Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?

The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.

We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.

The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).

Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.

Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on  clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).

So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.

The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at [email protected].

In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?

The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.

We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.

The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).

Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.

Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on  clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).

So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.

The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at [email protected].

In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?

The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.

We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.

The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).

Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.

Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on  clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).

So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.

The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at [email protected].

Who is in this video: Neil Kirschner, Ph.D., a clinical psychologist and the American College of Physicians’ senior associate for health policy and regulatory affairs; Dr. April Barbour, an associate professor of medicine and the director of general internal medicine and of the primary care residency program at George Washington University School of Medicine, Washington; Dr. James Griffith, the Leon M. Yochelson Professor of Psychiatry and Behavioral Sciences, and chair of psychiatry and psychosomatic medicine at George Washington University School of Medicine, Washington; Whitney McKnight, cohost and producer of Mental Health Consult.

Who is in this video: Neil Kirschner, Ph.D., a clinical psychologist and the American College of Physicians’ senior associate for health policy and regulatory affairs; Dr. April Barbour, an associate professor of medicine and the director of general internal medicine and of the primary care residency program at George Washington University School of Medicine, Washington; Dr. James Griffith, the Leon M. Yochelson Professor of Psychiatry and Behavioral Sciences, and chair of psychiatry and psychosomatic medicine at George Washington University School of Medicine, Washington; Whitney McKnight, cohost and producer of Mental Health Consult.

Who is in this video: Neil Kirschner, Ph.D., a clinical psychologist and the American College of Physicians’ senior associate for health policy and regulatory affairs; Dr. April Barbour, an associate professor of medicine and the director of general internal medicine and of the primary care residency program at George Washington University School of Medicine, Washington; Dr. James Griffith, the Leon M. Yochelson Professor of Psychiatry and Behavioral Sciences, and chair of psychiatry and psychosomatic medicine at George Washington University School of Medicine, Washington; Whitney McKnight, cohost and producer of Mental Health Consult.

To a psychiatrist, the idea of selling Prozac or Lexapro over the counter seems unthinkable. These medications, after all, carry a black box warning, and their adverse reactions can include the induction of mania as well as a usual laundry list of side effects.

Furthermore, used alone as a one-shot attempt to treat depression, they are not terribly effective. A trial of a single antidepressant will be effective about 30% of the time – about as often as a placebo – and it’s not until we try switching or augmentation strategies, or adding psychotherapy as part of comprehensive treatment, that we begin to see more robust success rates in the treatment of depression. Finally, there is the risk that a lay person might misdiagnose sadness or demoralization as depression and inappropriately treat himself.

With so much that can go wrong, why would I even ask such a provocative question?

So let me play devil’s advocate for a moment. We live in a country where 40,000 people a year die of suicide, and countless others are impaired or disabled with respect to their occupations and relationships because of depression and anxiety. And then there are those who are able to hide their symptoms, but live with psychic torment and suffering.

If you believe that the morbidity and mortality of psychiatric illness can be prevented with appropriate treatment, then you’re left to ask why people don’t get treatment for their psychiatric illnesses. The political mantra is that people don’t seek care because of stigma. Advocates for those with severe mental illnesses contend that people don’t seek treatment because they don’t believe they are ill. And then there are the difficult realities: It can be very hard to find a psychiatrist or even a nonphysician therapist. According to Dr. Thomas Insel, the former director of the National Institute of Mental Health, half the counties in this country have no mental health professionals at all. And while medical care of any type is expensive, psychiatry can be even more so in terms of out-of-pocket costs, because 45% of psychiatrists don’t participate with health insurance networks, compared with 89% of other physicians. Finally, some patients have had bad experiences with psychiatrists, or with the treatments that have been offered, and they are not open to the idea that there is a better experience to be had. So stigma, access to care, awareness that one has an illness, cost, and prior negative experiences all are deterrents to getting mental health treatment.

As it stands, most psychotropic medications are prescribed by primary care physicians. I don’t know what constitutes a psychiatric evaluation in these settings, but it’s not unusual for a patient to be given a year’s supply of medication without referrals for psychotherapy. I also don’t know how closely primary care physicians and nurse practitioners monitor patients, or if they warn them of the risk of mania or suicidal impulse. If medication trials are unsuccessful, or only partly helpful, do primary care physicians know how to switch and augment these agents? I’m sure this depends on the individual clinician, but chances are that some patients who seek treatment for psychiatric conditions are not treated adequately. Presumably, there is some evaluation and monitoring, and the patient has a prescriber to call if something goes wrong, so this is a better scenario than letting the patient pick up a bottle when she goes to buy deodorant.

