The Journal of Family Practice

For H pylori ulcers, 7 days of therapy does the trick

A 2005 meta-analysis of 6 RCTs with 862 patients compared 7 days of triple therapy with a PPI and 2 antibiotics with the same regimen followed by 2 to 4 additional weeks of PPI therapy.¹ One RCT studied both duodenal and gastric ulcers; the remaining 5 assessed only duodenal ulcers. Investigators included only studies that clearly identified both H pylori eradication and ulcer healing as treatment goals and specified the number of patients treated, the number who experienced successful healing, endoscopic ulcer confirmation, and no concurrent NSAID use.

Triple therapy regimens comprised either omeprazole or esomeprazole 20 mg twice daily plus clarithromycin and either metronidazole, amoxicillin, or tinidazole for 7 days. In all studies, patients randomly assigned to receive an additional 2 to 4 weeks of PPI treatment were given omeprazole 20 mg/d.

Mean ulcer healing rates were 91% (95% confidence interval [CI], 87%-95%) for 7 days of PPI triple therapy compared with 92% (95% CI, 89%-96%) when PPI treatment was extended for an additional 2 to 4 weeks (odds ratio=1.1; 95% CI, 0.71-1.7).

Longer PPI therapy works better for NSAID-associated gastric ulcers

A 1998 meta-analysis examined 2 large RCTs that evaluated healing rates of NSAID-associated ulcers at 4 weeks and 8 weeks in 656 patients with gastric or duodenal ulcers who were treated with omeprazole 20 mg/d or 40 mg/d.² Patients had ulcers 3 mm or larger or more than 10 erosions in the stomach or duodenum. Gastric ulcers outnumbered duodenal ulcers 2 to 1. Patients had taken continuous therapeutic doses of NSAIDs for at least 5 days per week during 2 weeks in the month preceding PPI therapy; about half were H pylori-positive.

For gastric ulcers, treatment success at 8 weeks was significantly higher at both PPI doses than at 4 weeks. The 208 patients taking the 20-mg dose showed 67% treatment success at 4 weeks and 83% at 8 weeks (P=.001). The 212 patients taking 40 mg had 67% treatment success at 4 weeks and 82% at 8 weeks (P=.002).

Duodenal ulcers showed no difference in healing at 4 and 8 weeks at either PPI dose. The 20-mg dose (116 patients) produced 84% treatment success at 4 weeks compared with 93% at 8 weeks (P=.2), and the 40-mg dose (120 patients) showed 86% treatment success at 4 weeks compared with 88% at 8 weeks (P=.8).

Procedure-induced ulcers respond similarly to 4- and 8-week regimens

A 2014 RCT assessed the effect of 4 and 8 weeks of PPI treatment on healing of gastric ulcers resulting from endoscopic submucosal dissection (ESD), a procedure used to treat early gastric cancer or adenoma that leaves a large ulcer at the site.³ The study randomly assigned 84 patients to treatment with lansoprazole 30 mg/d for 4 or 8 weeks after undergoing ESD. Exclusion criteria included NSAID use or ingestion of mucosal protective agents within 4 weeks of the procedure, illness that might influence PPI effects, history of gastric surgery, and pregnancy or breastfeeding.

All patients underwent endoscopy the day after ESD and again at 8 weeks. Ulcer dimension (mm²) was determined by multiplying the longest diameter by the diameter perpendicular to the longest diameter. The ulcer reduction ratio, an assessment of healing, was determined by dividing the ulcer dimension at 8 weeks after ESD by the initial ulcer dimension.

No significant difference was observed in the 4-week and 8-week groups in terms of ulcer healing (68% vs 69%, respectively; P=.93) or the ulcer reduction ratio (0.0081 vs 0.0037, respectively; P=.15).

For H pylori ulcers, 7 days of therapy does the trick

A 2005 meta-analysis of 6 RCTs with 862 patients compared 7 days of triple therapy with a PPI and 2 antibiotics with the same regimen followed by 2 to 4 additional weeks of PPI therapy.¹ One RCT studied both duodenal and gastric ulcers; the remaining 5 assessed only duodenal ulcers. Investigators included only studies that clearly identified both H pylori eradication and ulcer healing as treatment goals and specified the number of patients treated, the number who experienced successful healing, endoscopic ulcer confirmation, and no concurrent NSAID use.

Triple therapy regimens comprised either omeprazole or esomeprazole 20 mg twice daily plus clarithromycin and either metronidazole, amoxicillin, or tinidazole for 7 days. In all studies, patients randomly assigned to receive an additional 2 to 4 weeks of PPI treatment were given omeprazole 20 mg/d.

Mean ulcer healing rates were 91% (95% confidence interval [CI], 87%-95%) for 7 days of PPI triple therapy compared with 92% (95% CI, 89%-96%) when PPI treatment was extended for an additional 2 to 4 weeks (odds ratio=1.1; 95% CI, 0.71-1.7).

Longer PPI therapy works better for NSAID-associated gastric ulcers

A 1998 meta-analysis examined 2 large RCTs that evaluated healing rates of NSAID-associated ulcers at 4 weeks and 8 weeks in 656 patients with gastric or duodenal ulcers who were treated with omeprazole 20 mg/d or 40 mg/d.² Patients had ulcers 3 mm or larger or more than 10 erosions in the stomach or duodenum. Gastric ulcers outnumbered duodenal ulcers 2 to 1. Patients had taken continuous therapeutic doses of NSAIDs for at least 5 days per week during 2 weeks in the month preceding PPI therapy; about half were H pylori-positive.

For gastric ulcers, treatment success at 8 weeks was significantly higher at both PPI doses than at 4 weeks. The 208 patients taking the 20-mg dose showed 67% treatment success at 4 weeks and 83% at 8 weeks (P=.001). The 212 patients taking 40 mg had 67% treatment success at 4 weeks and 82% at 8 weeks (P=.002).

Duodenal ulcers showed no difference in healing at 4 and 8 weeks at either PPI dose. The 20-mg dose (116 patients) produced 84% treatment success at 4 weeks compared with 93% at 8 weeks (P=.2), and the 40-mg dose (120 patients) showed 86% treatment success at 4 weeks compared with 88% at 8 weeks (P=.8).

Procedure-induced ulcers respond similarly to 4- and 8-week regimens

A 2014 RCT assessed the effect of 4 and 8 weeks of PPI treatment on healing of gastric ulcers resulting from endoscopic submucosal dissection (ESD), a procedure used to treat early gastric cancer or adenoma that leaves a large ulcer at the site.³ The study randomly assigned 84 patients to treatment with lansoprazole 30 mg/d for 4 or 8 weeks after undergoing ESD. Exclusion criteria included NSAID use or ingestion of mucosal protective agents within 4 weeks of the procedure, illness that might influence PPI effects, history of gastric surgery, and pregnancy or breastfeeding.

All patients underwent endoscopy the day after ESD and again at 8 weeks. Ulcer dimension (mm²) was determined by multiplying the longest diameter by the diameter perpendicular to the longest diameter. The ulcer reduction ratio, an assessment of healing, was determined by dividing the ulcer dimension at 8 weeks after ESD by the initial ulcer dimension.

No significant difference was observed in the 4-week and 8-week groups in terms of ulcer healing (68% vs 69%, respectively; P=.93) or the ulcer reduction ratio (0.0081 vs 0.0037, respectively; P=.15).

For H pylori ulcers, 7 days of therapy does the trick

A 2005 meta-analysis of 6 RCTs with 862 patients compared 7 days of triple therapy with a PPI and 2 antibiotics with the same regimen followed by 2 to 4 additional weeks of PPI therapy.¹ One RCT studied both duodenal and gastric ulcers; the remaining 5 assessed only duodenal ulcers. Investigators included only studies that clearly identified both H pylori eradication and ulcer healing as treatment goals and specified the number of patients treated, the number who experienced successful healing, endoscopic ulcer confirmation, and no concurrent NSAID use.

