide-type diuretics as the first-line treatment for hypertension in metabolic syndrome, but until now, data have been inadequate to support this decision.

A subgroup analysis from the ALLHAT¹ concludes: “The ALLHAT findings fail to support the preference for calcium channel blockers, alpha-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the metabolic syndrome, despite their more favorable metabolic profiles. This was particularly true for black participants.”

ACE inhibitors and ARBs

The metabolic benefits of ACE inhibitors and angiotensin-receptor blockers (ARBs) are widely known. In comparative studies prior to this ALLHAT subgroup analysis, ACE inhibitors were thought to be preferable to thiazide diuretics and beta-blockers for patients with obesity⁷ or the metabolic syndrome.⁸ These agents also protect against diabetic nephropathy.⁹ Other studies attribute additional vascular benefits to ACE inhibitors,¹⁰ beyond that of lowering blood pressure.

A 2005 meta-analysis by Abuissa et al¹¹ showed that ACE inhibitors and ARBs were associated with significant reductions in the incidence of newly diagnosed diabetes, which, in turn, might lead to reduced heart disease. That report concluded that use of ACE inhibitors or ARBs should be considered in patients with prediabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease.

Calcium-channel blockers and alpha-blockers

Calcium-channel blockers and alpha-blockers also do not appear to have the adverse metabolic effects of thiazides, and have also been advocated over beta-blockers and thiazides for hypertensive patients with metabolic syndrome.^12-15

Racial differences

In a consensus statement developed before the findings from the ALLHAT subgroup analysis were available, it was noted that racial differences in metabolic syndrome may make the selection of antihypertensive agents particularly important in African American patients.¹⁶

ALLHAT and JNC7 recommendations

The 2002 ALLHAT demonstrated that chlorthalidone (a thiazide-type diuretic) is superior to lisinopril, amlodipine, and doxazosin in preventing 1 or more major forms of cardiovascular disease. No difference was observed, however, for fatal coronary heart disease, nonfatal myocardial infarction, or all-cause mortality.¹⁷ These findings persisted in sub-group analyses stratified by race, diabetic status, and level of renal function, but ALLHAT did not identify patients with metabolic syndrome a priori.

The ALLHAT influenced the 2003 Joint National Commission VII (JNC7) Report, which recommends thiazide diuretics for first-line treatment of hypertension in the absence of compelling indications to begin an alternative antihypertensive agent.¹⁸

Special consideration, but no recommendation. The JNC7 Report mentions the metabolic syndrome as a special consideration, but does not explicitly recommend a first-line therapy other than thiazides.

Anecdotally, we know many physicians who have adopted thiazide-type diuretics as the first-line treatment for hypertension in metabolic syndrome, but until now, data have been inadequate to support this decision.

STUDY SUMMARY: Chlorthalidone outcomes were equivalent or better

Wright and colleagues analyzed a sub-group¹ of the ALLHAT cohort, which consisted of 42,418 participants, aged ≥55, with hypertension and at least 1 other cardiovascular risk factor ( FIGURE ).

Patients were randomly assigned to therapy with chlorthalidone, amlodipine, lisinopril, or doxazosin. After randomization, if patients failed to reach the target blood pressure (<140/90 mm Hg) with their assigned therapy, they were started on atenolol, clonidine, or reserpine. If they required a third agent, they received hydralazine. The doxazosin arm was stopped early due to increased stroke and heart failure risk.

The ALLHAT was well done and designed for adequate power to evaluate clinical outcomes in racial subgroups, as well as the general population.

Outcomes were compared by race in hypertensive patients with and without metabolic syndrome.

A total of 23,077 (54%) patients met all criteria; 12,818 were black, 7327 (57%) of whom had metabolic syndrome.

Not surprisingly in a study of this size, the expected metabolic effects of all 4 antihypertensive agents were detected. Patients taking chlorthalidone had higher glucose levels (1–4 mg/dL) and higher levels of cholesterol, although these higher glucose and cholesterol levels were not statistically significant for all comparisons over time and between different drugs.

Outcomes in the chlorthalidone group were equivalent or superior to the 3 other therapies, generally. This pattern held true regardless of race ( TABLE ):

Heart failure rates were significantly higher in patients with metabolic syndrome across all treatments compared with chlorthalidone.

Combined cardiovascular disease rates were higher with lisinopril and doxazosin compared with chlorthalidone.

Stroke rates were higher among black participants only in the lisinopril group.

TABLE
Number needed to treat to prevent blood pressure-related adverse outcomes in patients with hypertension and metabolic syndrome

WHAT’S NEW: Most effective, least expensive

First-line use of thiazide diuretics for hypertension gained major support from the findings of the first ALLHAT report, published in 2002. A year later, JNC7 supported the practice. Yet questions have persisted about whether the choice of initial antihypertensive agent in patients with metabolic syndrome warrants special consideration.

The difference for one patient is small, but when you consider the high prevalence of hypertension, the cumulative benefit at a population level is significant. This subgroup analysis confirms that there is no harm, and potentially a small benefit, in using chlorthalidone as a first-line agent for treating hypertension in patients with metabolic syndrome, regardless of race—despite the measurable and presumably adverse effects of diuretic agents on metabolic measurements.

How large is the benefit of first-line thiazides, overall?

Although, statistically, the relative risks (RR) are not large, the sheer number of patients means that there is significant benefit to the selection of thiazides as first-line treatment in most patients.

CAVEATS: Is stroke a concern? Was follow-up sufficient?

In this study, the only finding of harm in the diuretic group was an increased risk for stroke compared with amlodipine among non-black patients with metabolic syndrome. While this finding does raise some uncertainty, we still think that, on balance, thiazides are the most beneficial, even in this subgroup, as there was a larger benefit in preventing heart failure.

Another theoretical possibility is that follow-up was too short to demonstrate harm from the metabolic effects of thiazides. However, the metabolic effects of thiazides are very small and we believe that the evidence of benefit shown during this study period easily outweighs any such theoretical harms.

We also assume that hydrochlorothiazide, a commonly prescribed thiazide, has the same benefits as chlorthalidone, the medication studied.

Most ALLHAT participants with metabolic syndrome already had diabetes: 67.6% of black participants and 51.8% of non-black participants. Another sub-group analysis of the ALLHAT studied patients with metabolic syndrome without diabetes, and found similar results.¹⁹

Of note, lisinopril reduced the onset of diabetes over 5 years (number needed to treat [NNT]=22.2), at the cost of increased heart failure (RR=1.31; 95% confidence interval [CI], 1.04-1.64) and combined cardiovascular disease (RR=1.19; 95% CI, 1.07-1.32). This potentially confounds the claim that thiazides are effective in preventing diabetes, since so many people had it to begin with.

The criteria for metabolic syndrome did not include waist circumference, which is the National Cholesterol Education Program definition. The World Health Organization definition, however, does allow substitution of BMI. Purists would have you believe waist circumference is necessary. In practice, we have come to use BMI as an adequate surrogate. Some say it has, in fact, replaced waist circumference.

CHALLENGES TO IMPLEMENTATION: Inertia

Few interventions are as simple as this. Thiazide diuretics are well tolerated, need to be taken only once daily, and are inexpensive. Because generics are available, little to no pharmaceutical marketing is done to promote their use. The major barriers to implementing this practice may be overcoming clinical inertia, and the message of pharmaceutical marketing on behalf of the more expensive alternatives.

Acknowledgement

We acknowledge Sofia Medvedev, PhD, University HealthSystem Consortium, Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at here.