Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), continues to be a major cause of morbidity and mortality among hospitalized patients. Although it is well-known that anticoagulation therapy is effective in the prevention and treatment of VTE events, these agents are some of the highest-risk medications a hospitalist will prescribe given the danger of major bleeding. With the recent approval of several newer anticoagulants, it is important for the practicing hospitalist to be comfortable initiating, maintaining, and stopping these agents in a wide variety of patient populations.

Guideline Updates

In February 2016, an update to the ninth edition of the antithrombotic guideline from the American College of Chest Physician (ACCP) was published and included updated recommendations on 12 topics in addition to three new topics. This 10th-edition guideline update is referred to as AT10.1

One of the most notable changes in the updated guideline is the recommended choice of anticoagulant in patients with acute DVT or PE without cancer. Now, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over warfarin. Although this is a weak recommendation based on moderate-quality evidence (grade 2B), this is the first time that warfarin is not considered first-line therapy. It should be emphasized that none of the four FDA-approved DOACs are preferred over another, and they should be avoided in patients who are pregnant or have severe renal disease. In patients with DVT or PE and cancer, low-molecular-weight heparin (LMWH) is still the preferred medication. If LMWH is not prescribed, AT10 does not have a preference for either a DOAC or warfarin for patients with cancer.

When it comes to duration of anticoagulation following a VTE event, the updated guideline continues to recommend three months for a provoked VTE event, with consideration for lifelong anticoagulation for an unprovoked event for patients at low or moderate bleeding risk. However, it now suggests that the recurrence risk factors of male sex and a positive D-dimer measured one month after stopping anticoagulant therapy should be taken into consideration when deciding whether extended anticoagulation is indicated.

AT10 also includes new recommendations concerning the role of aspirin for extended VTE treatment. Interestingly, the 2008 ACCP guideline gave a strong recommendation against the use of aspirin for VTE management in any patient population. In the 2012 guideline, the role of aspirin was not addressed for VTE treatment. Now, AT10 states that low-dose aspirin can be used in patients who stop anticoagulant therapy for treatment of an unprovoked proximal DVT or PE as an extended therapy (grade 2B). The significant change in this recommendation stems from two recent randomized trials that compared aspirin with placebo for the prevention of VTE recurrence in patients who have completed a course of anticoagulation for a first unprovoked proximal DVT or PE.2,3 Although the guideline doesn’t consider aspirin to be a reasonable alternative to anticoagulation for patients who require extended therapy and are agreeable to continue, for patients who have decided to stop anticoagulation, aspirin appears to reduce recurrent VTE by approximately one-third, with no significant increased risk of bleeding.

Another significant change in AT10 is the recommendation against the routine use of compression stockings to prevent postthrombotic syndrome (PTS). This change was influenced by a recent multicenter randomized trial showing that elastic compression stockings did not prevent PTS after an acute proximal DVT.4 The guideline authors remark that this recommendation focuses on the prevention of the chronic complications of PTS rather than treatment of the symptoms. Thus, for patients with acute or chronic leg pain or swelling from DVT, compression stockings may be justified.

A topic that was not addressed in the previous guideline was whether patients with a subsegmental PE should be treated. The guideline now suggests that patients with only subsegmental PE and no ultrasound-proven proximal DVT of the legs should undergo “clinical surveillance” rather than anticoagulation (grade 2C). Exceptions include patients at high risk for recurrent VTE (e.g., hospitalization, reduced mobility, active cancer, or irreversible VTE risk factors) and those with a low cardiopulmonary reserve or marked symptoms thought to be from PE. AT10 also states that patient preferences regarding anticoagulation treatment as well as the patient’s risk of bleeding should be taken into consideration. If the decision is made to not prescribe anticoagulation for subsegmental PE, patients should be advised to seek reevaluation if their symptoms persist or worsen.

The 2012 guideline included a new recommendation that patients with low-risk PE (typically defined by a low Pulmonary Embolism Severity Index [PESI] score) could be discharged “early” from the hospital. This recommendation has now been modified to state that patients with low-risk PE may be treated entirely at home. It is worth noting that outpatient management of low-risk PE has become much less complicated if using a DOAC, particularly rivaroxaban and apixaban as neither require initial treatment with parenteral anticoagulation.

AT10 has not changed the recommendation for which patients should receive thrombolytic therapy for treatment of PE. It recommends systemic thrombolytic therapy for patients with acute PE associated with hypotension (defined as systolic blood pressure less than 90 mmHg for 15 minutes) who are not at high risk for bleeding (grade 2B). Likewise, for patients with acute PE not associated with hypotension, the guideline recommends against systemic thrombolytics (grade 1B). If thrombolytics are implemented, AT10 favors systemic administration over catheter-directed thrombolysis (CDT) due to the higher-quality evidence available. However, the authors state that CDT may be preferred for patients at higher risk of bleeding and when local expertise is available. Lastly, catheter-assisted thrombus removal should be considered in patients with acute PE and hypotension who have a high bleeding risk, who have failed systemic thrombolytics, or who are in shock and likely to die before systemic thrombolytics become therapeutic.

Although no prospective trials have evaluated the management of patients with recurrent VTE events while on anticoagulation therapy, AT10 offers some guidance. After ensuring the patient truly had a recurrent VTE event while on therapeutic warfarin or compliant with a DOAC, the authors suggest switching to LMWH for at least one month (grade 2C). Furthermore, for patients who have a recurrent VTE event while compliant on long-term LMWH, the guideline suggests increasing the dose of LMWH by about one-quarter to one-third (grade 2C).

Guideline Analysis

It is important to note that of the 54 recommendations included in the complete guideline update, only 20 were strong recommendations (grade 1), and none were based on high-quality evidence (level A). It is obvious that more research is needed in this field. Regardless, the ACCP antithrombotic guideline remains the authoritative source in VTE management and has a strong influence on practice behavior. With the recent addition of several newer anticoagulants, AT10 is particularly useful in helping providers understand when and when not to use them. The authors indicate that future iterations will be continually updated, describing them as “living guidelines.” The format of AT10 was designed to facilitate this method with the goal of having discrete topics discussed as new evidence becomes available.

Hospital Medicine Takeaways

Despite the lack of randomized and prospective clinical trials, the updated recommendations from AT10 provide important information on challenging VTE issues that the hospitalist can apply to most patients most of the time. Important updates include:

• Prescribe DOACs as first-line agents for the treatment of acute VTE in patients without cancer.
• Use aspirin for the prevention of recurrent VTE in patients who stop anticoagulation for treatment of an unprovoked DVT or PE.
• Avoid compression stockings for the sole purpose of preventing postthrombotic syndrome.
• Do not admit patients with low-risk PE (as determined by the PESI score) to the hospital but rather treat them entirely at home.

Lastly, it is important to remember that VTE treatment decisions need to be individualized based on the clinical, imaging, and biochemical features of your patient.

Paul J. Grant, MD, SFHM, is assistant professor of medicine and director of perioperative and consultative medicine within the Department of Internal Medicine at the University of Michigan Health System in Ann Arbor.

References

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.
2. Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012;367(21):1979-1987.
3. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-1967.
4. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo controlled trial. Lancet. 2014;383(9920):880-888.

Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), continues to be a major cause of morbidity and mortality among hospitalized patients. Although it is well-known that anticoagulation therapy is effective in the prevention and treatment of VTE events, these agents are some of the highest-risk medications a hospitalist will prescribe given the danger of major bleeding. With the recent approval of several newer anticoagulants, it is important for the practicing hospitalist to be comfortable initiating, maintaining, and stopping these agents in a wide variety of patient populations.

Guideline Updates

In February 2016, an update to the ninth edition of the antithrombotic guideline from the American College of Chest Physician (ACCP) was published and included updated recommendations on 12 topics in addition to three new topics. This 10th-edition guideline update is referred to as AT10.1

One of the most notable changes in the updated guideline is the recommended choice of anticoagulant in patients with acute DVT or PE without cancer. Now, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over warfarin. Although this is a weak recommendation based on moderate-quality evidence (grade 2B), this is the first time that warfarin is not considered first-line therapy. It should be emphasized that none of the four FDA-approved DOACs are preferred over another, and they should be avoided in patients who are pregnant or have severe renal disease. In patients with DVT or PE and cancer, low-molecular-weight heparin (LMWH) is still the preferred medication. If LMWH is not prescribed, AT10 does not have a preference for either a DOAC or warfarin for patients with cancer.

When it comes to duration of anticoagulation following a VTE event, the updated guideline continues to recommend three months for a provoked VTE event, with consideration for lifelong anticoagulation for an unprovoked event for patients at low or moderate bleeding risk. However, it now suggests that the recurrence risk factors of male sex and a positive D-dimer measured one month after stopping anticoagulant therapy should be taken into consideration when deciding whether extended anticoagulation is indicated.

AT10 also includes new recommendations concerning the role of aspirin for extended VTE treatment. Interestingly, the 2008 ACCP guideline gave a strong recommendation against the use of aspirin for VTE management in any patient population. In the 2012 guideline, the role of aspirin was not addressed for VTE treatment. Now, AT10 states that low-dose aspirin can be used in patients who stop anticoagulant therapy for treatment of an unprovoked proximal DVT or PE as an extended therapy (grade 2B). The significant change in this recommendation stems from two recent randomized trials that compared aspirin with placebo for the prevention of VTE recurrence in patients who have completed a course of anticoagulation for a first unprovoked proximal DVT or PE.2,3 Although the guideline doesn’t consider aspirin to be a reasonable alternative to anticoagulation for patients who require extended therapy and are agreeable to continue, for patients who have decided to stop anticoagulation, aspirin appears to reduce recurrent VTE by approximately one-third, with no significant increased risk of bleeding.

Another significant change in AT10 is the recommendation against the routine use of compression stockings to prevent postthrombotic syndrome (PTS). This change was influenced by a recent multicenter randomized trial showing that elastic compression stockings did not prevent PTS after an acute proximal DVT.4 The guideline authors remark that this recommendation focuses on the prevention of the chronic complications of PTS rather than treatment of the symptoms. Thus, for patients with acute or chronic leg pain or swelling from DVT, compression stockings may be justified.

A topic that was not addressed in the previous guideline was whether patients with a subsegmental PE should be treated. The guideline now suggests that patients with only subsegmental PE and no ultrasound-proven proximal DVT of the legs should undergo “clinical surveillance” rather than anticoagulation (grade 2C). Exceptions include patients at high risk for recurrent VTE (e.g., hospitalization, reduced mobility, active cancer, or irreversible VTE risk factors) and those with a low cardiopulmonary reserve or marked symptoms thought to be from PE. AT10 also states that patient preferences regarding anticoagulation treatment as well as the patient’s risk of bleeding should be taken into consideration. If the decision is made to not prescribe anticoagulation for subsegmental PE, patients should be advised to seek reevaluation if their symptoms persist or worsen.

The 2012 guideline included a new recommendation that patients with low-risk PE (typically defined by a low Pulmonary Embolism Severity Index [PESI] score) could be discharged “early” from the hospital. This recommendation has now been modified to state that patients with low-risk PE may be treated entirely at home. It is worth noting that outpatient management of low-risk PE has become much less complicated if using a DOAC, particularly rivaroxaban and apixaban as neither require initial treatment with parenteral anticoagulation.

AT10 has not changed the recommendation for which patients should receive thrombolytic therapy for treatment of PE. It recommends systemic thrombolytic therapy for patients with acute PE associated with hypotension (defined as systolic blood pressure less than 90 mmHg for 15 minutes) who are not at high risk for bleeding (grade 2B). Likewise, for patients with acute PE not associated with hypotension, the guideline recommends against systemic thrombolytics (grade 1B). If thrombolytics are implemented, AT10 favors systemic administration over catheter-directed thrombolysis (CDT) due to the higher-quality evidence available. However, the authors state that CDT may be preferred for patients at higher risk of bleeding and when local expertise is available. Lastly, catheter-assisted thrombus removal should be considered in patients with acute PE and hypotension who have a high bleeding risk, who have failed systemic thrombolytics, or who are in shock and likely to die before systemic thrombolytics become therapeutic.

Although no prospective trials have evaluated the management of patients with recurrent VTE events while on anticoagulation therapy, AT10 offers some guidance. After ensuring the patient truly had a recurrent VTE event while on therapeutic warfarin or compliant with a DOAC, the authors suggest switching to LMWH for at least one month (grade 2C). Furthermore, for patients who have a recurrent VTE event while compliant on long-term LMWH, the guideline suggests increasing the dose of LMWH by about one-quarter to one-third (grade 2C).

Guideline Analysis

It is important to note that of the 54 recommendations included in the complete guideline update, only 20 were strong recommendations (grade 1), and none were based on high-quality evidence (level A). It is obvious that more research is needed in this field. Regardless, the ACCP antithrombotic guideline remains the authoritative source in VTE management and has a strong influence on practice behavior. With the recent addition of several newer anticoagulants, AT10 is particularly useful in helping providers understand when and when not to use them. The authors indicate that future iterations will be continually updated, describing them as “living guidelines.” The format of AT10 was designed to facilitate this method with the goal of having discrete topics discussed as new evidence becomes available.

Hospital Medicine Takeaways

Despite the lack of randomized and prospective clinical trials, the updated recommendations from AT10 provide important information on challenging VTE issues that the hospitalist can apply to most patients most of the time. Important updates include:

• Prescribe DOACs as first-line agents for the treatment of acute VTE in patients without cancer.
• Use aspirin for the prevention of recurrent VTE in patients who stop anticoagulation for treatment of an unprovoked DVT or PE.
• Avoid compression stockings for the sole purpose of preventing postthrombotic syndrome.
• Do not admit patients with low-risk PE (as determined by the PESI score) to the hospital but rather treat them entirely at home.