Triple therapy regimens comprised either omeprazole or esomeprazole 20 mg twice daily plus clarithromycin and either metronidazole, amoxicillin, or tinidazole for 7 days. In all studies, patients randomly assigned to receive an additional 2 to 4 weeks of PPI treatment were given omeprazole 20 mg/d.

Mean ulcer healing rates were 91% (95% confidence interval [CI], 87%-95%) for 7 days of PPI triple therapy compared with 92% (95% CI, 89%-96%) when PPI treatment was extended for an additional 2 to 4 weeks (odds ratio=1.1; 95% CI, 0.71-1.7).

Longer PPI therapy works better for NSAID-associated gastric ulcers

A 1998 meta-analysis examined 2 large RCTs that evaluated healing rates of NSAID-associated ulcers at 4 weeks and 8 weeks in 656 patients with gastric or duodenal ulcers who were treated with omeprazole 20 mg/d or 40 mg/d.² Patients had ulcers 3 mm or larger or more than 10 erosions in the stomach or duodenum. Gastric ulcers outnumbered duodenal ulcers 2 to 1. Patients had taken continuous therapeutic doses of NSAIDs for at least 5 days per week during 2 weeks in the month preceding PPI therapy; about half were H pylori-positive.

For gastric ulcers, treatment success at 8 weeks was significantly higher at both PPI doses than at 4 weeks. The 208 patients taking the 20-mg dose showed 67% treatment success at 4 weeks and 83% at 8 weeks (P=.001). The 212 patients taking 40 mg had 67% treatment success at 4 weeks and 82% at 8 weeks (P=.002).

Duodenal ulcers showed no difference in healing at 4 and 8 weeks at either PPI dose. The 20-mg dose (116 patients) produced 84% treatment success at 4 weeks compared with 93% at 8 weeks (P=.2), and the 40-mg dose (120 patients) showed 86% treatment success at 4 weeks compared with 88% at 8 weeks (P=.8).

Procedure-induced ulcers respond similarly to 4- and 8-week regimens

A 2014 RCT assessed the effect of 4 and 8 weeks of PPI treatment on healing of gastric ulcers resulting from endoscopic submucosal dissection (ESD), a procedure used to treat early gastric cancer or adenoma that leaves a large ulcer at the site.³ The study randomly assigned 84 patients to treatment with lansoprazole 30 mg/d for 4 or 8 weeks after undergoing ESD. Exclusion criteria included NSAID use or ingestion of mucosal protective agents within 4 weeks of the procedure, illness that might influence PPI effects, history of gastric surgery, and pregnancy or breastfeeding.

All patients underwent endoscopy the day after ESD and again at 8 weeks. Ulcer dimension (mm²) was determined by multiplying the longest diameter by the diameter perpendicular to the longest diameter. The ulcer reduction ratio, an assessment of healing, was determined by dividing the ulcer dimension at 8 weeks after ESD by the initial ulcer dimension.

No significant difference was observed in the 4-week and 8-week groups in terms of ulcer healing (68% vs 69%, respectively; P=.93) or the ulcer reduction ratio (0.0081 vs 0.0037, respectively; P=.15).

Patients who meet PTSD criteria show best response

A 2012 systematic review of prazosin (1-16 mg) for PTSD included 21 studies (4 RCTs, 4 open-label case series, 4 retrospective case series, and 9 case reports) with 285 patients, 85% of whom were combat veterans.¹ All the studies were limited by small sample sizes and a lack of demographic diversity.

To measure prazosin’s effect on nightmares, the studies used the Clinician-Administered PTSD Scale (CAPS-B2), scored from 0 to 8, which sums the frequency of nightmares (0=none in the past week, 4=daily nightmares) and the intensity of distressing dreams (0=none, 4=incapacitating distress).

The 3 highest-quality RCTs used similar methods and included only 63 patients who met diagnostic criteria for PTSD. Each found statistically significant reductions in nightmares among patients taking prazosin compared with placebo (CAPS-B2 improvements of 3.3, 3.3, and 1.5 for prazosin vs 0.4, 0.9, and 0 for placebo; P<.05 for all comparisons).

In the fourth RCT, comprised of 50 patients, only 58% of participants met full clinical diagnostic criteria for PTSD. The primary outcome was the number of recalled nightmares, which didn’t show a statistically significant decrease in the prazosin group compared with placebo (decrease in mean weekly nightmares of 0.7 with prazosin vs an increase of 0.1 with placebo).

Prazosin provides significant relief in small study of combat veterans

A 2013 RCT evaluated the effect of prazosin on nightmares in 67 soldiers with combat PTSD.² All patients met criteria for PTSD as outlined in the Diagnostic and Statistical Manual of Mental Disorders, 4^th edition. Men received doses titrated to a mean of 4 mg in the morning and 15.6 mg at bedtime; women received a mean of 1.7 mg in the morning and 7 mg at bedtime.

After 15 weeks, the CAPS-B2 score decreased by 3.1 for prazosin compared with 1.2 for placebo (P<.05).

Patients who meet PTSD criteria show best response

A 2012 systematic review of prazosin (1-16 mg) for PTSD included 21 studies (4 RCTs, 4 open-label case series, 4 retrospective case series, and 9 case reports) with 285 patients, 85% of whom were combat veterans.¹ All the studies were limited by small sample sizes and a lack of demographic diversity.

To measure prazosin’s effect on nightmares, the studies used the Clinician-Administered PTSD Scale (CAPS-B2), scored from 0 to 8, which sums the frequency of nightmares (0=none in the past week, 4=daily nightmares) and the intensity of distressing dreams (0=none, 4=incapacitating distress).

The 3 highest-quality RCTs used similar methods and included only 63 patients who met diagnostic criteria for PTSD. Each found statistically significant reductions in nightmares among patients taking prazosin compared with placebo (CAPS-B2 improvements of 3.3, 3.3, and 1.5 for prazosin vs 0.4, 0.9, and 0 for placebo; P<.05 for all comparisons).

In the fourth RCT, comprised of 50 patients, only 58% of participants met full clinical diagnostic criteria for PTSD. The primary outcome was the number of recalled nightmares, which didn’t show a statistically significant decrease in the prazosin group compared with placebo (decrease in mean weekly nightmares of 0.7 with prazosin vs an increase of 0.1 with placebo).

Prazosin provides significant relief in small study of combat veterans

A 2013 RCT evaluated the effect of prazosin on nightmares in 67 soldiers with combat PTSD.² All patients met criteria for PTSD as outlined in the Diagnostic and Statistical Manual of Mental Disorders, 4^th edition. Men received doses titrated to a mean of 4 mg in the morning and 15.6 mg at bedtime; women received a mean of 1.7 mg in the morning and 7 mg at bedtime.

After 15 weeks, the CAPS-B2 score decreased by 3.1 for prazosin compared with 1.2 for placebo (P<.05).

Patients who meet PTSD criteria show best response

A 2012 systematic review of prazosin (1-16 mg) for PTSD included 21 studies (4 RCTs, 4 open-label case series, 4 retrospective case series, and 9 case reports) with 285 patients, 85% of whom were combat veterans.¹ All the studies were limited by small sample sizes and a lack of demographic diversity.

To measure prazosin’s effect on nightmares, the studies used the Clinician-Administered PTSD Scale (CAPS-B2), scored from 0 to 8, which sums the frequency of nightmares (0=none in the past week, 4=daily nightmares) and the intensity of distressing dreams (0=none, 4=incapacitating distress).

The 3 highest-quality RCTs used similar methods and included only 63 patients who met diagnostic criteria for PTSD. Each found statistically significant reductions in nightmares among patients taking prazosin compared with placebo (CAPS-B2 improvements of 3.3, 3.3, and 1.5 for prazosin vs 0.4, 0.9, and 0 for placebo; P<.05 for all comparisons).