The antipsychiatry lobby would howl at the idea of offering antidepressants over the counter. They would contend that selective serotonin reuptake inhibitors cause violence and disability, and such a move would cause the rates of suicide, homicide, and mass murders to soar. And those who feel that psychiatry has overextended its arm to embrace normal human reactions and sufferings such that every discomfort calls for a pill would be appalled at the idea that people could be self-diagnosing and self-treating either transient distresses or serious mental illnesses.

So what would be the upside to having over-the-counter SSRIs? For starters, if you believe that medication alone constitutes treatment for depression – and certainly it does for some people – then it would allow people with no access to at least begin the process of getting treatment. It also would allow people to begin medications anonymously, without concerns for stigma or the consequences of being identified as a psychiatric patient. Certainly, if medications were available over the counter, there would be a percentage of people who would take them and get tremendous relief from their symptoms. The question would be whether the good done for some would outweigh the harm done to others.

Patients are unlikely to read the inserts that come with medications, but perhaps OTC antidepressants could come with a video that would give instructions as to dosing, duration, risks, and when to seek help from a physician or in an emergency facility. The presentation could emphasize that while SSRIs can be very effective in treating depression and anxiety, other strategies are available, and people should see a psychiatrist for a complete evaluation. Perhaps patients who had a partial response would be more willing to seek out a mental health professional if they saw some benefit, much the way people go to their doctor when drugstore remedies don’t work for headaches or acid reflux. Furthermore, the availability of drugstore antidepressants might decrease the overall stigma of taking psychopharmacologic agents.

There are risks, but many people tolerate SSRIs. Perhaps over-the-counter antidepressants would save and improve lives; we just don’t know.

As I said above, I’m playing devil’s advocate. My last article asked the question of whether psychiatric treatment actually prevents suicide, and I concluded that it probably does. Yet SSRIs have not conclusively been shown to decrease suicide rates – the only medications known to do so are lithium and clozapine. Still, if patients are unable or unwilling to avail themselves of traditional psychiatric settings, perhaps it’s worth at least asking if some form of access is better than none at all. Society is wrestling with how to address the shortage of psychiatrists. Proposed solutions include telepsychiatry or having psychiatrists serve as consultants in settings where they don’t even meet the patients for whom they make medication recommendations. I haven’t heard anyone suggest that we let the patients try by themselves.

As a psychiatrist who treats patients with medications in combination with psychotherapy, it does seem like a strange question to ask; our patients deserve more than a bottle off a shelf. But before you get too concerned, let me assure you that I have no special connections at the Food and Drug Administration, and I’m just tossing the idea out as food for thought.

Dr. Miller is coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University, 2011).

To a psychiatrist, the idea of selling Prozac or Lexapro over the counter seems unthinkable. These medications, after all, carry a black box warning, and their adverse reactions can include the induction of mania as well as a usual laundry list of side effects.

Furthermore, used alone as a one-shot attempt to treat depression, they are not terribly effective. A trial of a single antidepressant will be effective about 30% of the time – about as often as a placebo – and it’s not until we try switching or augmentation strategies, or adding psychotherapy as part of comprehensive treatment, that we begin to see more robust success rates in the treatment of depression. Finally, there is the risk that a lay person might misdiagnose sadness or demoralization as depression and inappropriately treat himself.

With so much that can go wrong, why would I even ask such a provocative question?

So let me play devil’s advocate for a moment. We live in a country where 40,000 people a year die of suicide, and countless others are impaired or disabled with respect to their occupations and relationships because of depression and anxiety. And then there are those who are able to hide their symptoms, but live with psychic torment and suffering.

If you believe that the morbidity and mortality of psychiatric illness can be prevented with appropriate treatment, then you’re left to ask why people don’t get treatment for their psychiatric illnesses. The political mantra is that people don’t seek care because of stigma. Advocates for those with severe mental illnesses contend that people don’t seek treatment because they don’t believe they are ill. And then there are the difficult realities: It can be very hard to find a psychiatrist or even a nonphysician therapist. According to Dr. Thomas Insel, the former director of the National Institute of Mental Health, half the counties in this country have no mental health professionals at all. And while medical care of any type is expensive, psychiatry can be even more so in terms of out-of-pocket costs, because 45% of psychiatrists don’t participate with health insurance networks, compared with 89% of other physicians. Finally, some patients have had bad experiences with psychiatrists, or with the treatments that have been offered, and they are not open to the idea that there is a better experience to be had. So stigma, access to care, awareness that one has an illness, cost, and prior negative experiences all are deterrents to getting mental health treatment.

