Eric G. Tangalos, MD

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

The Problem

A 32-year-old male with a history of carpel tunnel syndrome and cannabis dependence presents with a several-month history of aching right elbow pain. He works as a customer service representative for a cellular telephone company. The elbow pain is worse when opening jars, using his computer mouse, brushing his teeth, and eating with a utensil. He has been trying the tennis elbow strap recommended to him by a pharmacist with minimal relief. He takes ibuprofen as needed for pain. On examination, he has pain over the lateral epicondyle and pain with resisted pronation. You diagnose him with lateral epicondylitis.

The Question

In patients with lateral epicondylitis, what conservative therapies are more effective than placebo for improving pain and decreasing dysfunction?

The Search

You open PubMed, and use the PubMed "Clinical Queries" search. You enter "tendinopathy" and identify a meta-analysis on topical nitroglycerin.

Our Critique

The search strategy used to retrieve articles seemed exhaustive, data were extracted independently, and quality assessments were conducted. We found the use of nitroglycerin to be an exciting and somewhat novel therapy for tendinopathies. Nitroglycerin is believed to decrease pain, increase function, and promote healing through the promotion of fibroblastic synthesis of collagen. This therapy could be offered as a next line of conservative options for patients who fail to improve with the tennis elbow strap, NSAIDs, and simple rehabilitation exercises.

Clinical Decision

The evidence would suggest that nitroglycerin is likely to benefit this patient with chronic tendinopathy (of at least 6 weeks duration). You discuss the option with the patient and write for nitroglycerin 0.3% in plastibase and have him apply that once per day. He reports 50% improvement with the nitroglycerin but reports intermittent headache that is relieved through the smoked consumption of marijuana.

The Evidence

Gambito ED, Gonzalez-Suarez CB, Oquiñena TI, Agbayani RB. "Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis," (Arch. Phys. Med. Rehabil. 2010;91:1291-305).

• Criteria for study selection: Studies were eligible for inclusion if they were randomized, controlled clinical trials (RCTs) comparing topical nitroglycerin with placebo, a controlled comparison intervention, or standard care. Nitroglycerin formulations could be patches or ointments. Trials were further restricted to those including adults, using pain as an outcome measure, and subjects had a diagnosis of tendinopathy meeting criteria for acute (less than 2 weeks), subacute (2-6 weeks), and chronic (longer than 6 weeks). Searches involving multiple databases were conducted to identify articles published from January 1990 to March 2009.

• Outcomes: The primary outcome of interest was pain reduction measured subjectively with visual analog scales or Likert scales or objectively with local tenderness scales. Secondary outcomes included range of motion and strength.

• Findings: Searches retrieved 163 published articles, of which 7 were considered potentially relevant. The remaining articles were rejected because they were not RCTs. All seven included studies were deemed to be of high methodologic quality. Five studies evaluated chronic cases, one enrolled subacute and acute cases, and one study included only acute cases. Three studies evaluated patients with shoulder tendinopathies (chronic supraspinatus tendinopathy, acute/subacute rotator cuff tendinitis, acute supraspinatus tendinitis), two selected subjects with elbow tendinopathies (chronic lateral epicondylitis, chronic extensor tendinosis), and two studies evaluated patients with chronic noninsertional Achilles’ tendinopathy. The seven trials involved a total of 446 patients with ages ranging from 18 to 79 years. Five studies compared glyceryl trinitrate with placebo, one study compared nitroglycerin with local injection of a steroid-anesthetic solution, and one study evaluated topical nitroglycerin and tendon rehabilitation, compared with tendon rehabilitation alone. Three studies administered 1.25 mg/24 hours (or one-fourth of a 5 mg/24h patch) daily, one delivered 2.5 mg/24 hours combined with tendon rehabilitation for 24 weeks, one applied 5 mg/24 hours preparations daily for 3 days only, one applied 5 mg/24 hours daily for 3 days up to three trials of 15-day intervals, and one applied three different daily doses: (0.72 mg, 1.44 mg, and 3.6 mg) for 8 weeks. In the meta-analyses, nitroglycerin reduced pain during activities of daily living in chronic tendinopathies [odds ratio 4.44; 95% confidence interval: 2.34-8.40] and in both acute and chronic phases combined (OR 4.86; 95% CI: 2.62-9.02). Two studies reported enhanced joint mobility with topical nitroglycerin and one study (chronic supraspinatus tendinopathy) noted an increase in range of motion, increased shoulder abduction, and internal rotation. With respect to local tenderness, one study reported a reduction in local tenderness at 6 weeks and another observed a reduction at 12 weeks. Three studies reported a significant improvement in peak muscle force as assessed by a dynamometer at 24 weeks. Nitroglycerin is likely to cause headache (OR 1.73; 95% CI: 1.01-2.97), but does not appear to increase the risk for contact dermatitis.

Dr. Ebbert and Dr. Tangalos are with the Mayo Clinic in Rochester, Minn. They report having no conflicts of interest. To respond to this column or suggest topics for consideration, write to Dr. Ebbert and Dr. Tangalos at our editorial offices or e-mail them at [email protected].