In the fourth RCT, comprised of 50 patients, only 58% of participants met full clinical diagnostic criteria for PTSD. The primary outcome was the number of recalled nightmares, which didn’t show a statistically significant decrease in the prazosin group compared with placebo (decrease in mean weekly nightmares of 0.7 with prazosin vs an increase of 0.1 with placebo).

Prazosin provides significant relief in small study of combat veterans

A 2013 RCT evaluated the effect of prazosin on nightmares in 67 soldiers with combat PTSD.² All patients met criteria for PTSD as outlined in the Diagnostic and Statistical Manual of Mental Disorders, 4^th edition. Men received doses titrated to a mean of 4 mg in the morning and 15.6 mg at bedtime; women received a mean of 1.7 mg in the morning and 7 mg at bedtime.

After 15 weeks, the CAPS-B2 score decreased by 3.1 for prazosin compared with 1.2 for placebo (P<.05).

Illustrative case

A 75-year-old man comes to your office for surgical clearance before right knee replacement surgery. He has diabetes and high blood pressure, and is taking warfarin for atrial fibrillation. He is scheduled for surgery in a week. What is the safest way to manage his warfarin in the perioperative period?

More than 2 million people are being treated with oral anticoagulation in North America to prevent stroke, or to prevent or treat venous thromboembolism.² Since 2010, several new oral anticoagulants have been approved, including dabigatran, apixaban, and rivaroxaban. These new medications have a shorter half-life than older anticoagulants, which enables them to be stopped 1 to 2 days before surgery.

On the other hand, warfarin—which remains a common choice for anticoagulation—has a 3- to 7-day onset and elimination.^3,4 This long clinical half-life presents a special challenge during the perioperative period. To reduce the risk of operative bleeding, the warfarin must be stopped days prior to the procedure, but physicians often worry that this will increase the risk of arterial or venous thromboembolism, including stroke.

An estimated 250,000 patients need perioperative management of their anticoagulation each year.⁵ As the US population continues to age and the incidence of conditions requiring anticoagulation (particularly atrial fibrillation) increases, this number is only going to rise.⁶

Current guidelines on bridging. American College of Chest Physicians (ACCP) guidelines recommend transition to “a short-acting anticoagulant, consisting of subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin, for a 10- to 12-day period during interruption of vitamin K antagonist (VKA) therapy.”⁵ Furthermore, for an appropriate bridging regimen, the ACCP guidelines recommend stopping VKA therapy 5 days prior to the procedure and utilizing LMWH from within 24 to 48 hours of stopping VKA therapy until up to 24 hours before surgery.⁵ Postoperatively, VKA or LMWH therapy should be reinitiated within 24 hours and 24 to 72 hours, respectively, depending on the patient’s risk of bleeding during surgery.⁵

These guidelines recommend using CHADS₂ scoring (TABLE³) to determine arterial thromboembolism (ATE) risk in atrial fibrillation.^3,5 Patients at low risk for ATE (CHADS₂ score 0-2) should not be bridged, and patients at high risk (CHADS₂ score of 5-6) should always be bridged.⁵ These guidelines are less clear about bridging recommendations for moderate-risk patients (CHADS₂ score 3-4).

Previous evidence on bridging. A 2012 meta-analysis of 34 studies evaluated the safety and efficacy of perioperative bridging with heparin in patients receiving VKA.⁷ Researchers found no difference in ATE events in 8 studies that compared groups that received bridging vs groups that simply stopped anticoagulation (odds ratio [OR]=0.80; 95% confidence interval [CI], 0.42–1.54).⁷ The group that received bridging had an increased risk of overall bleeding in 13 studies, and of major bleeding in 5 studies.⁷ This meta-analysis was limited by poor study quality and variation in the indication for VKA therapy.

A 2015 subgroup analysis of a larger cohort study of patients receiving anticoagulants for atrial fibrillation found an increased risk of bleeding when their anticoagulation was interrupted for procedures (OR for major bleeding=3.84; 95% CI, 2.07-7.14; P<.0001).⁸

Douketis et al¹ conducted a randomized trial to clarify the need for and safety of bridging anticoagulation for ATE in patients with atrial fibrillation who were receiving warfarin.

STUDY SUMMARY: When it comes to stroke/TIA, there’s no advantage to bridging

This double blind, placebo-controlled trial compared bridging with dalteparin, a form of LMWH, to placebo among 1884 patients with atrial fibrillation on warfarin whose anticoagulation therapy needed to be interrupted for an elective procedure. Patients were included if they were receiving warfarin to prevent stroke, and had been on warfarin for at least 12 weeks, with a goal international normalized ratio (INR) of 2.0 to 3.0. Exclusion criteria included having a mechanical heart valve or having a stroke/transient ischemic attack (TIA; 12 weeks prior) or major bleeding (6 weeks prior). Cardiac, intracranial, and intraspinal surgeries were also excluded from the study.

The patients’ mean CHADS₂ score was 2.3; 38.3% of patients had a CHADS₂ score ≥3, and 9.4% of patients had a history of stroke. Forty-four percent of patients underwent a gastrointestinal procedure, 17.2% underwent a cardiothoracic procedure, and 9.2% underwent an orthopedic procedure.

Guidelines are not clear about whether patients at moderate risk of arterial thromboembolism need bridging.

Patients stopped taking warfarin 5 days before their procedure, and began subcutaneous dalteparin, 100 IU/kg, or an identical placebo 3 days before the procedure. The dalteparin/placebo was stopped 24 hours before the procedure and restarted after the procedure, until the patient’s INR was in the therapeutic range. Warfarin was resumed on the evening of the procedure or the following day.

The primary efficacy outcome was ATE, including stroke, TIA, or systemic embolism. The primary safety endpoint was major bleeding (defined as bleeding at a critical anatomic site, symptomatic or clinically overt bleeding, or a decrease in hemoglobin >2 g/dL). Secondary efficacy and safety outcomes included minor bleeding, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, and death. Outcomes were assessed within 37 days of the procedure.

The incidence of ATE was 0.4% (4 events) in the no-bridging group vs 0.3% (3 events) in the bridging group (95% CI, -0.6 to 0.8; P=.01 for non-inferiority; P=.73 for superiority). Major bleeding occurred in 1.3% of the no-bridging group (12 events) and in 3.2% of the bridging group (29 events), indicating that no bridging was superior in terms of the major bleeding outcome (number needed to harm [NNH]=53; relative risk [RR]=0.41; 95% CI, 0.20-0.78; P=.005). The no-bridging group also had significantly fewer minor bleeds in comparison to the bridging group (NNH=11; 12% vs 20.9%; P<.001). There were no differences between groups in other secondary outcomes.

WHAT'S NEW: High-quality evidence suggests it’s OK to stop warfarin before surgery

This is the largest good-quality study to evaluate perioperative bridging in patients with atrial fibrillation who were at low or moderate risk for ATE (CHADS₂ score 0-4). Previous studies suggested bridging increased bleeding and offered limited benefit for reducing the risk of ATE. However, this is the first study to include a large group of moderate-risk patients (CHADS₂ score 3-4). This trial provides high-quality evidence to support the practice of simply stopping warfarin in the perioperative period, rather than bridging with LMWH.

CAVEATS: Findings might not apply to patients at highest risk

Most patients in this study had a CHADS₂ score ≤3. About 3% had a CHADS₂ score ≥5 or higher. It’s not clear whether these findings apply to patients with a CHADS₂ score of 5 or 6.

This trial categorized ATE risk using the CHADS₂ score, rather than the CHA₂DS₂-VASc, which includes additional risk factors and may more accurately predict stroke risk. Both patients who received bridging therapy and those who did not had a lower rate of stroke than predicted by CHADs₂. This may reflect a limit of the predictive value of CHADS₂, but should not have affected the rate of bleeding or ATE outcomes in this study.