Lastly, it is important to remember that VTE treatment decisions need to be individualized based on the clinical, imaging, and biochemical features of your patient.

Paul J. Grant, MD, SFHM, is assistant professor of medicine and director of perioperative and consultative medicine within the Department of Internal Medicine at the University of Michigan Health System in Ann Arbor.

References

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.
2. Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012;367(21):1979-1987.
3. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-1967.
4. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo controlled trial. Lancet. 2014;383(9920):880-888.

Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), continues to be a major cause of morbidity and mortality among hospitalized patients. Although it is well-known that anticoagulation therapy is effective in the prevention and treatment of VTE events, these agents are some of the highest-risk medications a hospitalist will prescribe given the danger of major bleeding. With the recent approval of several newer anticoagulants, it is important for the practicing hospitalist to be comfortable initiating, maintaining, and stopping these agents in a wide variety of patient populations.

Guideline Updates

In February 2016, an update to the ninth edition of the antithrombotic guideline from the American College of Chest Physician (ACCP) was published and included updated recommendations on 12 topics in addition to three new topics. This 10th-edition guideline update is referred to as AT10.1

One of the most notable changes in the updated guideline is the recommended choice of anticoagulant in patients with acute DVT or PE without cancer. Now, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over warfarin. Although this is a weak recommendation based on moderate-quality evidence (grade 2B), this is the first time that warfarin is not considered first-line therapy. It should be emphasized that none of the four FDA-approved DOACs are preferred over another, and they should be avoided in patients who are pregnant or have severe renal disease. In patients with DVT or PE and cancer, low-molecular-weight heparin (LMWH) is still the preferred medication. If LMWH is not prescribed, AT10 does not have a preference for either a DOAC or warfarin for patients with cancer.

When it comes to duration of anticoagulation following a VTE event, the updated guideline continues to recommend three months for a provoked VTE event, with consideration for lifelong anticoagulation for an unprovoked event for patients at low or moderate bleeding risk. However, it now suggests that the recurrence risk factors of male sex and a positive D-dimer measured one month after stopping anticoagulant therapy should be taken into consideration when deciding whether extended anticoagulation is indicated.

AT10 also includes new recommendations concerning the role of aspirin for extended VTE treatment. Interestingly, the 2008 ACCP guideline gave a strong recommendation against the use of aspirin for VTE management in any patient population. In the 2012 guideline, the role of aspirin was not addressed for VTE treatment. Now, AT10 states that low-dose aspirin can be used in patients who stop anticoagulant therapy for treatment of an unprovoked proximal DVT or PE as an extended therapy (grade 2B). The significant change in this recommendation stems from two recent randomized trials that compared aspirin with placebo for the prevention of VTE recurrence in patients who have completed a course of anticoagulation for a first unprovoked proximal DVT or PE.2,3 Although the guideline doesn’t consider aspirin to be a reasonable alternative to anticoagulation for patients who require extended therapy and are agreeable to continue, for patients who have decided to stop anticoagulation, aspirin appears to reduce recurrent VTE by approximately one-third, with no significant increased risk of bleeding.

Another significant change in AT10 is the recommendation against the routine use of compression stockings to prevent postthrombotic syndrome (PTS). This change was influenced by a recent multicenter randomized trial showing that elastic compression stockings did not prevent PTS after an acute proximal DVT.4 The guideline authors remark that this recommendation focuses on the prevention of the chronic complications of PTS rather than treatment of the symptoms. Thus, for patients with acute or chronic leg pain or swelling from DVT, compression stockings may be justified.

A topic that was not addressed in the previous guideline was whether patients with a subsegmental PE should be treated. The guideline now suggests that patients with only subsegmental PE and no ultrasound-proven proximal DVT of the legs should undergo “clinical surveillance” rather than anticoagulation (grade 2C). Exceptions include patients at high risk for recurrent VTE (e.g., hospitalization, reduced mobility, active cancer, or irreversible VTE risk factors) and those with a low cardiopulmonary reserve or marked symptoms thought to be from PE. AT10 also states that patient preferences regarding anticoagulation treatment as well as the patient’s risk of bleeding should be taken into consideration. If the decision is made to not prescribe anticoagulation for subsegmental PE, patients should be advised to seek reevaluation if their symptoms persist or worsen.

The 2012 guideline included a new recommendation that patients with low-risk PE (typically defined by a low Pulmonary Embolism Severity Index [PESI] score) could be discharged “early” from the hospital. This recommendation has now been modified to state that patients with low-risk PE may be treated entirely at home. It is worth noting that outpatient management of low-risk PE has become much less complicated if using a DOAC, particularly rivaroxaban and apixaban as neither require initial treatment with parenteral anticoagulation.

AT10 has not changed the recommendation for which patients should receive thrombolytic therapy for treatment of PE. It recommends systemic thrombolytic therapy for patients with acute PE associated with hypotension (defined as systolic blood pressure less than 90 mmHg for 15 minutes) who are not at high risk for bleeding (grade 2B). Likewise, for patients with acute PE not associated with hypotension, the guideline recommends against systemic thrombolytics (grade 1B). If thrombolytics are implemented, AT10 favors systemic administration over catheter-directed thrombolysis (CDT) due to the higher-quality evidence available. However, the authors state that CDT may be preferred for patients at higher risk of bleeding and when local expertise is available. Lastly, catheter-assisted thrombus removal should be considered in patients with acute PE and hypotension who have a high bleeding risk, who have failed systemic thrombolytics, or who are in shock and likely to die before systemic thrombolytics become therapeutic.

Although no prospective trials have evaluated the management of patients with recurrent VTE events while on anticoagulation therapy, AT10 offers some guidance. After ensuring the patient truly had a recurrent VTE event while on therapeutic warfarin or compliant with a DOAC, the authors suggest switching to LMWH for at least one month (grade 2C). Furthermore, for patients who have a recurrent VTE event while compliant on long-term LMWH, the guideline suggests increasing the dose of LMWH by about one-quarter to one-third (grade 2C).

Guideline Analysis

It is important to note that of the 54 recommendations included in the complete guideline update, only 20 were strong recommendations (grade 1), and none were based on high-quality evidence (level A). It is obvious that more research is needed in this field. Regardless, the ACCP antithrombotic guideline remains the authoritative source in VTE management and has a strong influence on practice behavior. With the recent addition of several newer anticoagulants, AT10 is particularly useful in helping providers understand when and when not to use them. The authors indicate that future iterations will be continually updated, describing them as “living guidelines.” The format of AT10 was designed to facilitate this method with the goal of having discrete topics discussed as new evidence becomes available.

Hospital Medicine Takeaways

Despite the lack of randomized and prospective clinical trials, the updated recommendations from AT10 provide important information on challenging VTE issues that the hospitalist can apply to most patients most of the time. Important updates include:

• Prescribe DOACs as first-line agents for the treatment of acute VTE in patients without cancer.
• Use aspirin for the prevention of recurrent VTE in patients who stop anticoagulation for treatment of an unprovoked DVT or PE.
• Avoid compression stockings for the sole purpose of preventing postthrombotic syndrome.
• Do not admit patients with low-risk PE (as determined by the PESI score) to the hospital but rather treat them entirely at home.

Lastly, it is important to remember that VTE treatment decisions need to be individualized based on the clinical, imaging, and biochemical features of your patient.

Paul J. Grant, MD, SFHM, is assistant professor of medicine and director of perioperative and consultative medicine within the Department of Internal Medicine at the University of Michigan Health System in Ann Arbor.

References

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.
2. Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012;367(21):1979-1987.
3. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-1967.
4. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo controlled trial. Lancet. 2014;383(9920):880-888.

Emergency department team

caring for a patient

Photo by Tom Watanabe

A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.

The drug class most often implicated in ED visits was anticoagulants.

Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.

Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.

The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.

The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.

Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.

Results by drug class

The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).

Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.

Results by age

Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).

Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).

Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).

Changes over time

Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.

Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.

An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.

However, the population rates for other age groups were similar for both time periods.

Anticoagulants and antiplatelet agents

Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.

Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).

Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.

Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).

Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.

Emergency department team

caring for a patient

Photo by Tom Watanabe

A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.

The drug class most often implicated in ED visits was anticoagulants.

Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.

Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.

The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.

The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.

Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.

Results by drug class

The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).

Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.

Results by age

Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).

Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).

Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).

Changes over time

Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.

Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.

An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.

However, the population rates for other age groups were similar for both time periods.

Anticoagulants and antiplatelet agents

Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.

Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).

Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.

Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).

Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.

Emergency department team

caring for a patient

Photo by Tom Watanabe

A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.

The drug class most often implicated in ED visits was anticoagulants.

Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.

Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.

The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.

The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.

Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.

Results by drug class

The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).

Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.

Results by age

Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).

Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).

Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).

Changes over time

Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.

Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.

An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.

However, the population rates for other age groups were similar for both time periods.

Anticoagulants and antiplatelet agents

Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.

Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).

Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.

Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).

Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.

Overdose deaths remain epidemic throughout the U.S. The rates of unintentional overdose deaths, increasing by 137% between 2000 and 2014, have been driven by a 4-fold increase in prescription opioid overdoses during that period.^1-3

Veterans died of accidental overdose at a rate of 19.85 deaths/ 100,000 people compared with a rate of 10.49 deaths in the general population, based on 2005 data.⁴ There is wide state-by-state variation with the lowest age-adjusted opioid overdose death rate of 1.9 deaths/100,000 person-years among veterans in Mississippi and the highest rate in Utah of 33.9 deaths/100,000 person-years, using 2001 to 2009 data.⁵ These data can be compared with a crude general population overdose death rate of 10.6 deaths per 100,000 person-years in Mississippi and 18.4 deaths per 100,000 person-years in the general Utah population during that same period.⁶

Overdose deaths in the U.S. occur most often in persons aged 25 to 54 years.⁷ Older age has been associated with iatrogenic opioid overdose in hospitalized patients.⁸ Pulmonary, cardiovascular, and psychiatric disorders, including past or present substance use, have been associated with an increased risk of opioid overdose.⁹ However, veterans with substance use disorders are less likely to be prescribed opioids than are nonveterans with substance use disorders.¹⁰ Also, concomitant use of sedating medications, such as benzodiazepines (BZDs), can increase mortality from opioid overdose.¹¹ Patients prescribed opioids for chronic pain conditions often take BZDs for various reasons.¹² Veterans seem more likely to receive opioids to treat chronic pain but at lower average daily doses than the doses that nonveterans receive.¹⁰

Emergency management of life-threatening opioid overdose includes prompt administration of naloxone.¹³ Naloxone is FDA approved for complete or partial reversal of opioid-induced clinical effects, most critically respiratory depression.^14,15 Naloxone administration in the emergency department (ED) may serve as a surrogate for an overdose event. During the study period, naloxone take-home kits were not available in the VA setting.

A 2010 ED study described demographic information and comorbidities in opioid overdose, but the study did not include veterans.¹⁶ The clinical characteristics of veterans treated for opioid overdose have not been published. Because identifying characteristics of veterans who overdose may help tailor overdose prevention efforts, the objective of this study is to describe clinical characteristics of veterans treated for opioid overdose.

Methods

A retrospective chart review and archived data study was approved by the University of Utah and VA institutional review boards, and conducted at the George E. Wahlen VAMC in Salt Lake City, Utah. This chart review included veterans who were admitted to the ED and treated with naloxone between January 1, 2009 and January 1, 2013.

The authors used the Pharmacy Benefits Management Data Manager to extract data from the VA Data Warehouse and verified the data by open chart review (Table). The following data were collected: ED visit date (overdose date); demographic information, including age, gender, and race; evidence of next-of-kin or other contact at the same address as the veteran; diagnoses based on ICD-9 codes, including sleep apnea, obesitycardiac disease, pulmonary disease, mental health diagnoses (ICD-9 codes 290-302 [wild card characters (*) included many subdiagnoses]),
cancer, and substance use disorders and/or dependencies (SUDD); tobacco use; VA-issued prescription opioid and BZD availability, including dose, fill dates, quantities dispensed, and day supplies; specialty of opioid prescriber; urine drug screening (UDS) results; and outcome of the overdose.

No standardized research criteria identify overdose in medical chart review.¹⁷ For each identified patient, the authors reviewed provider and nursing notes charted during an ED visit that included naloxone administration. The event was included as an opioid overdose when notes indicated that the veteran was unresponsive and given naloxone, which resulted in increased respirations or increased responsiveness. Cases were excluded if the reason for naloxone administration was anything other than opioid overdose.

Medical, mental health, and SUDD diagnoses were included only if the veteran had more than 3 patient care encounters (PCE) with ICD-9 codes for a specific diagnosis entered by providers. A PCE used in the electronic medical record (EMR) helps collect, manage, and display outpatient encounter data, including providers, procedure codes, and diagnostic codes. Tobacco use was extracted from health factors documented during primary care visit screenings. (Health factors help capture data entered in note templates in the EMR and can be used to query trends.) A diagnosis of obesity was based on a calculated body mass index of > 30 kg/m² on the day of the ED visit date or the most recently charted height and weight. The type of SUDD was stratified into opioids (ICD-9 codes 304.0*), sedatives (ICD-9 code 304.1*), alcohol (ICD-9 code 303.*), and other (ICD-9 codes 304.2-305.9).

The dosage of opioids and BZDs available to a veteran was determined by using methods similar to those described by Gomes and colleagues: the dose of opioids and BZDs available based on prescriptions dispensed during the 120 days prior to the ED visit date and the dose available on the day of the ED visit date if prescription instructions were being followed.¹⁸ Prescription opioids and BZDs were converted to daily morphine equivalent dose (MED) and daily lorazepam-equivalent dose (LED), using established methods.^19,20

Veterans were stratified into 4 groups based on prescribed medication availability: opioids only, BZDs only, opioids and BZDs, and neither opioids nor BZDs. The specialty of the opioid prescribers was categorized as primary care, pain specialist, surgeon, emergency specialist, or hospitalist (discharge prescription). Veteran EMRs contain a list of medications obtained outside the VA facility, referred to as non-VA prescriptions. These medications werenot included in the analysis because accuracy could not be verified.