As it stands, most psychotropic medications are prescribed by primary care physicians. I don’t know what constitutes a psychiatric evaluation in these settings, but it’s not unusual for a patient to be given a year’s supply of medication without referrals for psychotherapy. I also don’t know how closely primary care physicians and nurse practitioners monitor patients, or if they warn them of the risk of mania or suicidal impulse. If medication trials are unsuccessful, or only partly helpful, do primary care physicians know how to switch and augment these agents? I’m sure this depends on the individual clinician, but chances are that some patients who seek treatment for psychiatric conditions are not treated adequately. Presumably, there is some evaluation and monitoring, and the patient has a prescriber to call if something goes wrong, so this is a better scenario than letting the patient pick up a bottle when she goes to buy deodorant.

The antipsychiatry lobby would howl at the idea of offering antidepressants over the counter. They would contend that selective serotonin reuptake inhibitors cause violence and disability, and such a move would cause the rates of suicide, homicide, and mass murders to soar. And those who feel that psychiatry has overextended its arm to embrace normal human reactions and sufferings such that every discomfort calls for a pill would be appalled at the idea that people could be self-diagnosing and self-treating either transient distresses or serious mental illnesses.

So what would be the upside to having over-the-counter SSRIs? For starters, if you believe that medication alone constitutes treatment for depression – and certainly it does for some people – then it would allow people with no access to at least begin the process of getting treatment. It also would allow people to begin medications anonymously, without concerns for stigma or the consequences of being identified as a psychiatric patient. Certainly, if medications were available over the counter, there would be a percentage of people who would take them and get tremendous relief from their symptoms. The question would be whether the good done for some would outweigh the harm done to others.

Patients are unlikely to read the inserts that come with medications, but perhaps OTC antidepressants could come with a video that would give instructions as to dosing, duration, risks, and when to seek help from a physician or in an emergency facility. The presentation could emphasize that while SSRIs can be very effective in treating depression and anxiety, other strategies are available, and people should see a psychiatrist for a complete evaluation. Perhaps patients who had a partial response would be more willing to seek out a mental health professional if they saw some benefit, much the way people go to their doctor when drugstore remedies don’t work for headaches or acid reflux. Furthermore, the availability of drugstore antidepressants might decrease the overall stigma of taking psychopharmacologic agents.

There are risks, but many people tolerate SSRIs. Perhaps over-the-counter antidepressants would save and improve lives; we just don’t know.

As I said above, I’m playing devil’s advocate. My last article asked the question of whether psychiatric treatment actually prevents suicide, and I concluded that it probably does. Yet SSRIs have not conclusively been shown to decrease suicide rates – the only medications known to do so are lithium and clozapine. Still, if patients are unable or unwilling to avail themselves of traditional psychiatric settings, perhaps it’s worth at least asking if some form of access is better than none at all. Society is wrestling with how to address the shortage of psychiatrists. Proposed solutions include telepsychiatry or having psychiatrists serve as consultants in settings where they don’t even meet the patients for whom they make medication recommendations. I haven’t heard anyone suggest that we let the patients try by themselves.

As a psychiatrist who treats patients with medications in combination with psychotherapy, it does seem like a strange question to ask; our patients deserve more than a bottle off a shelf. But before you get too concerned, let me assure you that I have no special connections at the Food and Drug Administration, and I’m just tossing the idea out as food for thought.

Dr. Miller is coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University, 2011).

To a psychiatrist, the idea of selling Prozac or Lexapro over the counter seems unthinkable. These medications, after all, carry a black box warning, and their adverse reactions can include the induction of mania as well as a usual laundry list of side effects.

Furthermore, used alone as a one-shot attempt to treat depression, they are not terribly effective. A trial of a single antidepressant will be effective about 30% of the time – about as often as a placebo – and it’s not until we try switching or augmentation strategies, or adding psychotherapy as part of comprehensive treatment, that we begin to see more robust success rates in the treatment of depression. Finally, there is the risk that a lay person might misdiagnose sadness or demoralization as depression and inappropriately treat himself.

With so much that can go wrong, why would I even ask such a provocative question?

So let me play devil’s advocate for a moment. We live in a country where 40,000 people a year die of suicide, and countless others are impaired or disabled with respect to their occupations and relationships because of depression and anxiety. And then there are those who are able to hide their symptoms, but live with psychic torment and suffering.