CHALLENGES TO IMPLEMENTATION: Physicians may hesitate to disregard current guidelines

Strokes are devastating events for patients, families, and physicians, and they pose a greater risk of morbidity and mortality compared to bleeding. However, this study suggests patients who receive bridging have a higher risk of bleeding than stroke, which is in contrast to some physicians’ experience and current recommendations.

A physician caring for a patient who’s had a stroke may be inclined to recommend bridging despite the lack of efficacy and evidence of bleeding risk. Additionally, until guidelines reflect the most current research, physicians may be reluctant to provide care in contrast to these recommendations.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was 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 75-year-old man comes to your office for surgical clearance before right knee replacement surgery. He has diabetes and high blood pressure, and is taking warfarin for atrial fibrillation. He is scheduled for surgery in a week. What is the safest way to manage his warfarin in the perioperative period?

More than 2 million people are being treated with oral anticoagulation in North America to prevent stroke, or to prevent or treat venous thromboembolism.² Since 2010, several new oral anticoagulants have been approved, including dabigatran, apixaban, and rivaroxaban. These new medications have a shorter half-life than older anticoagulants, which enables them to be stopped 1 to 2 days before surgery.

On the other hand, warfarin—which remains a common choice for anticoagulation—has a 3- to 7-day onset and elimination.^3,4 This long clinical half-life presents a special challenge during the perioperative period. To reduce the risk of operative bleeding, the warfarin must be stopped days prior to the procedure, but physicians often worry that this will increase the risk of arterial or venous thromboembolism, including stroke.

An estimated 250,000 patients need perioperative management of their anticoagulation each year.⁵ As the US population continues to age and the incidence of conditions requiring anticoagulation (particularly atrial fibrillation) increases, this number is only going to rise.⁶

Current guidelines on bridging. American College of Chest Physicians (ACCP) guidelines recommend transition to “a short-acting anticoagulant, consisting of subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin, for a 10- to 12-day period during interruption of vitamin K antagonist (VKA) therapy.”⁵ Furthermore, for an appropriate bridging regimen, the ACCP guidelines recommend stopping VKA therapy 5 days prior to the procedure and utilizing LMWH from within 24 to 48 hours of stopping VKA therapy until up to 24 hours before surgery.⁵ Postoperatively, VKA or LMWH therapy should be reinitiated within 24 hours and 24 to 72 hours, respectively, depending on the patient’s risk of bleeding during surgery.⁵

These guidelines recommend using CHADS₂ scoring (TABLE³) to determine arterial thromboembolism (ATE) risk in atrial fibrillation.^3,5 Patients at low risk for ATE (CHADS₂ score 0-2) should not be bridged, and patients at high risk (CHADS₂ score of 5-6) should always be bridged.⁵ These guidelines are less clear about bridging recommendations for moderate-risk patients (CHADS₂ score 3-4).

Previous evidence on bridging. A 2012 meta-analysis of 34 studies evaluated the safety and efficacy of perioperative bridging with heparin in patients receiving VKA.⁷ Researchers found no difference in ATE events in 8 studies that compared groups that received bridging vs groups that simply stopped anticoagulation (odds ratio [OR]=0.80; 95% confidence interval [CI], 0.42–1.54).⁷ The group that received bridging had an increased risk of overall bleeding in 13 studies, and of major bleeding in 5 studies.⁷ This meta-analysis was limited by poor study quality and variation in the indication for VKA therapy.

A 2015 subgroup analysis of a larger cohort study of patients receiving anticoagulants for atrial fibrillation found an increased risk of bleeding when their anticoagulation was interrupted for procedures (OR for major bleeding=3.84; 95% CI, 2.07-7.14; P<.0001).⁸

Douketis et al¹ conducted a randomized trial to clarify the need for and safety of bridging anticoagulation for ATE in patients with atrial fibrillation who were receiving warfarin.

STUDY SUMMARY: When it comes to stroke/TIA, there’s no advantage to bridging

This double blind, placebo-controlled trial compared bridging with dalteparin, a form of LMWH, to placebo among 1884 patients with atrial fibrillation on warfarin whose anticoagulation therapy needed to be interrupted for an elective procedure. Patients were included if they were receiving warfarin to prevent stroke, and had been on warfarin for at least 12 weeks, with a goal international normalized ratio (INR) of 2.0 to 3.0. Exclusion criteria included having a mechanical heart valve or having a stroke/transient ischemic attack (TIA; 12 weeks prior) or major bleeding (6 weeks prior). Cardiac, intracranial, and intraspinal surgeries were also excluded from the study.

The patients’ mean CHADS₂ score was 2.3; 38.3% of patients had a CHADS₂ score ≥3, and 9.4% of patients had a history of stroke. Forty-four percent of patients underwent a gastrointestinal procedure, 17.2% underwent a cardiothoracic procedure, and 9.2% underwent an orthopedic procedure.

Guidelines are not clear about whether patients at moderate risk of arterial thromboembolism need bridging.

Patients stopped taking warfarin 5 days before their procedure, and began subcutaneous dalteparin, 100 IU/kg, or an identical placebo 3 days before the procedure. The dalteparin/placebo was stopped 24 hours before the procedure and restarted after the procedure, until the patient’s INR was in the therapeutic range. Warfarin was resumed on the evening of the procedure or the following day.

The primary efficacy outcome was ATE, including stroke, TIA, or systemic embolism. The primary safety endpoint was major bleeding (defined as bleeding at a critical anatomic site, symptomatic or clinically overt bleeding, or a decrease in hemoglobin >2 g/dL). Secondary efficacy and safety outcomes included minor bleeding, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, and death. Outcomes were assessed within 37 days of the procedure.

The incidence of ATE was 0.4% (4 events) in the no-bridging group vs 0.3% (3 events) in the bridging group (95% CI, -0.6 to 0.8; P=.01 for non-inferiority; P=.73 for superiority). Major bleeding occurred in 1.3% of the no-bridging group (12 events) and in 3.2% of the bridging group (29 events), indicating that no bridging was superior in terms of the major bleeding outcome (number needed to harm [NNH]=53; relative risk [RR]=0.41; 95% CI, 0.20-0.78; P=.005). The no-bridging group also had significantly fewer minor bleeds in comparison to the bridging group (NNH=11; 12% vs 20.9%; P<.001). There were no differences between groups in other secondary outcomes.

WHAT'S NEW: High-quality evidence suggests it’s OK to stop warfarin before surgery

This is the largest good-quality study to evaluate perioperative bridging in patients with atrial fibrillation who were at low or moderate risk for ATE (CHADS₂ score 0-4). Previous studies suggested bridging increased bleeding and offered limited benefit for reducing the risk of ATE. However, this is the first study to include a large group of moderate-risk patients (CHADS₂ score 3-4). This trial provides high-quality evidence to support the practice of simply stopping warfarin in the perioperative period, rather than bridging with LMWH.

CAVEATS: Findings might not apply to patients at highest risk

Most patients in this study had a CHADS₂ score ≤3. About 3% had a CHADS₂ score ≥5 or higher. It’s not clear whether these findings apply to patients with a CHADS₂ score of 5 or 6.

This trial categorized ATE risk using the CHADS₂ score, rather than the CHA₂DS₂-VASc, which includes additional risk factors and may more accurately predict stroke risk. Both patients who received bridging therapy and those who did not had a lower rate of stroke than predicted by CHADs₂. This may reflect a limit of the predictive value of CHADS₂, but should not have affected the rate of bleeding or ATE outcomes in this study.

CHALLENGES TO IMPLEMENTATION: Physicians may hesitate to disregard current guidelines

Strokes are devastating events for patients, families, and physicians, and they pose a greater risk of morbidity and mortality compared to bleeding. However, this study suggests patients who receive bridging have a higher risk of bleeding than stroke, which is in contrast to some physicians’ experience and current recommendations.