A study author reviewed the results of any UDS performed up to 120 days before the ED visit date to determine whether the result reflected the currently prescribed prescription medications. If the UDS was positive for the prescribed opioids and/or BZDs and for any nonprescribed drug, including alcohol, the UDS was classified as not reflective. If the prescribed BZD was alprazolam, clonazepam, or lorazepam, a BZD-positive UDS was not required for the UDS to be considered reflective because of the sensitivity of the UDS BZD immunoassay
used at the George E. Wahlen VAMC clinical laboratory.²¹

Outcomes of the overdose were categorized as discharged, hospitalized, or deceased. Descriptive statistical analyses were performed using Microsoft Excel. Group comparisons were performed using Pearson chi-square or Student t test.

Results

The ED at the George E. Wahlen VAMC averages 64 visits per day, almost 94,000 visits within the study period. One hundred seventy ED visits between January 1, 2009 and January 1, 2013, involved naloxone administration. Ninety-two visits met the inclusion criteria of opioid overdose, representing about 0.002% of all ED visits at this facility (Figure 1). Six veterans had multiple ED visits within the study period, including 4 veterans who were in the opioid-only group.

The majority of veterans in this study were non-Hispanic white (n = 83, 90%), male (n = 88, 96%), with a mean age of 63 years. Less than 40% listed a next-of-kin or contact person living at their address.

Based on prescriptions available within 120 days before the overdose, 67 veterans (73%) possessed opioid and/or BZD prescriptions. In this group, the MED available on the day of the ED visit ranged from 7.5 mg to 830 mg. The MED was ≤ 200 mg in 71.6% and ≤ 50 mg in 34.3% of these cases. Veterans prescribed both opioids and BZDs had higher MED (average, 259 mg) available within 120 days of the ED visit than did those prescribed opioids only (average, 118 mg) (P = .015; SD, 132.9). The LED ranged from 1 mg to 12 mg for veterans with available BZDs.

Based on prescriptions available on the day of opioid overdose, 53 veterans (58%) had opioid prescriptions. The ranges of MED and LED available on the day of overdose were the same as the 120-day availability period. The average MED was 183 mg in veterans prescribed both opioids and BZDs and 126 mg in those prescribed opioids only (P = .283; SD, 168.65; Figure 2). The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

All veterans had at least 1 diagnosis that in previous studies was associated with increased risk of overdose.^9,15 The most common diagnoses included cardiovascular diseases, mental health disorders, pulmonary diseases, and cancer. Other SUDDs not including tobacco use were documented in at least half the veterans with prescribed opioids and/or BZDs. No veteran in the sample had a documented history of opioid SUDD.

Hydrocodone products were available in > 50% of cases. None of the veterans were prescribed buprenorphine products; other opioids, including tramadol, comprised the remainder (Figure 3). Primary care providers prescribed 72% of opioid prescriptions, with pain specialists, discharge physicians, ED providers, and surgeons prescribing the rest. When both opioids and BZDs were available, combinations of a hydrocodone product plus clonazepam or lorazepam were most common. The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

Overall, 64% of the sample had UDS results prior to the ED visit. Of veterans prescribed opioids and/or BZDs, 53% of UDSs reflected prescribed regimens.

On the day of the ED visit, 1 death occurred. Ninety-one veterans (99%) survived the overdose; 79 veterans (86%) were hospitalized, most for < 24 hours.

Discussion

This retrospective review identified 92 veterans who were treated with naloxone in the ED for opioid overdose during a 4-year period at the George E. Wahlen VAMC. Seventy-eight cases were excluded because the reason entered in charts for naloxone administration was itching, constipation, altered mental status, or unclear documentation.

Veterans in this study were older on average than the overdose fatalities in the U.S. Opioid overdose deaths in the U.S. and in Utah occur most frequently in non-Hispanic white men aged between 35 and 54 years.^7,22,23 In the 2010 Nationwide Emergency Department Sample of 136,000 opioid overdoses, of which 98% survived, most were aged 18 to 54 years.¹⁶ The older age in this study most likely reflects the age range of veterans served in the VHA; however, as more young veterans enter the VHA, the age range of overdose victims may more closely resemble the age ranges found in previous studies. Post hoc analysis showed 8 veterans (9%) with probable intentional opioid overdose based on chart review, whereas the incidence of intentional prescription drug overdose in the U.S. is 17.1%.²⁴

In Utah, almost 93% of fatal overdoses occur at a residential location.²² Less than half the veterans in this study had a contact or next-of-kin listed as living at the same address. Although veterans may not have identified someone living with them, in many cases, it is likely another person witnessed the overdose. Relying on EMRs to identify who should receive prevention education, in addition to the veteran, may result in missed opportunities to include another person likely to witness an overdose.²⁵ Prescribers should make a conscious effort to ask veterans to identify someone who may be able to assist with rescue efforts in the event of an overdose.

Diagnoses associated with increased risk of opioid overdose death include sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders and SUDD.^8,9,16 In a large sample of older veterans, only 64% had at least 1 medical or psychiatric diagnosis.²⁶ Less than half the 18,000 VA primary care patients in 5 VA centers had any psychiatric condition, and < 65% had cardiovascular disease, pulmonary disease, or cancer.²⁷ All veterans in this study had medical and psychiatric comorbidity.

In contrast, a large ED sample described by Yokell and colleagues found chronic mental conditions in 33.9%, circulatory disorders in 29.1%, and respiratory conditions in 25.6% of their sample.¹⁶ Bohnert and associates found a significantly elevated hazard ratio (HR) for any psychiatric disorder in a sample of nearly 4,500 veterans. There was variation in the HR when individual psychiatric diagnoses were broken out, with bipolar disorder having the largest HR and schizophrenia having the lowest but still elevated HR.⁹ In this study, individual diagnoses were not broken out because the smaller sample size could diminish the clinical significance of any apparent differences.

Edlund and colleagues found that < 8% of veterans treated with opioids for chronic noncancer pain had nonopioid SUDD.¹⁰ Bohnert and colleagues found an HR of 21.95 for overdose death among those with opioid-use disorders.⁹ The sample in this study had a much higher incidence of nonopioid SUDD compared with that ub the study by Edlund and colleagues, but none of the veterans in this study had a documented history of opioid use disorder. The absence of opioid use disorders in this sample is unexpected and points to a need for providers to screen for opioid use disorder whenever opioids are prescribed or renewed. If prevention practices were directed only to those with opioid SUDDs, none of the veterans in this study would have been included in those efforts. Non-SUDD providers should address the risks of opioid overdose in veterans with sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders.

Gomes and colleagues found that > 100 mg MED available on the day of overdose doubled the risk of opioid-related mortality.¹⁸ The VA/DoD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain identifies 200 mg MED as a threshold to define high-dose opioid therapy.²⁸ Fulton-Kehoe and colleagues found that 28% of overdose victims were prescribed < 50 mg MED.²⁹ In this study, the average dose available to veterans was > 100 mg MED; however, one-third of all study veterans had < 50 mg MED available. Using a threshold dose of 50 mg MED to target prevention efforts would capture only two-thirds of those who experienced overdose; a 200 mg MED threshold would exclude the majority, based on the average MED in each group in this study. Overdose education should be provided to veterans with access to any dose of opioids.

Use of BZDs with opioids may result in greater central nervous system (CNS) depression, pharmacokinetic interactions, or pharmacodynamic interactions at the µ opioid receptor.^30-32 About one-third of veterans in this study were prescribed opioids and BZDs concurrently, a combination noted in about 33% of opioid overdose deaths reported by the CDC.²⁴ Individuals taking methadone combined with BZDs have been found to have severe medical outcomes.³³ If preventive efforts are targeted to those receiving opioids and other CNS depressants, such as BZDs, about half (42%) the veterans in this study would not receive a potentially life-saving message about preventing overdoses. All veterans with opioids should be educated about the additional risk of overdose posed by drug interactions with other CNS depressants.

The time since the last fill of opioid prescription ranged from 0 to 28 days. This time frame indicates that some overdoses may have occurred on the day an opioid was filled but most occurred near the end of the expected days’ supply. Because information about adherence or use of the opioid was not studied, it cannot be assumed that medication misuse is the primary reason for the overdose. Delivering prevention efforts only at the time of medication dispensing would be insufficient. Clinicians should review local and remote prescription data, including via their states’ prescription drug monitoring program when discussing the risk of overdose with veterans.

Most veterans had at least 1 UDS result in the chart. Although half the UDSs obtained reflected prescribed medications, the possibility of aberrant behaviors, which increases the risk of overdose, cannot be ruled out with the methods used in this study.³⁴ Medication management agreements that require UDSs for veterans with chronic pain were not mandatory at the George E. Wahlen VAMC during the study period, and those used did not mandate discontinuation of opioid therapy if suspected aberrant behaviors were present.

A Utah study based on interviews of overdose victims’ next-of-kin found that 76% were concerned about victims’ aberrant behaviors, such as medication misuse, prior to the death.²² In contrast, a study of commercial and Medicaid recipients estimated medication misuse rates in
≤ 30% of the sample.³⁵ Urine drug screening results not reflective of the prescribed regimens have been found in up to 50% of patients receiving chronic opioid therapy.

The UDS findings in this study were determined by the authors and did not capture clinical decisions or interpretations made after results were available or whether these decisions resulted in overdose prevention strategies, such as targeted education or changes in prescription availability. Targeting preventive efforts toward veterans only with UDS results suggesting medication misuse would have missed more than half the veterans in this study. Urine drug screening should be used as a clinical monitoring tool whenever opioids, BZDs, or other substances are used or prescribed.

The VA now has a nationwide program, Opioid Overdose Education and Naloxone Distribution (OEND) promoting overdose education and take-home naloxone distribution for providers and patients to prevent opioid-related overdose deaths. A national SharePoint site has been created within the VA that lists resources to support this effort.

Almost all veterans in this review survived the overdose and were hospitalized following the ED visit. Other investigators also have found that the majority (51% to 98%) of overdose victims reaching the ED survived, but fewer patients (3% to 51%) in those studies were hospitalized.^16,36 It is unknown whether there are differences in risk factors associated with survived or fatal overdoses.

Limitations

Although Utah ranked third for drug overdose death rates in 2008 and had the highest death rate among veterans from 2001 to 2009, this review captured only overdoses among veterans treated during the study period at the George E. Wahlen VAMC ED.^5,6 The number and characteristics of veterans during this same period who were treated for overdose in other community EDs or urgent care centers throughout Utah is unknown.

The definition of opioid and BZD dose available in this study may not represent actual use of opioids or BZDs because it was based on chart review of prescription dispensing information and UDS procedures at the George E. Wahlen VAMC, and medication misuse cannot be ruled out. This study did not evaluate specific aberrant behaviors.

Conclusion

Current overdose prevention screening efforts primarily identify patients on high-dose opioids and those with SUDD. Many veterans in this study were older than the average U.S. victims’ age, did not have SUDD, were prescribed opioid doses not considered high risk by current guidelines, were nearer the end of their medication supply, and had UDS reflective of prescribed medications. This study suggests that any veteran with access to opioids, whether prescribed or not, is at risk for an opioid overdose. Established risk factors may aid in developing overdose prevention programs, but prevention should not be limited to veterans with prescribed opioids and known risk factors. Prescribers should screen for opioid use disorder whenever opioids are prescribed and continue to screen throughout therapy. Broader screening for overdose risk is needed to avoid missing important opportunities for overdose prevention.

Acknowledgments
Gale Anderson, VISN 19 PBM Data Manager, performed initial data query for the study.

Overdose deaths remain epidemic throughout the U.S. The rates of unintentional overdose deaths, increasing by 137% between 2000 and 2014, have been driven by a 4-fold increase in prescription opioid overdoses during that period.^1-3

Veterans died of accidental overdose at a rate of 19.85 deaths/ 100,000 people compared with a rate of 10.49 deaths in the general population, based on 2005 data.⁴ There is wide state-by-state variation with the lowest age-adjusted opioid overdose death rate of 1.9 deaths/100,000 person-years among veterans in Mississippi and the highest rate in Utah of 33.9 deaths/100,000 person-years, using 2001 to 2009 data.⁵ These data can be compared with a crude general population overdose death rate of 10.6 deaths per 100,000 person-years in Mississippi and 18.4 deaths per 100,000 person-years in the general Utah population during that same period.⁶

Overdose deaths in the U.S. occur most often in persons aged 25 to 54 years.⁷ Older age has been associated with iatrogenic opioid overdose in hospitalized patients.⁸ Pulmonary, cardiovascular, and psychiatric disorders, including past or present substance use, have been associated with an increased risk of opioid overdose.⁹ However, veterans with substance use disorders are less likely to be prescribed opioids than are nonveterans with substance use disorders.¹⁰ Also, concomitant use of sedating medications, such as benzodiazepines (BZDs), can increase mortality from opioid overdose.¹¹ Patients prescribed opioids for chronic pain conditions often take BZDs for various reasons.¹² Veterans seem more likely to receive opioids to treat chronic pain but at lower average daily doses than the doses that nonveterans receive.¹⁰

Emergency management of life-threatening opioid overdose includes prompt administration of naloxone.¹³ Naloxone is FDA approved for complete or partial reversal of opioid-induced clinical effects, most critically respiratory depression.^14,15 Naloxone administration in the emergency department (ED) may serve as a surrogate for an overdose event. During the study period, naloxone take-home kits were not available in the VA setting.

A 2010 ED study described demographic information and comorbidities in opioid overdose, but the study did not include veterans.¹⁶ The clinical characteristics of veterans treated for opioid overdose have not been published. Because identifying characteristics of veterans who overdose may help tailor overdose prevention efforts, the objective of this study is to describe clinical characteristics of veterans treated for opioid overdose.