The Problem

A 32-year-old male with a history of carpel tunnel syndrome and cannabis dependence presents with a several-month history of aching right elbow pain. He works as a customer service representative for a cellular telephone company. The elbow pain is worse when opening jars, using his computer mouse, brushing his teeth, and eating with a utensil. He has been trying the tennis elbow strap recommended to him by a pharmacist with minimal relief. He takes ibuprofen as needed for pain. On examination, he has pain over the lateral epicondyle and pain with resisted pronation. You diagnose him with lateral epicondylitis.

The Question

In patients with lateral epicondylitis, what conservative therapies are more effective than placebo for improving pain and decreasing dysfunction?

The Search

You open PubMed, and use the PubMed "Clinical Queries" search. You enter "tendinopathy" and identify a meta-analysis on topical nitroglycerin.

Our Critique

The search strategy used to retrieve articles seemed exhaustive, data were extracted independently, and quality assessments were conducted. We found the use of nitroglycerin to be an exciting and somewhat novel therapy for tendinopathies. Nitroglycerin is believed to decrease pain, increase function, and promote healing through the promotion of fibroblastic synthesis of collagen. This therapy could be offered as a next line of conservative options for patients who fail to improve with the tennis elbow strap, NSAIDs, and simple rehabilitation exercises.

Clinical Decision

The evidence would suggest that nitroglycerin is likely to benefit this patient with chronic tendinopathy (of at least 6 weeks duration). You discuss the option with the patient and write for nitroglycerin 0.3% in plastibase and have him apply that once per day. He reports 50% improvement with the nitroglycerin but reports intermittent headache that is relieved through the smoked consumption of marijuana.

The Evidence

Gambito ED, Gonzalez-Suarez CB, Oquiñena TI, Agbayani RB. "Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis," (Arch. Phys. Med. Rehabil. 2010;91:1291-305).

• Criteria for study selection: Studies were eligible for inclusion if they were randomized, controlled clinical trials (RCTs) comparing topical nitroglycerin with placebo, a controlled comparison intervention, or standard care. Nitroglycerin formulations could be patches or ointments. Trials were further restricted to those including adults, using pain as an outcome measure, and subjects had a diagnosis of tendinopathy meeting criteria for acute (less than 2 weeks), subacute (2-6 weeks), and chronic (longer than 6 weeks). Searches involving multiple databases were conducted to identify articles published from January 1990 to March 2009.

• Outcomes: The primary outcome of interest was pain reduction measured subjectively with visual analog scales or Likert scales or objectively with local tenderness scales. Secondary outcomes included range of motion and strength.

• Findings: Searches retrieved 163 published articles, of which 7 were considered potentially relevant. The remaining articles were rejected because they were not RCTs. All seven included studies were deemed to be of high methodologic quality. Five studies evaluated chronic cases, one enrolled subacute and acute cases, and one study included only acute cases. Three studies evaluated patients with shoulder tendinopathies (chronic supraspinatus tendinopathy, acute/subacute rotator cuff tendinitis, acute supraspinatus tendinitis), two selected subjects with elbow tendinopathies (chronic lateral epicondylitis, chronic extensor tendinosis), and two studies evaluated patients with chronic noninsertional Achilles’ tendinopathy. The seven trials involved a total of 446 patients with ages ranging from 18 to 79 years. Five studies compared glyceryl trinitrate with placebo, one study compared nitroglycerin with local injection of a steroid-anesthetic solution, and one study evaluated topical nitroglycerin and tendon rehabilitation, compared with tendon rehabilitation alone. Three studies administered 1.25 mg/24 hours (or one-fourth of a 5 mg/24h patch) daily, one delivered 2.5 mg/24 hours combined with tendon rehabilitation for 24 weeks, one applied 5 mg/24 hours preparations daily for 3 days only, one applied 5 mg/24 hours daily for 3 days up to three trials of 15-day intervals, and one applied three different daily doses: (0.72 mg, 1.44 mg, and 3.6 mg) for 8 weeks. In the meta-analyses, nitroglycerin reduced pain during activities of daily living in chronic tendinopathies [odds ratio 4.44; 95% confidence interval: 2.34-8.40] and in both acute and chronic phases combined (OR 4.86; 95% CI: 2.62-9.02). Two studies reported enhanced joint mobility with topical nitroglycerin and one study (chronic supraspinatus tendinopathy) noted an increase in range of motion, increased shoulder abduction, and internal rotation. With respect to local tenderness, one study reported a reduction in local tenderness at 6 weeks and another observed a reduction at 12 weeks. Three studies reported a significant improvement in peak muscle force as assessed by a dynamometer at 24 weeks. Nitroglycerin is likely to cause headache (OR 1.73; 95% CI: 1.01-2.97), but does not appear to increase the risk for contact dermatitis.

Dr. Ebbert and Dr. Tangalos are with the Mayo Clinic in Rochester, Minn. They report having no conflicts of interest. To respond to this column or suggest topics for consideration, write to Dr. Ebbert and Dr. Tangalos at our editorial offices or e-mail them at [email protected].