A physician caring for a patient who’s had a stroke may be inclined to recommend bridging despite the lack of efficacy and evidence of bleeding risk. Additionally, until guidelines reflect the most current research, physicians may be reluctant to provide care in contrast to these recommendations.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was 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 75-year-old man comes to your office for surgical clearance before right knee replacement surgery. He has diabetes and high blood pressure, and is taking warfarin for atrial fibrillation. He is scheduled for surgery in a week. What is the safest way to manage his warfarin in the perioperative period?

More than 2 million people are being treated with oral anticoagulation in North America to prevent stroke, or to prevent or treat venous thromboembolism.² Since 2010, several new oral anticoagulants have been approved, including dabigatran, apixaban, and rivaroxaban. These new medications have a shorter half-life than older anticoagulants, which enables them to be stopped 1 to 2 days before surgery.

On the other hand, warfarin—which remains a common choice for anticoagulation—has a 3- to 7-day onset and elimination.^3,4 This long clinical half-life presents a special challenge during the perioperative period. To reduce the risk of operative bleeding, the warfarin must be stopped days prior to the procedure, but physicians often worry that this will increase the risk of arterial or venous thromboembolism, including stroke.

An estimated 250,000 patients need perioperative management of their anticoagulation each year.⁵ As the US population continues to age and the incidence of conditions requiring anticoagulation (particularly atrial fibrillation) increases, this number is only going to rise.⁶

Current guidelines on bridging. American College of Chest Physicians (ACCP) guidelines recommend transition to “a short-acting anticoagulant, consisting of subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin, for a 10- to 12-day period during interruption of vitamin K antagonist (VKA) therapy.”⁵ Furthermore, for an appropriate bridging regimen, the ACCP guidelines recommend stopping VKA therapy 5 days prior to the procedure and utilizing LMWH from within 24 to 48 hours of stopping VKA therapy until up to 24 hours before surgery.⁵ Postoperatively, VKA or LMWH therapy should be reinitiated within 24 hours and 24 to 72 hours, respectively, depending on the patient’s risk of bleeding during surgery.⁵

These guidelines recommend using CHADS₂ scoring (TABLE³) to determine arterial thromboembolism (ATE) risk in atrial fibrillation.^3,5 Patients at low risk for ATE (CHADS₂ score 0-2) should not be bridged, and patients at high risk (CHADS₂ score of 5-6) should always be bridged.⁵ These guidelines are less clear about bridging recommendations for moderate-risk patients (CHADS₂ score 3-4).

Previous evidence on bridging. A 2012 meta-analysis of 34 studies evaluated the safety and efficacy of perioperative bridging with heparin in patients receiving VKA.⁷ Researchers found no difference in ATE events in 8 studies that compared groups that received bridging vs groups that simply stopped anticoagulation (odds ratio [OR]=0.80; 95% confidence interval [CI], 0.42–1.54).⁷ The group that received bridging had an increased risk of overall bleeding in 13 studies, and of major bleeding in 5 studies.⁷ This meta-analysis was limited by poor study quality and variation in the indication for VKA therapy.

A 2015 subgroup analysis of a larger cohort study of patients receiving anticoagulants for atrial fibrillation found an increased risk of bleeding when their anticoagulation was interrupted for procedures (OR for major bleeding=3.84; 95% CI, 2.07-7.14; P<.0001).⁸

Douketis et al¹ conducted a randomized trial to clarify the need for and safety of bridging anticoagulation for ATE in patients with atrial fibrillation who were receiving warfarin.

STUDY SUMMARY: When it comes to stroke/TIA, there’s no advantage to bridging

This double blind, placebo-controlled trial compared bridging with dalteparin, a form of LMWH, to placebo among 1884 patients with atrial fibrillation on warfarin whose anticoagulation therapy needed to be interrupted for an elective procedure. Patients were included if they were receiving warfarin to prevent stroke, and had been on warfarin for at least 12 weeks, with a goal international normalized ratio (INR) of 2.0 to 3.0. Exclusion criteria included having a mechanical heart valve or having a stroke/transient ischemic attack (TIA; 12 weeks prior) or major bleeding (6 weeks prior). Cardiac, intracranial, and intraspinal surgeries were also excluded from the study.

The patients’ mean CHADS₂ score was 2.3; 38.3% of patients had a CHADS₂ score ≥3, and 9.4% of patients had a history of stroke. Forty-four percent of patients underwent a gastrointestinal procedure, 17.2% underwent a cardiothoracic procedure, and 9.2% underwent an orthopedic procedure.

Guidelines are not clear about whether patients at moderate risk of arterial thromboembolism need bridging.

Patients stopped taking warfarin 5 days before their procedure, and began subcutaneous dalteparin, 100 IU/kg, or an identical placebo 3 days before the procedure. The dalteparin/placebo was stopped 24 hours before the procedure and restarted after the procedure, until the patient’s INR was in the therapeutic range. Warfarin was resumed on the evening of the procedure or the following day.

The primary efficacy outcome was ATE, including stroke, TIA, or systemic embolism. The primary safety endpoint was major bleeding (defined as bleeding at a critical anatomic site, symptomatic or clinically overt bleeding, or a decrease in hemoglobin >2 g/dL). Secondary efficacy and safety outcomes included minor bleeding, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, and death. Outcomes were assessed within 37 days of the procedure.

The incidence of ATE was 0.4% (4 events) in the no-bridging group vs 0.3% (3 events) in the bridging group (95% CI, -0.6 to 0.8; P=.01 for non-inferiority; P=.73 for superiority). Major bleeding occurred in 1.3% of the no-bridging group (12 events) and in 3.2% of the bridging group (29 events), indicating that no bridging was superior in terms of the major bleeding outcome (number needed to harm [NNH]=53; relative risk [RR]=0.41; 95% CI, 0.20-0.78; P=.005). The no-bridging group also had significantly fewer minor bleeds in comparison to the bridging group (NNH=11; 12% vs 20.9%; P<.001). There were no differences between groups in other secondary outcomes.

WHAT'S NEW: High-quality evidence suggests it’s OK to stop warfarin before surgery

This is the largest good-quality study to evaluate perioperative bridging in patients with atrial fibrillation who were at low or moderate risk for ATE (CHADS₂ score 0-4). Previous studies suggested bridging increased bleeding and offered limited benefit for reducing the risk of ATE. However, this is the first study to include a large group of moderate-risk patients (CHADS₂ score 3-4). This trial provides high-quality evidence to support the practice of simply stopping warfarin in the perioperative period, rather than bridging with LMWH.

CAVEATS: Findings might not apply to patients at highest risk

Most patients in this study had a CHADS₂ score ≤3. About 3% had a CHADS₂ score ≥5 or higher. It’s not clear whether these findings apply to patients with a CHADS₂ score of 5 or 6.

This trial categorized ATE risk using the CHADS₂ score, rather than the CHA₂DS₂-VASc, which includes additional risk factors and may more accurately predict stroke risk. Both patients who received bridging therapy and those who did not had a lower rate of stroke than predicted by CHADs₂. This may reflect a limit of the predictive value of CHADS₂, but should not have affected the rate of bleeding or ATE outcomes in this study.

CHALLENGES TO IMPLEMENTATION: Physicians may hesitate to disregard current guidelines

Strokes are devastating events for patients, families, and physicians, and they pose a greater risk of morbidity and mortality compared to bleeding. However, this study suggests patients who receive bridging have a higher risk of bleeding than stroke, which is in contrast to some physicians’ experience and current recommendations.

A physician caring for a patient who’s had a stroke may be inclined to recommend bridging despite the lack of efficacy and evidence of bleeding risk. Additionally, until guidelines reflect the most current research, physicians may be reluctant to provide care in contrast to these recommendations.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was 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.

The Advisory Committee on Immunization Practices (ACIP) voted at its June 2015 meeting to make a “B” recommendation for the use of meningococcal B vaccine for individuals 16 through 23 years of age. The Committee felt that the vaccine can be used if one desires it, but at this time it should not be included in the category of a routinely recommended vaccine.