Methods

A retrospective chart review and archived data study was approved by the University of Utah and VA institutional review boards, and conducted at the George E. Wahlen VAMC in Salt Lake City, Utah. This chart review included veterans who were admitted to the ED and treated with naloxone between January 1, 2009 and January 1, 2013.

The authors used the Pharmacy Benefits Management Data Manager to extract data from the VA Data Warehouse and verified the data by open chart review (Table). The following data were collected: ED visit date (overdose date); demographic information, including age, gender, and race; evidence of next-of-kin or other contact at the same address as the veteran; diagnoses based on ICD-9 codes, including sleep apnea, obesitycardiac disease, pulmonary disease, mental health diagnoses (ICD-9 codes 290-302 [wild card characters (*) included many subdiagnoses]),
cancer, and substance use disorders and/or dependencies (SUDD); tobacco use; VA-issued prescription opioid and BZD availability, including dose, fill dates, quantities dispensed, and day supplies; specialty of opioid prescriber; urine drug screening (UDS) results; and outcome of the overdose.

No standardized research criteria identify overdose in medical chart review.¹⁷ For each identified patient, the authors reviewed provider and nursing notes charted during an ED visit that included naloxone administration. The event was included as an opioid overdose when notes indicated that the veteran was unresponsive and given naloxone, which resulted in increased respirations or increased responsiveness. Cases were excluded if the reason for naloxone administration was anything other than opioid overdose.

Medical, mental health, and SUDD diagnoses were included only if the veteran had more than 3 patient care encounters (PCE) with ICD-9 codes for a specific diagnosis entered by providers. A PCE used in the electronic medical record (EMR) helps collect, manage, and display outpatient encounter data, including providers, procedure codes, and diagnostic codes. Tobacco use was extracted from health factors documented during primary care visit screenings. (Health factors help capture data entered in note templates in the EMR and can be used to query trends.) A diagnosis of obesity was based on a calculated body mass index of > 30 kg/m² on the day of the ED visit date or the most recently charted height and weight. The type of SUDD was stratified into opioids (ICD-9 codes 304.0*), sedatives (ICD-9 code 304.1*), alcohol (ICD-9 code 303.*), and other (ICD-9 codes 304.2-305.9).

The dosage of opioids and BZDs available to a veteran was determined by using methods similar to those described by Gomes and colleagues: the dose of opioids and BZDs available based on prescriptions dispensed during the 120 days prior to the ED visit date and the dose available on the day of the ED visit date if prescription instructions were being followed.¹⁸ Prescription opioids and BZDs were converted to daily morphine equivalent dose (MED) and daily lorazepam-equivalent dose (LED), using established methods.^19,20

Veterans were stratified into 4 groups based on prescribed medication availability: opioids only, BZDs only, opioids and BZDs, and neither opioids nor BZDs. The specialty of the opioid prescribers was categorized as primary care, pain specialist, surgeon, emergency specialist, or hospitalist (discharge prescription). Veteran EMRs contain a list of medications obtained outside the VA facility, referred to as non-VA prescriptions. These medications werenot included in the analysis because accuracy could not be verified.

A study author reviewed the results of any UDS performed up to 120 days before the ED visit date to determine whether the result reflected the currently prescribed prescription medications. If the UDS was positive for the prescribed opioids and/or BZDs and for any nonprescribed drug, including alcohol, the UDS was classified as not reflective. If the prescribed BZD was alprazolam, clonazepam, or lorazepam, a BZD-positive UDS was not required for the UDS to be considered reflective because of the sensitivity of the UDS BZD immunoassay
used at the George E. Wahlen VAMC clinical laboratory.²¹

Outcomes of the overdose were categorized as discharged, hospitalized, or deceased. Descriptive statistical analyses were performed using Microsoft Excel. Group comparisons were performed using Pearson chi-square or Student t test.

Results

The ED at the George E. Wahlen VAMC averages 64 visits per day, almost 94,000 visits within the study period. One hundred seventy ED visits between January 1, 2009 and January 1, 2013, involved naloxone administration. Ninety-two visits met the inclusion criteria of opioid overdose, representing about 0.002% of all ED visits at this facility (Figure 1). Six veterans had multiple ED visits within the study period, including 4 veterans who were in the opioid-only group.

The majority of veterans in this study were non-Hispanic white (n = 83, 90%), male (n = 88, 96%), with a mean age of 63 years. Less than 40% listed a next-of-kin or contact person living at their address.

Based on prescriptions available within 120 days before the overdose, 67 veterans (73%) possessed opioid and/or BZD prescriptions. In this group, the MED available on the day of the ED visit ranged from 7.5 mg to 830 mg. The MED was ≤ 200 mg in 71.6% and ≤ 50 mg in 34.3% of these cases. Veterans prescribed both opioids and BZDs had higher MED (average, 259 mg) available within 120 days of the ED visit than did those prescribed opioids only (average, 118 mg) (P = .015; SD, 132.9). The LED ranged from 1 mg to 12 mg for veterans with available BZDs.

Based on prescriptions available on the day of opioid overdose, 53 veterans (58%) had opioid prescriptions. The ranges of MED and LED available on the day of overdose were the same as the 120-day availability period. The average MED was 183 mg in veterans prescribed both opioids and BZDs and 126 mg in those prescribed opioids only (P = .283; SD, 168.65; Figure 2). The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

All veterans had at least 1 diagnosis that in previous studies was associated with increased risk of overdose.^9,15 The most common diagnoses included cardiovascular diseases, mental health disorders, pulmonary diseases, and cancer. Other SUDDs not including tobacco use were documented in at least half the veterans with prescribed opioids and/or BZDs. No veteran in the sample had a documented history of opioid SUDD.

Hydrocodone products were available in > 50% of cases. None of the veterans were prescribed buprenorphine products; other opioids, including tramadol, comprised the remainder (Figure 3). Primary care providers prescribed 72% of opioid prescriptions, with pain specialists, discharge physicians, ED providers, and surgeons prescribing the rest. When both opioids and BZDs were available, combinations of a hydrocodone product plus clonazepam or lorazepam were most common. The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

Overall, 64% of the sample had UDS results prior to the ED visit. Of veterans prescribed opioids and/or BZDs, 53% of UDSs reflected prescribed regimens.

On the day of the ED visit, 1 death occurred. Ninety-one veterans (99%) survived the overdose; 79 veterans (86%) were hospitalized, most for < 24 hours.

Discussion

This retrospective review identified 92 veterans who were treated with naloxone in the ED for opioid overdose during a 4-year period at the George E. Wahlen VAMC. Seventy-eight cases were excluded because the reason entered in charts for naloxone administration was itching, constipation, altered mental status, or unclear documentation.

Veterans in this study were older on average than the overdose fatalities in the U.S. Opioid overdose deaths in the U.S. and in Utah occur most frequently in non-Hispanic white men aged between 35 and 54 years.^7,22,23 In the 2010 Nationwide Emergency Department Sample of 136,000 opioid overdoses, of which 98% survived, most were aged 18 to 54 years.¹⁶ The older age in this study most likely reflects the age range of veterans served in the VHA; however, as more young veterans enter the VHA, the age range of overdose victims may more closely resemble the age ranges found in previous studies. Post hoc analysis showed 8 veterans (9%) with probable intentional opioid overdose based on chart review, whereas the incidence of intentional prescription drug overdose in the U.S. is 17.1%.²⁴

In Utah, almost 93% of fatal overdoses occur at a residential location.²² Less than half the veterans in this study had a contact or next-of-kin listed as living at the same address. Although veterans may not have identified someone living with them, in many cases, it is likely another person witnessed the overdose. Relying on EMRs to identify who should receive prevention education, in addition to the veteran, may result in missed opportunities to include another person likely to witness an overdose.²⁵ Prescribers should make a conscious effort to ask veterans to identify someone who may be able to assist with rescue efforts in the event of an overdose.

Diagnoses associated with increased risk of opioid overdose death include sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders and SUDD.^8,9,16 In a large sample of older veterans, only 64% had at least 1 medical or psychiatric diagnosis.²⁶ Less than half the 18,000 VA primary care patients in 5 VA centers had any psychiatric condition, and < 65% had cardiovascular disease, pulmonary disease, or cancer.²⁷ All veterans in this study had medical and psychiatric comorbidity.

In contrast, a large ED sample described by Yokell and colleagues found chronic mental conditions in 33.9%, circulatory disorders in 29.1%, and respiratory conditions in 25.6% of their sample.¹⁶ Bohnert and associates found a significantly elevated hazard ratio (HR) for any psychiatric disorder in a sample of nearly 4,500 veterans. There was variation in the HR when individual psychiatric diagnoses were broken out, with bipolar disorder having the largest HR and schizophrenia having the lowest but still elevated HR.⁹ In this study, individual diagnoses were not broken out because the smaller sample size could diminish the clinical significance of any apparent differences.

Edlund and colleagues found that < 8% of veterans treated with opioids for chronic noncancer pain had nonopioid SUDD.¹⁰ Bohnert and colleagues found an HR of 21.95 for overdose death among those with opioid-use disorders.⁹ The sample in this study had a much higher incidence of nonopioid SUDD compared with that ub the study by Edlund and colleagues, but none of the veterans in this study had a documented history of opioid use disorder. The absence of opioid use disorders in this sample is unexpected and points to a need for providers to screen for opioid use disorder whenever opioids are prescribed or renewed. If prevention practices were directed only to those with opioid SUDDs, none of the veterans in this study would have been included in those efforts. Non-SUDD providers should address the risks of opioid overdose in veterans with sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders.

Gomes and colleagues found that > 100 mg MED available on the day of overdose doubled the risk of opioid-related mortality.¹⁸ The VA/DoD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain identifies 200 mg MED as a threshold to define high-dose opioid therapy.²⁸ Fulton-Kehoe and colleagues found that 28% of overdose victims were prescribed < 50 mg MED.²⁹ In this study, the average dose available to veterans was > 100 mg MED; however, one-third of all study veterans had < 50 mg MED available. Using a threshold dose of 50 mg MED to target prevention efforts would capture only two-thirds of those who experienced overdose; a 200 mg MED threshold would exclude the majority, based on the average MED in each group in this study. Overdose education should be provided to veterans with access to any dose of opioids.

Use of BZDs with opioids may result in greater central nervous system (CNS) depression, pharmacokinetic interactions, or pharmacodynamic interactions at the µ opioid receptor.^30-32 About one-third of veterans in this study were prescribed opioids and BZDs concurrently, a combination noted in about 33% of opioid overdose deaths reported by the CDC.²⁴ Individuals taking methadone combined with BZDs have been found to have severe medical outcomes.³³ If preventive efforts are targeted to those receiving opioids and other CNS depressants, such as BZDs, about half (42%) the veterans in this study would not receive a potentially life-saving message about preventing overdoses. All veterans with opioids should be educated about the additional risk of overdose posed by drug interactions with other CNS depressants.

The time since the last fill of opioid prescription ranged from 0 to 28 days. This time frame indicates that some overdoses may have occurred on the day an opioid was filled but most occurred near the end of the expected days’ supply. Because information about adherence or use of the opioid was not studied, it cannot be assumed that medication misuse is the primary reason for the overdose. Delivering prevention efforts only at the time of medication dispensing would be insufficient. Clinicians should review local and remote prescription data, including via their states’ prescription drug monitoring program when discussing the risk of overdose with veterans.

Most veterans had at least 1 UDS result in the chart. Although half the UDSs obtained reflected prescribed medications, the possibility of aberrant behaviors, which increases the risk of overdose, cannot be ruled out with the methods used in this study.³⁴ Medication management agreements that require UDSs for veterans with chronic pain were not mandatory at the George E. Wahlen VAMC during the study period, and those used did not mandate discontinuation of opioid therapy if suspected aberrant behaviors were present.

A Utah study based on interviews of overdose victims’ next-of-kin found that 76% were concerned about victims’ aberrant behaviors, such as medication misuse, prior to the death.²² In contrast, a study of commercial and Medicaid recipients estimated medication misuse rates in
≤ 30% of the sample.³⁵ Urine drug screening results not reflective of the prescribed regimens have been found in up to 50% of patients receiving chronic opioid therapy.

The UDS findings in this study were determined by the authors and did not capture clinical decisions or interpretations made after results were available or whether these decisions resulted in overdose prevention strategies, such as targeted education or changes in prescription availability. Targeting preventive efforts toward veterans only with UDS results suggesting medication misuse would have missed more than half the veterans in this study. Urine drug screening should be used as a clinical monitoring tool whenever opioids, BZDs, or other substances are used or prescribed.

The VA now has a nationwide program, Opioid Overdose Education and Naloxone Distribution (OEND) promoting overdose education and take-home naloxone distribution for providers and patients to prevent opioid-related overdose deaths. A national SharePoint site has been created within the VA that lists resources to support this effort.

Almost all veterans in this review survived the overdose and were hospitalized following the ED visit. Other investigators also have found that the majority (51% to 98%) of overdose victims reaching the ED survived, but fewer patients (3% to 51%) in those studies were hospitalized.^16,36 It is unknown whether there are differences in risk factors associated with survived or fatal overdoses.

Limitations

Although Utah ranked third for drug overdose death rates in 2008 and had the highest death rate among veterans from 2001 to 2009, this review captured only overdoses among veterans treated during the study period at the George E. Wahlen VAMC ED.^5,6 The number and characteristics of veterans during this same period who were treated for overdose in other community EDs or urgent care centers throughout Utah is unknown.

The definition of opioid and BZD dose available in this study may not represent actual use of opioids or BZDs because it was based on chart review of prescription dispensing information and UDS procedures at the George E. Wahlen VAMC, and medication misuse cannot be ruled out. This study did not evaluate specific aberrant behaviors.