The Problem

A 32-year-old male with a history of carpel tunnel syndrome and cannabis dependence presents with a several-month history of aching right elbow pain. He works as a customer service representative for a cellular telephone company. The elbow pain is worse when opening jars, using his computer mouse, brushing his teeth, and eating with a utensil. He has been trying the tennis elbow strap recommended to him by a pharmacist with minimal relief. He takes ibuprofen as needed for pain. On examination, he has pain over the lateral epicondyle and pain with resisted pronation. You diagnose him with lateral epicondylitis.

The Question

In patients with lateral epicondylitis, what conservative therapies are more effective than placebo for improving pain and decreasing dysfunction?

The Search

You open PubMed, and use the PubMed "Clinical Queries" search. You enter "tendinopathy" and identify a meta-analysis on topical nitroglycerin.

Our Critique

The search strategy used to retrieve articles seemed exhaustive, data were extracted independently, and quality assessments were conducted. We found the use of nitroglycerin to be an exciting and somewhat novel therapy for tendinopathies. Nitroglycerin is believed to decrease pain, increase function, and promote healing through the promotion of fibroblastic synthesis of collagen. This therapy could be offered as a next line of conservative options for patients who fail to improve with the tennis elbow strap, NSAIDs, and simple rehabilitation exercises.

Clinical Decision

The evidence would suggest that nitroglycerin is likely to benefit this patient with chronic tendinopathy (of at least 6 weeks duration). You discuss the option with the patient and write for nitroglycerin 0.3% in plastibase and have him apply that once per day. He reports 50% improvement with the nitroglycerin but reports intermittent headache that is relieved through the smoked consumption of marijuana.

The Evidence

Gambito ED, Gonzalez-Suarez CB, Oquiñena TI, Agbayani RB. "Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis," (Arch. Phys. Med. Rehabil. 2010;91:1291-305).

• Criteria for study selection: Studies were eligible for inclusion if they were randomized, controlled clinical trials (RCTs) comparing topical nitroglycerin with placebo, a controlled comparison intervention, or standard care. Nitroglycerin formulations could be patches or ointments. Trials were further restricted to those including adults, using pain as an outcome measure, and subjects had a diagnosis of tendinopathy meeting criteria for acute (less than 2 weeks), subacute (2-6 weeks), and chronic (longer than 6 weeks). Searches involving multiple databases were conducted to identify articles published from January 1990 to March 2009.

• Outcomes: The primary outcome of interest was pain reduction measured subjectively with visual analog scales or Likert scales or objectively with local tenderness scales. Secondary outcomes included range of motion and strength.

• Findings: Searches retrieved 163 published articles, of which 7 were considered potentially relevant. The remaining articles were rejected because they were not RCTs. All seven included studies were deemed to be of high methodologic quality. Five studies evaluated chronic cases, one enrolled subacute and acute cases, and one study included only acute cases. Three studies evaluated patients with shoulder tendinopathies (chronic supraspinatus tendinopathy, acute/subacute rotator cuff tendinitis, acute supraspinatus tendinitis), two selected subjects with elbow tendinopathies (chronic lateral epicondylitis, chronic extensor tendinosis), and two studies evaluated patients with chronic noninsertional Achilles’ tendinopathy. The seven trials involved a total of 446 patients with ages ranging from 18 to 79 years. Five studies compared glyceryl trinitrate with placebo, one study compared nitroglycerin with local injection of a steroid-anesthetic solution, and one study evaluated topical nitroglycerin and tendon rehabilitation, compared with tendon rehabilitation alone. Three studies administered 1.25 mg/24 hours (or one-fourth of a 5 mg/24h patch) daily, one delivered 2.5 mg/24 hours combined with tendon rehabilitation for 24 weeks, one applied 5 mg/24 hours preparations daily for 3 days only, one applied 5 mg/24 hours daily for 3 days up to three trials of 15-day intervals, and one applied three different daily doses: (0.72 mg, 1.44 mg, and 3.6 mg) for 8 weeks. In the meta-analyses, nitroglycerin reduced pain during activities of daily living in chronic tendinopathies [odds ratio 4.44; 95% confidence interval: 2.34-8.40] and in both acute and chronic phases combined (OR 4.86; 95% CI: 2.62-9.02). Two studies reported enhanced joint mobility with topical nitroglycerin and one study (chronic supraspinatus tendinopathy) noted an increase in range of motion, increased shoulder abduction, and internal rotation. With respect to local tenderness, one study reported a reduction in local tenderness at 6 weeks and another observed a reduction at 12 weeks. Three studies reported a significant improvement in peak muscle force as assessed by a dynamometer at 24 weeks. Nitroglycerin is likely to cause headache (OR 1.73; 95% CI: 1.01-2.97), but does not appear to increase the risk for contact dermatitis.

Dr. Ebbert and Dr. Tangalos are with the Mayo Clinic in Rochester, Minn. They report having no conflicts of interest. To respond to this column or suggest topics for consideration, write to Dr. Ebbert and Dr. Tangalos at our editorial offices or e-mail them at [email protected].