Meningococcal meningitis caused by serogroup B is a serious disease, but it is rare. From 2009 to 2013, the annual number of meningococcal B cases in individuals ages 11 to 24 years ranged from 54 to 67, with 5 to 10 deaths and 5 to 13 serious sequelae.¹ Since 2009, there have been outbreaks on 7 university campuses with cases-per-outbreak numbering 2 to 13.¹ These well publicized outbreaks created much disruption and an impression of increased risk among college students. But the surveillance system of the Centers for Disease Control and Prevention (CDC) demonstrates that the rate of infection among college students is actually lower than it is among individuals the same age who are not in college (TABLE 1).¹

The combined incidence of 0.14/100,000 means that to prevent one case, 714,000 individuals need to be vaccinated; 5 million need to be vaccinated to prevent one death.¹ These numbers are subject to yearly variation and would be more favorable should the incidence of the disease increase. (For a look at the historical incidence of meningococcal meningitis from all serotypes, see the FIGURE.¹) The question facing ACIP was whether the current very low levels of meningococcal B disease merit widespread, routinely-recommended use of the vaccine.

A look at the 2 meningococcal B vaccines

Two meningococcal B vaccines are now licensed for use in the United States. MenB-FHbp (Trumenba, Pfizer) was licensed in October 2014 as a 3-dose series given at 0, 2, and 6 months.² MenB-4C (Bexsero, Novartis/GSK) was licensed in January 2015 and requires 2 doses at 0 and ≥1 month.³ Both vaccines induce a level of antibody production that is considered immunogenic in a high proportion of those vaccinated, but the level of immunity wanes after 6 to 24 months. The clinical significance of this drop in immunity is unknown and cannot be tested currently because of the rarity of the disease. Unfortunately, the rate of asymptomatic carriage of meningococcal B does not appear to be affected by vaccination.¹

Both vaccines produce local and systemic reactions at rates higher than other recommended vaccines for this age group: pain at the injection site (83%-85%), headache (33%-35%), myalgia (30%-48%), fatigue (35%-40%), induration (28%), nausea (18%), chills (15%), and arthralgia (13%).^2,3 There is some theoretical concern about the potential for autoimmune disease from the use of meningococcal B vaccines that will be studied as the vaccines are used more widely.¹ In addition, the CDC estimates that serious anaphylactic reactions can occur after administration of any vaccine, estimated at about one per every million doses.¹

Meningococcal serotype B bacteria consist of different strains. The 2 approved vaccines cover today’s most frequently found strains in the United States, but it’s uncertain if this will hold true in the future.

Recommendation considerations that came into play

A number of factors affected ACIP’s recommendation decision: the low incidence of the meningococcal B disease; the large number-needed-to-vaccinate to prevent a case and a death; uncertainties regarding the duration of protection; cost, lack of effect on carriage rates, and limited safety data with the potential for serious reactions to exceed the number of cases prevented; and the severity of the disease and the concern it elicits.

ACIP has multiple options when considering a vaccine: recommend it routinely for everyone or everyone in a defined group (A recommendation), recommend for individual decision making (B recommendation), recommend against use, and make no recommendation at all. Given that 2 meningococcal B vaccines are licensed in the United States and can be used by those who want them—and the Committee’s opinion that these vaccines should not (at this time) be included in the schedule of routinely-recommended vaccines—ACIP chose to make a B recommendation on their use (TABLE 2).¹ Vaccines recommended by ACIP (both A and B recommendations) are mandated in the Affordable Care Act to be provided by commercial health insurance at no out-of-pocket expense to the patient.

A word about high-risk populations

At its February 2015 meeting, ACIP voted to recommend meningococcal B vaccine for use in high-risk populations and during outbreaks (TABLE 3).⁴ This recommendation—plus the most recent B recommendation for general use—comprise the totality of current recommendations for the prevention of meningococcal B disease in the United States.

The Advisory Committee on Immunization Practices (ACIP) voted at its June 2015 meeting to make a “B” recommendation for the use of meningococcal B vaccine for individuals 16 through 23 years of age. The Committee felt that the vaccine can be used if one desires it, but at this time it should not be included in the category of a routinely recommended vaccine.

Meningococcal meningitis caused by serogroup B is a serious disease, but it is rare. From 2009 to 2013, the annual number of meningococcal B cases in individuals ages 11 to 24 years ranged from 54 to 67, with 5 to 10 deaths and 5 to 13 serious sequelae.¹ Since 2009, there have been outbreaks on 7 university campuses with cases-per-outbreak numbering 2 to 13.¹ These well publicized outbreaks created much disruption and an impression of increased risk among college students. But the surveillance system of the Centers for Disease Control and Prevention (CDC) demonstrates that the rate of infection among college students is actually lower than it is among individuals the same age who are not in college (TABLE 1).¹

The combined incidence of 0.14/100,000 means that to prevent one case, 714,000 individuals need to be vaccinated; 5 million need to be vaccinated to prevent one death.¹ These numbers are subject to yearly variation and would be more favorable should the incidence of the disease increase. (For a look at the historical incidence of meningococcal meningitis from all serotypes, see the FIGURE.¹) The question facing ACIP was whether the current very low levels of meningococcal B disease merit widespread, routinely-recommended use of the vaccine.

A look at the 2 meningococcal B vaccines

Two meningococcal B vaccines are now licensed for use in the United States. MenB-FHbp (Trumenba, Pfizer) was licensed in October 2014 as a 3-dose series given at 0, 2, and 6 months.² MenB-4C (Bexsero, Novartis/GSK) was licensed in January 2015 and requires 2 doses at 0 and ≥1 month.³ Both vaccines induce a level of antibody production that is considered immunogenic in a high proportion of those vaccinated, but the level of immunity wanes after 6 to 24 months. The clinical significance of this drop in immunity is unknown and cannot be tested currently because of the rarity of the disease. Unfortunately, the rate of asymptomatic carriage of meningococcal B does not appear to be affected by vaccination.¹

Both vaccines produce local and systemic reactions at rates higher than other recommended vaccines for this age group: pain at the injection site (83%-85%), headache (33%-35%), myalgia (30%-48%), fatigue (35%-40%), induration (28%), nausea (18%), chills (15%), and arthralgia (13%).^2,3 There is some theoretical concern about the potential for autoimmune disease from the use of meningococcal B vaccines that will be studied as the vaccines are used more widely.¹ In addition, the CDC estimates that serious anaphylactic reactions can occur after administration of any vaccine, estimated at about one per every million doses.¹

Meningococcal serotype B bacteria consist of different strains. The 2 approved vaccines cover today’s most frequently found strains in the United States, but it’s uncertain if this will hold true in the future.

Recommendation considerations that came into play

A number of factors affected ACIP’s recommendation decision: the low incidence of the meningococcal B disease; the large number-needed-to-vaccinate to prevent a case and a death; uncertainties regarding the duration of protection; cost, lack of effect on carriage rates, and limited safety data with the potential for serious reactions to exceed the number of cases prevented; and the severity of the disease and the concern it elicits.

ACIP has multiple options when considering a vaccine: recommend it routinely for everyone or everyone in a defined group (A recommendation), recommend for individual decision making (B recommendation), recommend against use, and make no recommendation at all. Given that 2 meningococcal B vaccines are licensed in the United States and can be used by those who want them—and the Committee’s opinion that these vaccines should not (at this time) be included in the schedule of routinely-recommended vaccines—ACIP chose to make a B recommendation on their use (TABLE 2).¹ Vaccines recommended by ACIP (both A and B recommendations) are mandated in the Affordable Care Act to be provided by commercial health insurance at no out-of-pocket expense to the patient.

A word about high-risk populations

At its February 2015 meeting, ACIP voted to recommend meningococcal B vaccine for use in high-risk populations and during outbreaks (TABLE 3).⁴ This recommendation—plus the most recent B recommendation for general use—comprise the totality of current recommendations for the prevention of meningococcal B disease in the United States.