Conclusion

Current overdose prevention screening efforts primarily identify patients on high-dose opioids and those with SUDD. Many veterans in this study were older than the average U.S. victims’ age, did not have SUDD, were prescribed opioid doses not considered high risk by current guidelines, were nearer the end of their medication supply, and had UDS reflective of prescribed medications. This study suggests that any veteran with access to opioids, whether prescribed or not, is at risk for an opioid overdose. Established risk factors may aid in developing overdose prevention programs, but prevention should not be limited to veterans with prescribed opioids and known risk factors. Prescribers should screen for opioid use disorder whenever opioids are prescribed and continue to screen throughout therapy. Broader screening for overdose risk is needed to avoid missing important opportunities for overdose prevention.

Acknowledgments
Gale Anderson, VISN 19 PBM Data Manager, performed initial data query for the study.

Overdose deaths remain epidemic throughout the U.S. The rates of unintentional overdose deaths, increasing by 137% between 2000 and 2014, have been driven by a 4-fold increase in prescription opioid overdoses during that period.^1-3

Veterans died of accidental overdose at a rate of 19.85 deaths/ 100,000 people compared with a rate of 10.49 deaths in the general population, based on 2005 data.⁴ There is wide state-by-state variation with the lowest age-adjusted opioid overdose death rate of 1.9 deaths/100,000 person-years among veterans in Mississippi and the highest rate in Utah of 33.9 deaths/100,000 person-years, using 2001 to 2009 data.⁵ These data can be compared with a crude general population overdose death rate of 10.6 deaths per 100,000 person-years in Mississippi and 18.4 deaths per 100,000 person-years in the general Utah population during that same period.⁶

Overdose deaths in the U.S. occur most often in persons aged 25 to 54 years.⁷ Older age has been associated with iatrogenic opioid overdose in hospitalized patients.⁸ Pulmonary, cardiovascular, and psychiatric disorders, including past or present substance use, have been associated with an increased risk of opioid overdose.⁹ However, veterans with substance use disorders are less likely to be prescribed opioids than are nonveterans with substance use disorders.¹⁰ Also, concomitant use of sedating medications, such as benzodiazepines (BZDs), can increase mortality from opioid overdose.¹¹ Patients prescribed opioids for chronic pain conditions often take BZDs for various reasons.¹² Veterans seem more likely to receive opioids to treat chronic pain but at lower average daily doses than the doses that nonveterans receive.¹⁰

Emergency management of life-threatening opioid overdose includes prompt administration of naloxone.¹³ Naloxone is FDA approved for complete or partial reversal of opioid-induced clinical effects, most critically respiratory depression.^14,15 Naloxone administration in the emergency department (ED) may serve as a surrogate for an overdose event. During the study period, naloxone take-home kits were not available in the VA setting.

A 2010 ED study described demographic information and comorbidities in opioid overdose, but the study did not include veterans.¹⁶ The clinical characteristics of veterans treated for opioid overdose have not been published. Because identifying characteristics of veterans who overdose may help tailor overdose prevention efforts, the objective of this study is to describe clinical characteristics of veterans treated for opioid overdose.

Methods

A retrospective chart review and archived data study was approved by the University of Utah and VA institutional review boards, and conducted at the George E. Wahlen VAMC in Salt Lake City, Utah. This chart review included veterans who were admitted to the ED and treated with naloxone between January 1, 2009 and January 1, 2013.

The authors used the Pharmacy Benefits Management Data Manager to extract data from the VA Data Warehouse and verified the data by open chart review (Table). The following data were collected: ED visit date (overdose date); demographic information, including age, gender, and race; evidence of next-of-kin or other contact at the same address as the veteran; diagnoses based on ICD-9 codes, including sleep apnea, obesitycardiac disease, pulmonary disease, mental health diagnoses (ICD-9 codes 290-302 [wild card characters (*) included many subdiagnoses]),
cancer, and substance use disorders and/or dependencies (SUDD); tobacco use; VA-issued prescription opioid and BZD availability, including dose, fill dates, quantities dispensed, and day supplies; specialty of opioid prescriber; urine drug screening (UDS) results; and outcome of the overdose.

No standardized research criteria identify overdose in medical chart review.¹⁷ For each identified patient, the authors reviewed provider and nursing notes charted during an ED visit that included naloxone administration. The event was included as an opioid overdose when notes indicated that the veteran was unresponsive and given naloxone, which resulted in increased respirations or increased responsiveness. Cases were excluded if the reason for naloxone administration was anything other than opioid overdose.

Medical, mental health, and SUDD diagnoses were included only if the veteran had more than 3 patient care encounters (PCE) with ICD-9 codes for a specific diagnosis entered by providers. A PCE used in the electronic medical record (EMR) helps collect, manage, and display outpatient encounter data, including providers, procedure codes, and diagnostic codes. Tobacco use was extracted from health factors documented during primary care visit screenings. (Health factors help capture data entered in note templates in the EMR and can be used to query trends.) A diagnosis of obesity was based on a calculated body mass index of > 30 kg/m² on the day of the ED visit date or the most recently charted height and weight. The type of SUDD was stratified into opioids (ICD-9 codes 304.0*), sedatives (ICD-9 code 304.1*), alcohol (ICD-9 code 303.*), and other (ICD-9 codes 304.2-305.9).

The dosage of opioids and BZDs available to a veteran was determined by using methods similar to those described by Gomes and colleagues: the dose of opioids and BZDs available based on prescriptions dispensed during the 120 days prior to the ED visit date and the dose available on the day of the ED visit date if prescription instructions were being followed.¹⁸ Prescription opioids and BZDs were converted to daily morphine equivalent dose (MED) and daily lorazepam-equivalent dose (LED), using established methods.^19,20

Veterans were stratified into 4 groups based on prescribed medication availability: opioids only, BZDs only, opioids and BZDs, and neither opioids nor BZDs. The specialty of the opioid prescribers was categorized as primary care, pain specialist, surgeon, emergency specialist, or hospitalist (discharge prescription). Veteran EMRs contain a list of medications obtained outside the VA facility, referred to as non-VA prescriptions. These medications werenot included in the analysis because accuracy could not be verified.

A study author reviewed the results of any UDS performed up to 120 days before the ED visit date to determine whether the result reflected the currently prescribed prescription medications. If the UDS was positive for the prescribed opioids and/or BZDs and for any nonprescribed drug, including alcohol, the UDS was classified as not reflective. If the prescribed BZD was alprazolam, clonazepam, or lorazepam, a BZD-positive UDS was not required for the UDS to be considered reflective because of the sensitivity of the UDS BZD immunoassay
used at the George E. Wahlen VAMC clinical laboratory.²¹

Outcomes of the overdose were categorized as discharged, hospitalized, or deceased. Descriptive statistical analyses were performed using Microsoft Excel. Group comparisons were performed using Pearson chi-square or Student t test.

Results

The ED at the George E. Wahlen VAMC averages 64 visits per day, almost 94,000 visits within the study period. One hundred seventy ED visits between January 1, 2009 and January 1, 2013, involved naloxone administration. Ninety-two visits met the inclusion criteria of opioid overdose, representing about 0.002% of all ED visits at this facility (Figure 1). Six veterans had multiple ED visits within the study period, including 4 veterans who were in the opioid-only group.

The majority of veterans in this study were non-Hispanic white (n = 83, 90%), male (n = 88, 96%), with a mean age of 63 years. Less than 40% listed a next-of-kin or contact person living at their address.

Based on prescriptions available within 120 days before the overdose, 67 veterans (73%) possessed opioid and/or BZD prescriptions. In this group, the MED available on the day of the ED visit ranged from 7.5 mg to 830 mg. The MED was ≤ 200 mg in 71.6% and ≤ 50 mg in 34.3% of these cases. Veterans prescribed both opioids and BZDs had higher MED (average, 259 mg) available within 120 days of the ED visit than did those prescribed opioids only (average, 118 mg) (P = .015; SD, 132.9). The LED ranged from 1 mg to 12 mg for veterans with available BZDs.

Based on prescriptions available on the day of opioid overdose, 53 veterans (58%) had opioid prescriptions. The ranges of MED and LED available on the day of overdose were the same as the 120-day availability period. The average MED was 183 mg in veterans prescribed both opioids and BZDs and 126 mg in those prescribed opioids only (P = .283; SD, 168.65; Figure 2). The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

All veterans had at least 1 diagnosis that in previous studies was associated with increased risk of overdose.^9,15 The most common diagnoses included cardiovascular diseases, mental health disorders, pulmonary diseases, and cancer. Other SUDDs not including tobacco use were documented in at least half the veterans with prescribed opioids and/or BZDs. No veteran in the sample had a documented history of opioid SUDD.

Hydrocodone products were available in > 50% of cases. None of the veterans were prescribed buprenorphine products; other opioids, including tramadol, comprised the remainder (Figure 3). Primary care providers prescribed 72% of opioid prescriptions, with pain specialists, discharge physicians, ED providers, and surgeons prescribing the rest. When both opioids and BZDs were available, combinations of a hydrocodone product plus clonazepam or lorazepam were most common. The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

Overall, 64% of the sample had UDS results prior to the ED visit. Of veterans prescribed opioids and/or BZDs, 53% of UDSs reflected prescribed regimens.

On the day of the ED visit, 1 death occurred. Ninety-one veterans (99%) survived the overdose; 79 veterans (86%) were hospitalized, most for < 24 hours.

Discussion

This retrospective review identified 92 veterans who were treated with naloxone in the ED for opioid overdose during a 4-year period at the George E. Wahlen VAMC. Seventy-eight cases were excluded because the reason entered in charts for naloxone administration was itching, constipation, altered mental status, or unclear documentation.

Veterans in this study were older on average than the overdose fatalities in the U.S. Opioid overdose deaths in the U.S. and in Utah occur most frequently in non-Hispanic white men aged between 35 and 54 years.^7,22,23 In the 2010 Nationwide Emergency Department Sample of 136,000 opioid overdoses, of which 98% survived, most were aged 18 to 54 years.¹⁶ The older age in this study most likely reflects the age range of veterans served in the VHA; however, as more young veterans enter the VHA, the age range of overdose victims may more closely resemble the age ranges found in previous studies. Post hoc analysis showed 8 veterans (9%) with probable intentional opioid overdose based on chart review, whereas the incidence of intentional prescription drug overdose in the U.S. is 17.1%.²⁴

In Utah, almost 93% of fatal overdoses occur at a residential location.²² Less than half the veterans in this study had a contact or next-of-kin listed as living at the same address. Although veterans may not have identified someone living with them, in many cases, it is likely another person witnessed the overdose. Relying on EMRs to identify who should receive prevention education, in addition to the veteran, may result in missed opportunities to include another person likely to witness an overdose.²⁵ Prescribers should make a conscious effort to ask veterans to identify someone who may be able to assist with rescue efforts in the event of an overdose.

Diagnoses associated with increased risk of opioid overdose death include sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders and SUDD.^8,9,16 In a large sample of older veterans, only 64% had at least 1 medical or psychiatric diagnosis.²⁶ Less than half the 18,000 VA primary care patients in 5 VA centers had any psychiatric condition, and < 65% had cardiovascular disease, pulmonary disease, or cancer.²⁷ All veterans in this study had medical and psychiatric comorbidity.

In contrast, a large ED sample described by Yokell and colleagues found chronic mental conditions in 33.9%, circulatory disorders in 29.1%, and respiratory conditions in 25.6% of their sample.¹⁶ Bohnert and associates found a significantly elevated hazard ratio (HR) for any psychiatric disorder in a sample of nearly 4,500 veterans. There was variation in the HR when individual psychiatric diagnoses were broken out, with bipolar disorder having the largest HR and schizophrenia having the lowest but still elevated HR.⁹ In this study, individual diagnoses were not broken out because the smaller sample size could diminish the clinical significance of any apparent differences.

Edlund and colleagues found that < 8% of veterans treated with opioids for chronic noncancer pain had nonopioid SUDD.¹⁰ Bohnert and colleagues found an HR of 21.95 for overdose death among those with opioid-use disorders.⁹ The sample in this study had a much higher incidence of nonopioid SUDD compared with that ub the study by Edlund and colleagues, but none of the veterans in this study had a documented history of opioid use disorder. The absence of opioid use disorders in this sample is unexpected and points to a need for providers to screen for opioid use disorder whenever opioids are prescribed or renewed. If prevention practices were directed only to those with opioid SUDDs, none of the veterans in this study would have been included in those efforts. Non-SUDD providers should address the risks of opioid overdose in veterans with sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders.

Gomes and colleagues found that > 100 mg MED available on the day of overdose doubled the risk of opioid-related mortality.¹⁸ The VA/DoD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain identifies 200 mg MED as a threshold to define high-dose opioid therapy.²⁸ Fulton-Kehoe and colleagues found that 28% of overdose victims were prescribed < 50 mg MED.²⁹ In this study, the average dose available to veterans was > 100 mg MED; however, one-third of all study veterans had < 50 mg MED available. Using a threshold dose of 50 mg MED to target prevention efforts would capture only two-thirds of those who experienced overdose; a 200 mg MED threshold would exclude the majority, based on the average MED in each group in this study. Overdose education should be provided to veterans with access to any dose of opioids.

Use of BZDs with opioids may result in greater central nervous system (CNS) depression, pharmacokinetic interactions, or pharmacodynamic interactions at the µ opioid receptor.^30-32 About one-third of veterans in this study were prescribed opioids and BZDs concurrently, a combination noted in about 33% of opioid overdose deaths reported by the CDC.²⁴ Individuals taking methadone combined with BZDs have been found to have severe medical outcomes.³³ If preventive efforts are targeted to those receiving opioids and other CNS depressants, such as BZDs, about half (42%) the veterans in this study would not receive a potentially life-saving message about preventing overdoses. All veterans with opioids should be educated about the additional risk of overdose posed by drug interactions with other CNS depressants.

The time since the last fill of opioid prescription ranged from 0 to 28 days. This time frame indicates that some overdoses may have occurred on the day an opioid was filled but most occurred near the end of the expected days’ supply. Because information about adherence or use of the opioid was not studied, it cannot be assumed that medication misuse is the primary reason for the overdose. Delivering prevention efforts only at the time of medication dispensing would be insufficient. Clinicians should review local and remote prescription data, including via their states’ prescription drug monitoring program when discussing the risk of overdose with veterans.

Most veterans had at least 1 UDS result in the chart. Although half the UDSs obtained reflected prescribed medications, the possibility of aberrant behaviors, which increases the risk of overdose, cannot be ruled out with the methods used in this study.³⁴ Medication management agreements that require UDSs for veterans with chronic pain were not mandatory at the George E. Wahlen VAMC during the study period, and those used did not mandate discontinuation of opioid therapy if suspected aberrant behaviors were present.

A Utah study based on interviews of overdose victims’ next-of-kin found that 76% were concerned about victims’ aberrant behaviors, such as medication misuse, prior to the death.²² In contrast, a study of commercial and Medicaid recipients estimated medication misuse rates in
≤ 30% of the sample.³⁵ Urine drug screening results not reflective of the prescribed regimens have been found in up to 50% of patients receiving chronic opioid therapy.

The UDS findings in this study were determined by the authors and did not capture clinical decisions or interpretations made after results were available or whether these decisions resulted in overdose prevention strategies, such as targeted education or changes in prescription availability. Targeting preventive efforts toward veterans only with UDS results suggesting medication misuse would have missed more than half the veterans in this study. Urine drug screening should be used as a clinical monitoring tool whenever opioids, BZDs, or other substances are used or prescribed.

The VA now has a nationwide program, Opioid Overdose Education and Naloxone Distribution (OEND) promoting overdose education and take-home naloxone distribution for providers and patients to prevent opioid-related overdose deaths. A national SharePoint site has been created within the VA that lists resources to support this effort.

Almost all veterans in this review survived the overdose and were hospitalized following the ED visit. Other investigators also have found that the majority (51% to 98%) of overdose victims reaching the ED survived, but fewer patients (3% to 51%) in those studies were hospitalized.^16,36 It is unknown whether there are differences in risk factors associated with survived or fatal overdoses.

Limitations

Although Utah ranked third for drug overdose death rates in 2008 and had the highest death rate among veterans from 2001 to 2009, this review captured only overdoses among veterans treated during the study period at the George E. Wahlen VAMC ED.^5,6 The number and characteristics of veterans during this same period who were treated for overdose in other community EDs or urgent care centers throughout Utah is unknown.

The definition of opioid and BZD dose available in this study may not represent actual use of opioids or BZDs because it was based on chart review of prescription dispensing information and UDS procedures at the George E. Wahlen VAMC, and medication misuse cannot be ruled out. This study did not evaluate specific aberrant behaviors.

Conclusion

Current overdose prevention screening efforts primarily identify patients on high-dose opioids and those with SUDD. Many veterans in this study were older than the average U.S. victims’ age, did not have SUDD, were prescribed opioid doses not considered high risk by current guidelines, were nearer the end of their medication supply, and had UDS reflective of prescribed medications. This study suggests that any veteran with access to opioids, whether prescribed or not, is at risk for an opioid overdose. Established risk factors may aid in developing overdose prevention programs, but prevention should not be limited to veterans with prescribed opioids and known risk factors. Prescribers should screen for opioid use disorder whenever opioids are prescribed and continue to screen throughout therapy. Broader screening for overdose risk is needed to avoid missing important opportunities for overdose prevention.

Acknowledgments
Gale Anderson, VISN 19 PBM Data Manager, performed initial data query for the study.

Blood for transfusion

Photo by Elise Amendola

There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.

Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.

However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.

The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.

“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.

“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”

Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.

To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.

All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.

The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.

Results

The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.

However, there were no other significant differences between the sex-discordant and same-sex groups.

The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.

However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.

The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.

Blood for transfusion

Photo by Elise Amendola

There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.

Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.

However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.

The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.

“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.

“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”

Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.

To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.

All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.

The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.

Results

The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.

However, there were no other significant differences between the sex-discordant and same-sex groups.

The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.

However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.

The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.

Blood for transfusion

Photo by Elise Amendola

There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.

Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.

However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.

The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.

“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.

“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”

Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.

To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.

All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.

The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.

Results

The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.

However, there were no other significant differences between the sex-discordant and same-sex groups.

The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.

However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.

The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.

Red blood cells

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Red blood cells

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Red blood cells

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Unicompartmental knee arthroplasty (UKA) is considered a less invasive approach for the treatment of unicompartmental knee arthritis when compared with total knee arthroplasty (TKA), with optimal preservation of kinematics.¹ Despite excellent functional outcomes, conversion to TKA may be necessary if the UKA fails, or in patients with progressive knee arthritis. Some studies have found UKA conversion to TKA to be comparable with primary TKA,^2,3 whereas others have found that conversion often requires bone graft, augments, and stemmed components and has increased complications and inferior results compared to primary TKA.^4-7 While some studies report that <10% of UKA conversions to TKA require augments,² others have found that as many as 76% require augments.^4-8

Schwarzkopf and colleagues⁹ recently demonstrated that UKA conversion to TKA is comparable with primary TKA when a conservative tibial resection is performed during the index procedure. However, they reported increased complexity when greater tibial resection was performed and thicker polyethylene inserts were used at the time of the index UKA. The odds ratio of needing an augment or stem during the conversion to TKA was 26.8 (95% confidence interval, 3.71-194) when an aggressive tibial resection was performed during the UKA.⁹ Tibial resection thickness may thus be predictive of anticipated complexity of UKA revision to TKA and may aid in preoperative planning.

Robotic assistance has been shown to enhance the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, the enhanced accuracy of robotic technology may result in more conservative tibial resection when compared to conventional UKA and may be advantageous if conversion to TKA becomes necessary.

The purpose of this study was to compare the distribution of polyethylene insert sizes implanted during conventional and robotic-assisted UKA. We hypothesized that robotic assistance would demonstrate more conservative tibial resection compared to conventional methods of bone preparation.

Methods

We retrospectively compared the distribution of polyethylene insert sizes implanted during consecutive conventional and robotic-assisted UKA procedures. Several manufacturers were queried to provide a listing of the polyethylene insert sizes utilized, ranging from 8 mm to 14 mm. The analysis included 8421 robotic-assisted UKA cases and 27,989 conventional UKA cases. Data were provided by Zimmer Biomet and Smith & Nephew regarding conventional cases, as well as Blue Belt Technologies (now part of Smith & Nephew) and MAKO Surgical (now part of Stryker) regarding robotic-assisted cases. (Dr. Lonner has an ongoing relationship as a consultant with Blue Belt Technologies, whose data was utilized in this study.) Using tibial insert thickness as a surrogate measure of the extent of tibial resection, an insert size of ≥10 mm was defined as aggressive while <10 mm was considered conservative. This cutoff was established based on its corresponding resection level with primary TKA and the anticipated need for augments. Statistical analysis was performed using a Mann-Whitney-Wilcoxon test. Significance was set at P < .05.

Results

Tibial resection thickness was found to be most commonly conservative in nature, with sizes 8-mm and 9-mm polyethylene inserts utilized in the majority of both robotic-assisted and conventional UKA cases. However, statistically more 8-mm and 9-mm polyethylene inserts were used in the robotic group (93.6%) than in the conventional group (84.5%) (P < .0001; Figure). Aggressive tibial resection, requiring tibial inserts ≥10 mm, was performed in 6.4% of robotic-assisted cases and 15.5% of conventional cases.

Discussion

Robotic assistance enhances the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, we demonstrate that the enhanced accuracy of robotic technology results in more conservative tibial resection when compared to conventional techniques with a potential benefit suggested in the literature upon conversion to TKA.

The findings of this study have important implications for patients undergoing conversion of UKA to TKA, potentially optimizing the ease of revision and clinical outcomes. The outcomes of UKA conversion to TKA are often considered inferior to those of primary TKA, compromised by bone loss, need for augmentation, and challenges of restoring the joint line and rotation.^9,16-22 Barrett and Scott¹⁸ reported only 66% of patients had good or excellent results at an average of 4.6 years of follow-up after UKA conversion to TKA. Over 50% required stemmed implants and bone graft or bone cement augmentation to address osseous insufficiency. The authors suggested that the primary determinant of the complexity of the conversion to TKA was the surgical technique used in the index procedure. They concluded that UKA conversion to TKA can be as successful as a primary TKA and primary TKA implants can be used without bone augmentation or stems during the revision procedure if minimal tibial bone is resected at the time of the index UKA.¹⁸ Schwarzkopf and colleagues⁹ supported this conclusion when they found that aggressive tibial resection during UKA resulted in the need for bone graft, stem, wedge, or augment in 70% of cases when converted to TKA. Similarly, Khan and colleagues²³ found that 26% of patients required bone grafting and 26% required some form of augmentation, and Springer and colleagues³ reported that 68% required a graft, augment, or stem.^3,22 Using data from the New Zealand Joint Registry, Pearse and colleagues⁵ reported that revision TKA components were necessary in 28% of patients and concluded that converting a UKA to TKA gives a less reliable result than primary TKA, and with functional results that are not significantly better than a revision from a TKA.

Conservative tibial resection during UKA minimizes the complexity and concerns of bone loss upon conversion to TKA. Schwarzkopf and colleagues⁹ found 96.6% of patients with conservative tibial resection received a primary TKA implant, without augments or stems. Furthermore, patients with a primary TKA implant showed improved tibial survivorship, with revision as an end point, compared with patients who received a TKA implant that required stems and augments or bone graft for support.⁹ Also emphasizing the importance of minimal tibial resection, O’Donnell and colleagues⁸ compared a cohort of patients undergoing conversion of a minimal resection resurfacing onlay-type UKA to TKA with a cohort of patients undergoing primary TKA. They found that 40% of patients required bone grafting for contained defects, 3.6% required metal augments, and 1.8% required stems.⁸ There was no significant difference between the groups in terms of range of motion, functional outcome, or radiologic outcomes. The authors concluded that revision of minimal resection resurfacing implants to TKA is associated with similar results to primary TKA and is superior to revision of UKA with greater bone loss. Prior studies have shown that one of the advantages of robotic-assisted UKA is the accuracy and precision of bone resection. The present study supports this premise by showing that tibial resection is significantly more conservative using robotic-assisted techniques when using tibial component thickness as a surrogate for extent of bone resection. While our study did not address implant durability or the impact of conservative resection on conversion to TKA, studies referenced above suggest that the conservative nature of bone preparation would have a relevant impact on the revision of the implant to TKA.

Our study is a retrospective case series that reports tibial component thickness as a surrogate for volume of tibial resection during UKA. While the implication is that more conservative tibial resection may optimize durability and ease of conversion to TKA, future study will be needed to compare robotic-assisted and conventional cases of UKA upon conversion to TKA in order to ascertain whether the more conventional resections of robotic-assisted UKA in fact lead to revision that is comparable with primary TKA in terms of bone loss at the time of revision, components utilized, the need for bone graft, augments, or stems, and clinical outcomes. Given the method of data collection in this study, we could not control for clinical deformity, selection bias, surgeon experience, or medial vs lateral knee compartments. These potential confounders represent weaknesses of this study.

In conclusion, conversion of UKA to TKA may be associated with significant osseous insufficiency, which may compromise patient outcomes in comparison to primary TKA. Studies have shown that UKA conversion to TKA is comparable to primary TKA when minimal tibial resection is performed during the UKA, and the need for augmentation, grafting or stems is increased with more aggressive tibial resection. This study has shown that when robotic assistance is utilized, tibial resection is more precise, less variable, and more conservative compared to conventional techniques.

Am J Orthop. 2016;45(7):E465-E468. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Unicompartmental knee arthroplasty (UKA) is considered a less invasive approach for the treatment of unicompartmental knee arthritis when compared with total knee arthroplasty (TKA), with optimal preservation of kinematics.¹ Despite excellent functional outcomes, conversion to TKA may be necessary if the UKA fails, or in patients with progressive knee arthritis. Some studies have found UKA conversion to TKA to be comparable with primary TKA,^2,3 whereas others have found that conversion often requires bone graft, augments, and stemmed components and has increased complications and inferior results compared to primary TKA.^4-7 While some studies report that <10% of UKA conversions to TKA require augments,² others have found that as many as 76% require augments.^4-8

Schwarzkopf and colleagues⁹ recently demonstrated that UKA conversion to TKA is comparable with primary TKA when a conservative tibial resection is performed during the index procedure. However, they reported increased complexity when greater tibial resection was performed and thicker polyethylene inserts were used at the time of the index UKA. The odds ratio of needing an augment or stem during the conversion to TKA was 26.8 (95% confidence interval, 3.71-194) when an aggressive tibial resection was performed during the UKA.⁹ Tibial resection thickness may thus be predictive of anticipated complexity of UKA revision to TKA and may aid in preoperative planning.

Robotic assistance has been shown to enhance the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, the enhanced accuracy of robotic technology may result in more conservative tibial resection when compared to conventional UKA and may be advantageous if conversion to TKA becomes necessary.

The purpose of this study was to compare the distribution of polyethylene insert sizes implanted during conventional and robotic-assisted UKA. We hypothesized that robotic assistance would demonstrate more conservative tibial resection compared to conventional methods of bone preparation.