The Advisory Committee on Immunization Practices (ACIP) voted at its June 2015 meeting to make a “B” recommendation for the use of meningococcal B vaccine for individuals 16 through 23 years of age. The Committee felt that the vaccine can be used if one desires it, but at this time it should not be included in the category of a routinely recommended vaccine.

Meningococcal meningitis caused by serogroup B is a serious disease, but it is rare. From 2009 to 2013, the annual number of meningococcal B cases in individuals ages 11 to 24 years ranged from 54 to 67, with 5 to 10 deaths and 5 to 13 serious sequelae.¹ Since 2009, there have been outbreaks on 7 university campuses with cases-per-outbreak numbering 2 to 13.¹ These well publicized outbreaks created much disruption and an impression of increased risk among college students. But the surveillance system of the Centers for Disease Control and Prevention (CDC) demonstrates that the rate of infection among college students is actually lower than it is among individuals the same age who are not in college (TABLE 1).¹

The combined incidence of 0.14/100,000 means that to prevent one case, 714,000 individuals need to be vaccinated; 5 million need to be vaccinated to prevent one death.¹ These numbers are subject to yearly variation and would be more favorable should the incidence of the disease increase. (For a look at the historical incidence of meningococcal meningitis from all serotypes, see the FIGURE.¹) The question facing ACIP was whether the current very low levels of meningococcal B disease merit widespread, routinely-recommended use of the vaccine.

A look at the 2 meningococcal B vaccines

Two meningococcal B vaccines are now licensed for use in the United States. MenB-FHbp (Trumenba, Pfizer) was licensed in October 2014 as a 3-dose series given at 0, 2, and 6 months.² MenB-4C (Bexsero, Novartis/GSK) was licensed in January 2015 and requires 2 doses at 0 and ≥1 month.³ Both vaccines induce a level of antibody production that is considered immunogenic in a high proportion of those vaccinated, but the level of immunity wanes after 6 to 24 months. The clinical significance of this drop in immunity is unknown and cannot be tested currently because of the rarity of the disease. Unfortunately, the rate of asymptomatic carriage of meningococcal B does not appear to be affected by vaccination.¹

Both vaccines produce local and systemic reactions at rates higher than other recommended vaccines for this age group: pain at the injection site (83%-85%), headache (33%-35%), myalgia (30%-48%), fatigue (35%-40%), induration (28%), nausea (18%), chills (15%), and arthralgia (13%).^2,3 There is some theoretical concern about the potential for autoimmune disease from the use of meningococcal B vaccines that will be studied as the vaccines are used more widely.¹ In addition, the CDC estimates that serious anaphylactic reactions can occur after administration of any vaccine, estimated at about one per every million doses.¹

Meningococcal serotype B bacteria consist of different strains. The 2 approved vaccines cover today’s most frequently found strains in the United States, but it’s uncertain if this will hold true in the future.

Recommendation considerations that came into play

A number of factors affected ACIP’s recommendation decision: the low incidence of the meningococcal B disease; the large number-needed-to-vaccinate to prevent a case and a death; uncertainties regarding the duration of protection; cost, lack of effect on carriage rates, and limited safety data with the potential for serious reactions to exceed the number of cases prevented; and the severity of the disease and the concern it elicits.

ACIP has multiple options when considering a vaccine: recommend it routinely for everyone or everyone in a defined group (A recommendation), recommend for individual decision making (B recommendation), recommend against use, and make no recommendation at all. Given that 2 meningococcal B vaccines are licensed in the United States and can be used by those who want them—and the Committee’s opinion that these vaccines should not (at this time) be included in the schedule of routinely-recommended vaccines—ACIP chose to make a B recommendation on their use (TABLE 2).¹ Vaccines recommended by ACIP (both A and B recommendations) are mandated in the Affordable Care Act to be provided by commercial health insurance at no out-of-pocket expense to the patient.

A word about high-risk populations

At its February 2015 meeting, ACIP voted to recommend meningococcal B vaccine for use in high-risk populations and during outbreaks (TABLE 3).⁴ This recommendation—plus the most recent B recommendation for general use—comprise the totality of current recommendations for the prevention of meningococcal B disease in the United States.

Over the past several years, prolotherapy has been gaining support as an option for patients with tendinopathies and painful osteoarthritic conditions. Yet the technique lacks both a consistent definition and an abundance of evidence.

Because the prefix “prolo” is thought to refer to proliferation or regeneration, some physicians prefer the term “sclerotherapy” when injecting sclerosing agents. Others point out that “prolotherapy” refers to the proliferation of tissue that the injections provoke, which has never been proven. We believe that the material injected should dictate the term used to describe it—dextrose prolotherapy (DPT) or platelet-rich plasma therapy (PRP), for example.

In this update, we focus on DPT—the injection of a solution containing hypertonic dextrose into ligaments, tendons, and joints to promote healing. You’ll find an overview of the proposed mechanism of action and a description of the technique (see “How DPT works”^1-9), as well as a look at the evidence of its effectiveness for a variety of musculoskeletal conditions in the text and TABLE^9-19 that follow. Our review is limited by the dearth of large, definitive studies, and consists mainly of anecdotal evidence, case reports, and other low-quality studies.

Considering DPT—for which patients?

Even for conditions for which the evidence of its efficacy is unequivocal, DPT is only one part of a comprehensive treatment plan. Functional assessment and correction of any weaknesses, inflexibilities, and/or training errors are also essential.

Dextrose prolotherapy is rarely covered by health insurance and is often considered only after conservative treatment has failed.

There are a number of other considerations, as well. For one thing, DPT is rarely covered by health insurance²⁰ and is often considered only after conservative treatment has failed. What’s more, it is not suited to every patient.

Absolute contraindications include acute infections at the injection site, such as cellulitis, abscess, or septic arthritis. Relative contraindications include acute gout flare and acute fracture near the site.⁶

When DPT is a viable alternative, keep in mind that the procedure should only be done by a physician experienced in the technique—and that ultrasound guidance should be used to ensure precise anatomical delivery (FIGURE 1).²¹ Consent must be obtained and documented, and universal precautions observed.

Read on to find out whether to consider DPT for particular patients.

Achilles tendinopathy: DPT decreases pain, improves function (SOR A)

Non-insertional Achilles tendinopathy can be treated with prolotherapy to decrease pain and tendon thickness (FIGURE 2). A small, single blind randomized trial compared the effectiveness of eccentric exercise (ie, contractions performed to lengthen the muscle), DPT alone, and a combination of DPT and exercise for patients with chronic Achilles tendinopathy.¹⁰

The investigators found greater improvement in the Victorian Institute of Sport Assessment-Achilles (VISA-A) score at 12 months with the combined therapy (41.1 on a 0-100 scale) vs either eccentric exercise (23.7) or DPT (27.5) alone. The increase from baseline was greater for those who received combination therapy at 6 weeks (+11.7) compared with the eccentric-only group.¹⁰ Adding DPT (injected into the tender points of the subcutaneous tissues adjacent to the Achilles tendon) to eccentric exercise resulted in a more rapid and sustained improvement in pain, function, and stiffness.

In an earlier observational study, researchers achieved improvement in pain scores using a different DPT technique.²² Here, patients with chronic Achilles tendinosis received ultrasound-guided intratendinous dextrose injections every 6 weeks until symptoms resolved. Pain scores, calculated using a visual analogue scale (VAS), showed a mean reduction at rest (88%), during normal daily activities (84%), and during physical activity (78%). The mean number of treatment sessions was 4, and the mean time to achieve results was 30 weeks.²²

Knee osteoarthritis: Pain level and movement improve (SOR A)

In a study of patients with knee osteoarthritis (OA) and pain lasting 6 months or more, participants received bimonthly injections of either DPT with lidocaine or lidocaine alone. At 12 months, only those in the DPT group had achieved significant improvement in VAS pain score (44%), self-reported swelling (63%), and knee flexion (14%).¹¹

A more recent study randomized 90 adults with painful knee OA of at least 3 months’ duration to blinded injection (either DPT or saline) or at-home exercise.⁹ The injections involved both intra- and extra-articular techniques, performed monthly for a total of 3 to 5 injections. At 52 weeks, the DPT group had improved scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) by 15.3 points compared with the saline group (7.6 points) and the exercise-only group (8.2 points).