Methods

We retrospectively compared the distribution of polyethylene insert sizes implanted during consecutive conventional and robotic-assisted UKA procedures. Several manufacturers were queried to provide a listing of the polyethylene insert sizes utilized, ranging from 8 mm to 14 mm. The analysis included 8421 robotic-assisted UKA cases and 27,989 conventional UKA cases. Data were provided by Zimmer Biomet and Smith & Nephew regarding conventional cases, as well as Blue Belt Technologies (now part of Smith & Nephew) and MAKO Surgical (now part of Stryker) regarding robotic-assisted cases. (Dr. Lonner has an ongoing relationship as a consultant with Blue Belt Technologies, whose data was utilized in this study.) Using tibial insert thickness as a surrogate measure of the extent of tibial resection, an insert size of ≥10 mm was defined as aggressive while <10 mm was considered conservative. This cutoff was established based on its corresponding resection level with primary TKA and the anticipated need for augments. Statistical analysis was performed using a Mann-Whitney-Wilcoxon test. Significance was set at P < .05.

Results

Tibial resection thickness was found to be most commonly conservative in nature, with sizes 8-mm and 9-mm polyethylene inserts utilized in the majority of both robotic-assisted and conventional UKA cases. However, statistically more 8-mm and 9-mm polyethylene inserts were used in the robotic group (93.6%) than in the conventional group (84.5%) (P < .0001; Figure). Aggressive tibial resection, requiring tibial inserts ≥10 mm, was performed in 6.4% of robotic-assisted cases and 15.5% of conventional cases.

Discussion

Robotic assistance enhances the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, we demonstrate that the enhanced accuracy of robotic technology results in more conservative tibial resection when compared to conventional techniques with a potential benefit suggested in the literature upon conversion to TKA.

The findings of this study have important implications for patients undergoing conversion of UKA to TKA, potentially optimizing the ease of revision and clinical outcomes. The outcomes of UKA conversion to TKA are often considered inferior to those of primary TKA, compromised by bone loss, need for augmentation, and challenges of restoring the joint line and rotation.^9,16-22 Barrett and Scott¹⁸ reported only 66% of patients had good or excellent results at an average of 4.6 years of follow-up after UKA conversion to TKA. Over 50% required stemmed implants and bone graft or bone cement augmentation to address osseous insufficiency. The authors suggested that the primary determinant of the complexity of the conversion to TKA was the surgical technique used in the index procedure. They concluded that UKA conversion to TKA can be as successful as a primary TKA and primary TKA implants can be used without bone augmentation or stems during the revision procedure if minimal tibial bone is resected at the time of the index UKA.¹⁸ Schwarzkopf and colleagues⁹ supported this conclusion when they found that aggressive tibial resection during UKA resulted in the need for bone graft, stem, wedge, or augment in 70% of cases when converted to TKA. Similarly, Khan and colleagues²³ found that 26% of patients required bone grafting and 26% required some form of augmentation, and Springer and colleagues³ reported that 68% required a graft, augment, or stem.^3,22 Using data from the New Zealand Joint Registry, Pearse and colleagues⁵ reported that revision TKA components were necessary in 28% of patients and concluded that converting a UKA to TKA gives a less reliable result than primary TKA, and with functional results that are not significantly better than a revision from a TKA.

Conservative tibial resection during UKA minimizes the complexity and concerns of bone loss upon conversion to TKA. Schwarzkopf and colleagues⁹ found 96.6% of patients with conservative tibial resection received a primary TKA implant, without augments or stems. Furthermore, patients with a primary TKA implant showed improved tibial survivorship, with revision as an end point, compared with patients who received a TKA implant that required stems and augments or bone graft for support.⁹ Also emphasizing the importance of minimal tibial resection, O’Donnell and colleagues⁸ compared a cohort of patients undergoing conversion of a minimal resection resurfacing onlay-type UKA to TKA with a cohort of patients undergoing primary TKA. They found that 40% of patients required bone grafting for contained defects, 3.6% required metal augments, and 1.8% required stems.⁸ There was no significant difference between the groups in terms of range of motion, functional outcome, or radiologic outcomes. The authors concluded that revision of minimal resection resurfacing implants to TKA is associated with similar results to primary TKA and is superior to revision of UKA with greater bone loss. Prior studies have shown that one of the advantages of robotic-assisted UKA is the accuracy and precision of bone resection. The present study supports this premise by showing that tibial resection is significantly more conservative using robotic-assisted techniques when using tibial component thickness as a surrogate for extent of bone resection. While our study did not address implant durability or the impact of conservative resection on conversion to TKA, studies referenced above suggest that the conservative nature of bone preparation would have a relevant impact on the revision of the implant to TKA.

Our study is a retrospective case series that reports tibial component thickness as a surrogate for volume of tibial resection during UKA. While the implication is that more conservative tibial resection may optimize durability and ease of conversion to TKA, future study will be needed to compare robotic-assisted and conventional cases of UKA upon conversion to TKA in order to ascertain whether the more conventional resections of robotic-assisted UKA in fact lead to revision that is comparable with primary TKA in terms of bone loss at the time of revision, components utilized, the need for bone graft, augments, or stems, and clinical outcomes. Given the method of data collection in this study, we could not control for clinical deformity, selection bias, surgeon experience, or medial vs lateral knee compartments. These potential confounders represent weaknesses of this study.

In conclusion, conversion of UKA to TKA may be associated with significant osseous insufficiency, which may compromise patient outcomes in comparison to primary TKA. Studies have shown that UKA conversion to TKA is comparable to primary TKA when minimal tibial resection is performed during the UKA, and the need for augmentation, grafting or stems is increased with more aggressive tibial resection. This study has shown that when robotic assistance is utilized, tibial resection is more precise, less variable, and more conservative compared to conventional techniques.

Am J Orthop. 2016;45(7):E465-E468. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Unicompartmental knee arthroplasty (UKA) is considered a less invasive approach for the treatment of unicompartmental knee arthritis when compared with total knee arthroplasty (TKA), with optimal preservation of kinematics.¹ Despite excellent functional outcomes, conversion to TKA may be necessary if the UKA fails, or in patients with progressive knee arthritis. Some studies have found UKA conversion to TKA to be comparable with primary TKA,^2,3 whereas others have found that conversion often requires bone graft, augments, and stemmed components and has increased complications and inferior results compared to primary TKA.^4-7 While some studies report that <10% of UKA conversions to TKA require augments,² others have found that as many as 76% require augments.^4-8

Schwarzkopf and colleagues⁹ recently demonstrated that UKA conversion to TKA is comparable with primary TKA when a conservative tibial resection is performed during the index procedure. However, they reported increased complexity when greater tibial resection was performed and thicker polyethylene inserts were used at the time of the index UKA. The odds ratio of needing an augment or stem during the conversion to TKA was 26.8 (95% confidence interval, 3.71-194) when an aggressive tibial resection was performed during the UKA.⁹ Tibial resection thickness may thus be predictive of anticipated complexity of UKA revision to TKA and may aid in preoperative planning.

Robotic assistance has been shown to enhance the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, the enhanced accuracy of robotic technology may result in more conservative tibial resection when compared to conventional UKA and may be advantageous if conversion to TKA becomes necessary.

The purpose of this study was to compare the distribution of polyethylene insert sizes implanted during conventional and robotic-assisted UKA. We hypothesized that robotic assistance would demonstrate more conservative tibial resection compared to conventional methods of bone preparation.

Methods

We retrospectively compared the distribution of polyethylene insert sizes implanted during consecutive conventional and robotic-assisted UKA procedures. Several manufacturers were queried to provide a listing of the polyethylene insert sizes utilized, ranging from 8 mm to 14 mm. The analysis included 8421 robotic-assisted UKA cases and 27,989 conventional UKA cases. Data were provided by Zimmer Biomet and Smith & Nephew regarding conventional cases, as well as Blue Belt Technologies (now part of Smith & Nephew) and MAKO Surgical (now part of Stryker) regarding robotic-assisted cases. (Dr. Lonner has an ongoing relationship as a consultant with Blue Belt Technologies, whose data was utilized in this study.) Using tibial insert thickness as a surrogate measure of the extent of tibial resection, an insert size of ≥10 mm was defined as aggressive while <10 mm was considered conservative. This cutoff was established based on its corresponding resection level with primary TKA and the anticipated need for augments. Statistical analysis was performed using a Mann-Whitney-Wilcoxon test. Significance was set at P < .05.

Results

Tibial resection thickness was found to be most commonly conservative in nature, with sizes 8-mm and 9-mm polyethylene inserts utilized in the majority of both robotic-assisted and conventional UKA cases. However, statistically more 8-mm and 9-mm polyethylene inserts were used in the robotic group (93.6%) than in the conventional group (84.5%) (P < .0001; Figure). Aggressive tibial resection, requiring tibial inserts ≥10 mm, was performed in 6.4% of robotic-assisted cases and 15.5% of conventional cases.

Discussion

Robotic assistance enhances the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, we demonstrate that the enhanced accuracy of robotic technology results in more conservative tibial resection when compared to conventional techniques with a potential benefit suggested in the literature upon conversion to TKA.

The findings of this study have important implications for patients undergoing conversion of UKA to TKA, potentially optimizing the ease of revision and clinical outcomes. The outcomes of UKA conversion to TKA are often considered inferior to those of primary TKA, compromised by bone loss, need for augmentation, and challenges of restoring the joint line and rotation.^9,16-22 Barrett and Scott¹⁸ reported only 66% of patients had good or excellent results at an average of 4.6 years of follow-up after UKA conversion to TKA. Over 50% required stemmed implants and bone graft or bone cement augmentation to address osseous insufficiency. The authors suggested that the primary determinant of the complexity of the conversion to TKA was the surgical technique used in the index procedure. They concluded that UKA conversion to TKA can be as successful as a primary TKA and primary TKA implants can be used without bone augmentation or stems during the revision procedure if minimal tibial bone is resected at the time of the index UKA.¹⁸ Schwarzkopf and colleagues⁹ supported this conclusion when they found that aggressive tibial resection during UKA resulted in the need for bone graft, stem, wedge, or augment in 70% of cases when converted to TKA. Similarly, Khan and colleagues²³ found that 26% of patients required bone grafting and 26% required some form of augmentation, and Springer and colleagues³ reported that 68% required a graft, augment, or stem.^3,22 Using data from the New Zealand Joint Registry, Pearse and colleagues⁵ reported that revision TKA components were necessary in 28% of patients and concluded that converting a UKA to TKA gives a less reliable result than primary TKA, and with functional results that are not significantly better than a revision from a TKA.

Conservative tibial resection during UKA minimizes the complexity and concerns of bone loss upon conversion to TKA. Schwarzkopf and colleagues⁹ found 96.6% of patients with conservative tibial resection received a primary TKA implant, without augments or stems. Furthermore, patients with a primary TKA implant showed improved tibial survivorship, with revision as an end point, compared with patients who received a TKA implant that required stems and augments or bone graft for support.⁹ Also emphasizing the importance of minimal tibial resection, O’Donnell and colleagues⁸ compared a cohort of patients undergoing conversion of a minimal resection resurfacing onlay-type UKA to TKA with a cohort of patients undergoing primary TKA. They found that 40% of patients required bone grafting for contained defects, 3.6% required metal augments, and 1.8% required stems.⁸ There was no significant difference between the groups in terms of range of motion, functional outcome, or radiologic outcomes. The authors concluded that revision of minimal resection resurfacing implants to TKA is associated with similar results to primary TKA and is superior to revision of UKA with greater bone loss. Prior studies have shown that one of the advantages of robotic-assisted UKA is the accuracy and precision of bone resection. The present study supports this premise by showing that tibial resection is significantly more conservative using robotic-assisted techniques when using tibial component thickness as a surrogate for extent of bone resection. While our study did not address implant durability or the impact of conservative resection on conversion to TKA, studies referenced above suggest that the conservative nature of bone preparation would have a relevant impact on the revision of the implant to TKA.

Our study is a retrospective case series that reports tibial component thickness as a surrogate for volume of tibial resection during UKA. While the implication is that more conservative tibial resection may optimize durability and ease of conversion to TKA, future study will be needed to compare robotic-assisted and conventional cases of UKA upon conversion to TKA in order to ascertain whether the more conventional resections of robotic-assisted UKA in fact lead to revision that is comparable with primary TKA in terms of bone loss at the time of revision, components utilized, the need for bone graft, augments, or stems, and clinical outcomes. Given the method of data collection in this study, we could not control for clinical deformity, selection bias, surgeon experience, or medial vs lateral knee compartments. These potential confounders represent weaknesses of this study.

In conclusion, conversion of UKA to TKA may be associated with significant osseous insufficiency, which may compromise patient outcomes in comparison to primary TKA. Studies have shown that UKA conversion to TKA is comparable to primary TKA when minimal tibial resection is performed during the UKA, and the need for augmentation, grafting or stems is increased with more aggressive tibial resection. This study has shown that when robotic assistance is utilized, tibial resection is more precise, less variable, and more conservative compared to conventional techniques.

Am J Orthop. 2016;45(7):E465-E468. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Tracy Gulling-Leftwich, DO, remembers Chewy very well. He was a 70-pound English bulldog she was caring for last year on behalf of the Rescue Ohio English Bulldogs, an English bulldog rescue group.

She soon learned that Chewy was anemic and suffered from bone cancer of the jaw. Ironically, considering his name, he could barely chew, so Dr. Gulling-Leftwich and her husband, Samuel Leftwich, pureed his food, spoon-fed the animal, and administered around-the-clock pain medications for roughly two weeks. But his pain grew too intense, and Chewy had to be euthanized.

For many people, that would end their experience with an animal organization. People typically compare the heartbreaking experience to losing a beloved family member or friend. But as an animal lover and hospitalist at the Cleveland Clinic, Dr. Gulling-Leftwich has no intentions of looking the other way whenever an animal—or human—is in need. Ever since she was in college, she has been rescuing lab rats and dogs, trying to keep them happy, healthy, and loved throughout their relatively short lives.