Half of those receiving DPT improved by 12 or more points, compared with less than a third of those receiving saline and a quarter of those treated with exercise alone. Knee Pain Scale (KPS)-based pain frequency and severity were also significantly reduced in the DPT group vs both comparison groups.⁹

Finger OA. One small randomized study tested the efficacy of DPT in patients with symptomatic finger OA affecting the distal or proximal interphalangeal joint or the trapeziometacarpal (thumb) joint.²³ Participants received either DPT with xylocaine or xylocaine alone. Injections were done on the medial and lateral aspects of the affected joints at baseline, 2, and 4 months. Pain (VAS score) during active finger movement improved by 45% in the DPT group vs 15% in the group treated with xylocaine alone. After 6 months, those in the xylocaine-only group received the DPT protocol, and their pain reduction scores rose, on average, from 18% to 54%.²³

Low back pain: Little help for chronic condition (SOR A)

Early studies of DPT for the treatment of low back pain had conflicting results. In 2004, the largest (N=110) and most rigorous study of DPT for chronic non-specific low back pain to date¹² found no significant improvement.

Participants received either DPT or normal saline injections into tender lumbopelvic ligaments every 2 weeks for a total of 6 treatments. They were then randomized to either core and low back strengthening exercises or normal activity for 6 months. At 12 months, VAS pain and disability scores significantly decreased from baseline in all the groups, with a decline ranging from 26% to 44% for pain and 30% to 44% for disability. However, at no point were there significant differences between injection groups or activity groups.¹²

A 2007 Cochrane review found insufficient evidence to support the use of DPT alone for the treatment of non-specific low back pain but suggested that, as an adjunct, it may improve pain and disability scores.¹³ And in 2011, a Cochrane review confirmed that there was insufficient evidence for the use of DPT in sub-acute and chronic low back pain.¹⁴ Other studies on the use of DPT for specific low back conditions, including sacroiliac joint pain,^24,25 coccydynia,²⁶ and degenerative disc disease,²⁷ have shown trends toward improvement in pain scores^24-27 and disability,²⁵ but only one of these was a randomized controlled trial (RCT).²⁵

Lateral epicondylosis: More effective than saline (SOR B)

A single RCT compared DPT to placebo in patients with 6 months of moderate to severe lateral epicondylosis who had failed conservative treatment. Patients received 3 injections of either hypertonic dextrose or saline tendon insertions every 4 weeks, with needle touching bone at the supracondylar ridge, lateral epicondyle, and annular ligament.¹⁵ Patients randomly assigned to DPT experienced significant pain relief from baseline to 16 weeks, with a Likert score decline from 5.1 to 0.5, compared with the saline group (4.5 at baseline and 3.5 at 16 weeks). Clinical improvement was maintained at 52-week follow-up.¹⁵

Osgood-Schlatter: DPT improves pain relief (SOR B)

In one of the few studies of prolotherapy for adolescents, patients with recalcitrant Osgood-Schlatter disease were randomized to either structured physical therapy or 3 monthly injections of lidocaine, with or without dextrose, over the apophysis and patellar tendon origin.¹⁶ Injections began at the most distal point of tenderness and were repeated at 1 cm intervals for a total of 3 to 4 midline injections. The proximal injections were deep to the patellar tendon, on the tibia above the tuberosity.

Pain scores, measured by the Nirschl Pain Phase Scale (0-7), improved significantly more in the DPT group (3.9) compared with either the lidocaine group (2.4) or the exercise group (1.2). Dextrose-treated knees were significantly more likely than knees treated with lidocaine (14 of 21 vs 5 of 22) to be asymptomatic with sport activity. After 3 months, patients in the lidocaine and exercise groups who had not responded adequately were given the option of receiving DPT; those who underwent the 3-month DPT protocol achieved the same level of improvement as the initial DPT group.¹⁶

When considering or recommending DPT for an adolescent with Osgood-Schlatter disease, however, it is particularly important that he or she be referred to a physician with expertise in prolotherapy.

Plantar fasciosis: A possibility when conservative treatment fails (SOR B)

An early case series showed that DPT effectively improved pain at rest and during activity in patients with chronic plantar fasciosis refractory to conservative care.¹⁷ A small RCT recently compared PRP with DPT in such patients.¹⁸

Pain, disability, and activity limitation were measured by the Foot Functional Index. The PRP group improved by 29.7%, 26.6%, and 28% in pain, disability, and activity limitation, respectively, vs improvements of 17%, 14.5%, and 12.4% in the DPT group. Although there was a trend for PRP to be superior, the results were not statistically significant.¹⁸ This suggests that DPT may be an additional treatment option for patients with plantar fasciosis when conservative treatment fails.

Chondromalacia patella: Not enough is known (SOR C)

One study showed that DPT improved self-reported pain and function scores in patients with chronic knee pain secondary to chondromalacia patella. However, the study had no control group and no standardized injected solution; rather, the solution was tailored for each individual.¹⁹ Thus, there is insufficient data to make recommendations regarding the effectiveness of DPT in treating chondromalacia patella or other causes of patellofemoral pain syndrome.

What to tell patients about recovery and adverse effects

Injection of dextrose into ligaments, tendons, and joints carries the theoretical risks of light-headedness, allergic reaction, infection, and structural damage. However, there have been no reports of serious or significant adverse events associated with DPT when used for peripheral joint indications.

To avoid inhibiting the desired inflammatory response to prolotherapy, nonsteroidal anti-inflammatory drugs should not be used to treat post-injection pain.

The most common risks of DPT are needle trauma-induced pain, mild bleeding, and bruising. A sense of fullness, stiffness, and occasional numbness at the site at the time of injection are common, benign, and typically self-limiting.⁶ If post-procedure numbness continues, the patient should follow up in 48 to 72 hours to rule out nerve damage.

Post-injection pain flare during the first 72 hours may occur. In a study of prolotherapy for knee OA pain, 10% to 20% of patients experienced such flares.¹⁵ Most patients respond well to acetaminophen and experience resolution of pain within a week. Non-steroidal anti-inflammatory drugs should not be used to treat post-procedure pain because they may interfere with the local inflammatory response needed for healing. Regular activities can be resumed immediately after an injection into a large joint, such as the knee, or after full sensation and proprioception returns if an anesthetic was used in combination with the hypertonic dextrose.

There is a theoretical risk of tendon weakening and rupture with tenotomy/intra-substance injections into weight-bearing tendons, but there are no known published reports of this complication with DPT. Nonetheless, we recommend that patients limit ballistic weight bearing or full strength activity for 48 hours after an injection into a non-weight bearing tendon and for 5 to7 days for injection into a weight-bearing tendon.

Physical/occupational therapy is important in chronic tendinopathy, and we encourage rapid return (24-48 hours) to low-intensity rehabilitation with gradual return (5-7 days) to full rehabilitation exercises.

Ballistic weight bearing and full strength activity should be limited for 48 hours after an injection into a non-weight bearing tendon and for 5 to 7 days for a weight-bearing tendon.

The number of DPT injection sessions is variable. We recommend follow-up between 3 and 6 weeks for reevaluation. If the patient’s pain and/or function has not improved after 2 sets of injections—or DPT is initially successful but pain or dysfunction returns—another round of treatment should be offered in 3 to 6 weeks.

CORRESPONDENCE
Carlton J. Covey, MD, FAAFP, Fort Belvoir Community Hospital, Sports Medicine, Eagle Pavilion, 9300 Dewitt Loop, Fort Belvoir, VA 22060; carlton.covey@usuhs.edu.