Underground Railroad

Dr. Gulling-Leftwich graduated from the Lake Erie College of Osteopathic Medicine in Erie, Penn., in 2007. The following year, she pursued an osteopathic rotating internship at the University of Connecticut. While attending the same university from 2008 to 2010, she completed a traditional, categorical, allopathic medicine residency.

After completing her medical education, she held several positions. She worked as a teaching hospitalist at the Hartford Hospital for one year, served as a primary-care physician for the next three years at The Hospital of Central Connecticut, and then joined the Cleveland Clinic as a hospitalist in 2014.

Her involvement in animal rescue began many years earlier while attending undergraduate school at Westminster College in New Wilmington, Penn. She tells the story how one student at the college kidnapped a rat from the school’s neuroscience lab just before Christmas break.

Since the student’s mother would not allow her to bring a rat home over the six-week holiday, Dr. Gulling-Leftwich babysat him until she returned. However, the student intended on releasing him into the wild. Fearing the worst, that the rat could not fend for itself since it had been caged and fed for many months, Dr. Gulling-Leftwich convinced the student to relinquish custody of the rat to her.

That’s how it all began. Dr. Gulling-Leftwich named the rat Templeton. She suspects he died of a pituitary tumor four years later; still, that’s a long life for a rat. Most live just two years. Just shows what a little love can do.

Since then, she has rescued approximately 21 rats from Kentucky and Connecticut. Years ago, she says, there were multiple Yahoo chat groups of people involved in an underground railroad of sorts for rescued lab rats. People would often drive the rats to different cities, even across state borders, so these rats could enjoy a permanent home.

While she has never broken into a research lab, her opinion is torn on animal research. She believes it is not necessary for consumer products, such as makeup, but can see its value in other fields of science like the development of new medications.

“What I can hope for is that we work toward finding a way of not requiring animals for research in the future,” she says.

Full House

After getting married in 2013, Dr. Gulling-Leftwich told her husband she wanted a dog. But because of their hectic schedules, no one would be home to care for the animal, so the couple waited another two years to adopt a rescue animal.

In 2015, they had purchased a house in Cleveland when they adopted Boomer, a pug and beagle designer breed, as their family pet.

“I had really wanted an English bulldog. They’re just cute, their face is squishy,” she says, adding she had been monitoring English bulldog rescue websites. “I won’t buy a puppy. I will only get a dog that needs a home.”

In September that year, the rescue organization emailed a desperate plea to its followers. Can anyone rescue an English bulldog named Chewy? Dr. Gulling-Leftwich immediately filled out the paperwork and adopted him. But Chewy only stayed with them for two weeks before he was euthanized. She brought him to the vet after he attacked Boomer.

“Chewy wasn’t being a jerk,” she says. “His attacking behavior had to do with his pain and discomfort. He had blood everywhere around his mouth. We had a hard time letting him go.”

One month later, another English bulldog named Olive joined their family. She’s roughly two years old and weighs only 30 pounds mainly because of her disease: congenital cardiomyopathy. They plan to care for Olive until she dies.

She says Olive takes six pills a day for her condition and occasionally receives nitroglycerin when she overexerts herself and passes out.

Meanwhile, Dr. Gulling-Leftwich and her husband care for one rat named Harvey and a cat called Lily in addition to the two dogs. Boomer doesn’t like Olive. Olive doesn’t like the cat. And both dogs and the cat pay no attention to the rat.

“My husband says rescuing animals and taking care of people is one of my more endearing qualities,” she says. “Then he follows it up with, ‘No, you can’t have that bunny that needs a home.’”

She believes caring for these animals balances her work in hospital medicine. While hospital patients often are in pain, act grouchy, and appear unappreciative, she says her four-legged family members are always excited to see her and routinely demonstrate unconditional love.

“You definitely have to be open-minded because you never know what you’ll be walking into when you rescue an animal,” she says, adding that rescue groups tend to pay for vet bills and medicine. “You have to be prepared for what potentially could be the worst.”

Carol Patton is a freelance writer in Las Vegas.

Tracy Gulling-Leftwich, DO, remembers Chewy very well. He was a 70-pound English bulldog she was caring for last year on behalf of the Rescue Ohio English Bulldogs, an English bulldog rescue group.

She soon learned that Chewy was anemic and suffered from bone cancer of the jaw. Ironically, considering his name, he could barely chew, so Dr. Gulling-Leftwich and her husband, Samuel Leftwich, pureed his food, spoon-fed the animal, and administered around-the-clock pain medications for roughly two weeks. But his pain grew too intense, and Chewy had to be euthanized.

For many people, that would end their experience with an animal organization. People typically compare the heartbreaking experience to losing a beloved family member or friend. But as an animal lover and hospitalist at the Cleveland Clinic, Dr. Gulling-Leftwich has no intentions of looking the other way whenever an animal—or human—is in need. Ever since she was in college, she has been rescuing lab rats and dogs, trying to keep them happy, healthy, and loved throughout their relatively short lives.

Underground Railroad

Dr. Gulling-Leftwich graduated from the Lake Erie College of Osteopathic Medicine in Erie, Penn., in 2007. The following year, she pursued an osteopathic rotating internship at the University of Connecticut. While attending the same university from 2008 to 2010, she completed a traditional, categorical, allopathic medicine residency.

After completing her medical education, she held several positions. She worked as a teaching hospitalist at the Hartford Hospital for one year, served as a primary-care physician for the next three years at The Hospital of Central Connecticut, and then joined the Cleveland Clinic as a hospitalist in 2014.

Her involvement in animal rescue began many years earlier while attending undergraduate school at Westminster College in New Wilmington, Penn. She tells the story how one student at the college kidnapped a rat from the school’s neuroscience lab just before Christmas break.

Since the student’s mother would not allow her to bring a rat home over the six-week holiday, Dr. Gulling-Leftwich babysat him until she returned. However, the student intended on releasing him into the wild. Fearing the worst, that the rat could not fend for itself since it had been caged and fed for many months, Dr. Gulling-Leftwich convinced the student to relinquish custody of the rat to her.

That’s how it all began. Dr. Gulling-Leftwich named the rat Templeton. She suspects he died of a pituitary tumor four years later; still, that’s a long life for a rat. Most live just two years. Just shows what a little love can do.

Since then, she has rescued approximately 21 rats from Kentucky and Connecticut. Years ago, she says, there were multiple Yahoo chat groups of people involved in an underground railroad of sorts for rescued lab rats. People would often drive the rats to different cities, even across state borders, so these rats could enjoy a permanent home.

While she has never broken into a research lab, her opinion is torn on animal research. She believes it is not necessary for consumer products, such as makeup, but can see its value in other fields of science like the development of new medications.

“What I can hope for is that we work toward finding a way of not requiring animals for research in the future,” she says.

Full House

After getting married in 2013, Dr. Gulling-Leftwich told her husband she wanted a dog. But because of their hectic schedules, no one would be home to care for the animal, so the couple waited another two years to adopt a rescue animal.

In 2015, they had purchased a house in Cleveland when they adopted Boomer, a pug and beagle designer breed, as their family pet.

“I had really wanted an English bulldog. They’re just cute, their face is squishy,” she says, adding she had been monitoring English bulldog rescue websites. “I won’t buy a puppy. I will only get a dog that needs a home.”

In September that year, the rescue organization emailed a desperate plea to its followers. Can anyone rescue an English bulldog named Chewy? Dr. Gulling-Leftwich immediately filled out the paperwork and adopted him. But Chewy only stayed with them for two weeks before he was euthanized. She brought him to the vet after he attacked Boomer.

“Chewy wasn’t being a jerk,” she says. “His attacking behavior had to do with his pain and discomfort. He had blood everywhere around his mouth. We had a hard time letting him go.”

One month later, another English bulldog named Olive joined their family. She’s roughly two years old and weighs only 30 pounds mainly because of her disease: congenital cardiomyopathy. They plan to care for Olive until she dies.

She says Olive takes six pills a day for her condition and occasionally receives nitroglycerin when she overexerts herself and passes out.

Meanwhile, Dr. Gulling-Leftwich and her husband care for one rat named Harvey and a cat called Lily in addition to the two dogs. Boomer doesn’t like Olive. Olive doesn’t like the cat. And both dogs and the cat pay no attention to the rat.

“My husband says rescuing animals and taking care of people is one of my more endearing qualities,” she says. “Then he follows it up with, ‘No, you can’t have that bunny that needs a home.’”

She believes caring for these animals balances her work in hospital medicine. While hospital patients often are in pain, act grouchy, and appear unappreciative, she says her four-legged family members are always excited to see her and routinely demonstrate unconditional love.

“You definitely have to be open-minded because you never know what you’ll be walking into when you rescue an animal,” she says, adding that rescue groups tend to pay for vet bills and medicine. “You have to be prepared for what potentially could be the worst.”

Carol Patton is a freelance writer in Las Vegas.

Tracy Gulling-Leftwich, DO, remembers Chewy very well. He was a 70-pound English bulldog she was caring for last year on behalf of the Rescue Ohio English Bulldogs, an English bulldog rescue group.

She soon learned that Chewy was anemic and suffered from bone cancer of the jaw. Ironically, considering his name, he could barely chew, so Dr. Gulling-Leftwich and her husband, Samuel Leftwich, pureed his food, spoon-fed the animal, and administered around-the-clock pain medications for roughly two weeks. But his pain grew too intense, and Chewy had to be euthanized.

For many people, that would end their experience with an animal organization. People typically compare the heartbreaking experience to losing a beloved family member or friend. But as an animal lover and hospitalist at the Cleveland Clinic, Dr. Gulling-Leftwich has no intentions of looking the other way whenever an animal—or human—is in need. Ever since she was in college, she has been rescuing lab rats and dogs, trying to keep them happy, healthy, and loved throughout their relatively short lives.

Underground Railroad

Dr. Gulling-Leftwich graduated from the Lake Erie College of Osteopathic Medicine in Erie, Penn., in 2007. The following year, she pursued an osteopathic rotating internship at the University of Connecticut. While attending the same university from 2008 to 2010, she completed a traditional, categorical, allopathic medicine residency.

After completing her medical education, she held several positions. She worked as a teaching hospitalist at the Hartford Hospital for one year, served as a primary-care physician for the next three years at The Hospital of Central Connecticut, and then joined the Cleveland Clinic as a hospitalist in 2014.

Her involvement in animal rescue began many years earlier while attending undergraduate school at Westminster College in New Wilmington, Penn. She tells the story how one student at the college kidnapped a rat from the school’s neuroscience lab just before Christmas break.

Since the student’s mother would not allow her to bring a rat home over the six-week holiday, Dr. Gulling-Leftwich babysat him until she returned. However, the student intended on releasing him into the wild. Fearing the worst, that the rat could not fend for itself since it had been caged and fed for many months, Dr. Gulling-Leftwich convinced the student to relinquish custody of the rat to her.

That’s how it all began. Dr. Gulling-Leftwich named the rat Templeton. She suspects he died of a pituitary tumor four years later; still, that’s a long life for a rat. Most live just two years. Just shows what a little love can do.

Since then, she has rescued approximately 21 rats from Kentucky and Connecticut. Years ago, she says, there were multiple Yahoo chat groups of people involved in an underground railroad of sorts for rescued lab rats. People would often drive the rats to different cities, even across state borders, so these rats could enjoy a permanent home.

While she has never broken into a research lab, her opinion is torn on animal research. She believes it is not necessary for consumer products, such as makeup, but can see its value in other fields of science like the development of new medications.

“What I can hope for is that we work toward finding a way of not requiring animals for research in the future,” she says.

Full House

After getting married in 2013, Dr. Gulling-Leftwich told her husband she wanted a dog. But because of their hectic schedules, no one would be home to care for the animal, so the couple waited another two years to adopt a rescue animal.

In 2015, they had purchased a house in Cleveland when they adopted Boomer, a pug and beagle designer breed, as their family pet.

“I had really wanted an English bulldog. They’re just cute, their face is squishy,” she says, adding she had been monitoring English bulldog rescue websites. “I won’t buy a puppy. I will only get a dog that needs a home.”

In September that year, the rescue organization emailed a desperate plea to its followers. Can anyone rescue an English bulldog named Chewy? Dr. Gulling-Leftwich immediately filled out the paperwork and adopted him. But Chewy only stayed with them for two weeks before he was euthanized. She brought him to the vet after he attacked Boomer.

“Chewy wasn’t being a jerk,” she says. “His attacking behavior had to do with his pain and discomfort. He had blood everywhere around his mouth. We had a hard time letting him go.”

One month later, another English bulldog named Olive joined their family. She’s roughly two years old and weighs only 30 pounds mainly because of her disease: congenital cardiomyopathy. They plan to care for Olive until she dies.

She says Olive takes six pills a day for her condition and occasionally receives nitroglycerin when she overexerts herself and passes out.

Meanwhile, Dr. Gulling-Leftwich and her husband care for one rat named Harvey and a cat called Lily in addition to the two dogs. Boomer doesn’t like Olive. Olive doesn’t like the cat. And both dogs and the cat pay no attention to the rat.

“My husband says rescuing animals and taking care of people is one of my more endearing qualities,” she says. “Then he follows it up with, ‘No, you can’t have that bunny that needs a home.’”

She believes caring for these animals balances her work in hospital medicine. While hospital patients often are in pain, act grouchy, and appear unappreciative, she says her four-legged family members are always excited to see her and routinely demonstrate unconditional love.

“You definitely have to be open-minded because you never know what you’ll be walking into when you rescue an animal,” she says, adding that rescue groups tend to pay for vet bills and medicine. “You have to be prepared for what potentially could be the worst.”

Carol Patton is a freelance writer in Las Vegas.

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.