If you believe that the morbidity and mortality of psychiatric illness can be prevented with appropriate treatment, then you’re left to ask why people don’t get treatment for their psychiatric illnesses. The political mantra is that people don’t seek care because of stigma. Advocates for those with severe mental illnesses contend that people don’t seek treatment because they don’t believe they are ill. And then there are the difficult realities: It can be very hard to find a psychiatrist or even a nonphysician therapist. According to Dr. Thomas Insel, the former director of the National Institute of Mental Health, half the counties in this country have no mental health professionals at all. And while medical care of any type is expensive, psychiatry can be even more so in terms of out-of-pocket costs, because 45% of psychiatrists don’t participate with health insurance networks, compared with 89% of other physicians. Finally, some patients have had bad experiences with psychiatrists, or with the treatments that have been offered, and they are not open to the idea that there is a better experience to be had. So stigma, access to care, awareness that one has an illness, cost, and prior negative experiences all are deterrents to getting mental health treatment.

As it stands, most psychotropic medications are prescribed by primary care physicians. I don’t know what constitutes a psychiatric evaluation in these settings, but it’s not unusual for a patient to be given a year’s supply of medication without referrals for psychotherapy. I also don’t know how closely primary care physicians and nurse practitioners monitor patients, or if they warn them of the risk of mania or suicidal impulse. If medication trials are unsuccessful, or only partly helpful, do primary care physicians know how to switch and augment these agents? I’m sure this depends on the individual clinician, but chances are that some patients who seek treatment for psychiatric conditions are not treated adequately. Presumably, there is some evaluation and monitoring, and the patient has a prescriber to call if something goes wrong, so this is a better scenario than letting the patient pick up a bottle when she goes to buy deodorant.

The antipsychiatry lobby would howl at the idea of offering antidepressants over the counter. They would contend that selective serotonin reuptake inhibitors cause violence and disability, and such a move would cause the rates of suicide, homicide, and mass murders to soar. And those who feel that psychiatry has overextended its arm to embrace normal human reactions and sufferings such that every discomfort calls for a pill would be appalled at the idea that people could be self-diagnosing and self-treating either transient distresses or serious mental illnesses.

So what would be the upside to having over-the-counter SSRIs? For starters, if you believe that medication alone constitutes treatment for depression – and certainly it does for some people – then it would allow people with no access to at least begin the process of getting treatment. It also would allow people to begin medications anonymously, without concerns for stigma or the consequences of being identified as a psychiatric patient. Certainly, if medications were available over the counter, there would be a percentage of people who would take them and get tremendous relief from their symptoms. The question would be whether the good done for some would outweigh the harm done to others.

Patients are unlikely to read the inserts that come with medications, but perhaps OTC antidepressants could come with a video that would give instructions as to dosing, duration, risks, and when to seek help from a physician or in an emergency facility. The presentation could emphasize that while SSRIs can be very effective in treating depression and anxiety, other strategies are available, and people should see a psychiatrist for a complete evaluation. Perhaps patients who had a partial response would be more willing to seek out a mental health professional if they saw some benefit, much the way people go to their doctor when drugstore remedies don’t work for headaches or acid reflux. Furthermore, the availability of drugstore antidepressants might decrease the overall stigma of taking psychopharmacologic agents.

There are risks, but many people tolerate SSRIs. Perhaps over-the-counter antidepressants would save and improve lives; we just don’t know.

As I said above, I’m playing devil’s advocate. My last article asked the question of whether psychiatric treatment actually prevents suicide, and I concluded that it probably does. Yet SSRIs have not conclusively been shown to decrease suicide rates – the only medications known to do so are lithium and clozapine. Still, if patients are unable or unwilling to avail themselves of traditional psychiatric settings, perhaps it’s worth at least asking if some form of access is better than none at all. Society is wrestling with how to address the shortage of psychiatrists. Proposed solutions include telepsychiatry or having psychiatrists serve as consultants in settings where they don’t even meet the patients for whom they make medication recommendations. I haven’t heard anyone suggest that we let the patients try by themselves.

As a psychiatrist who treats patients with medications in combination with psychotherapy, it does seem like a strange question to ask; our patients deserve more than a bottle off a shelf. But before you get too concerned, let me assure you that I have no special connections at the Food and Drug Administration, and I’m just tossing the idea out as food for thought.

Dr. Miller is coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University, 2011).

People in this video: Whitney McKnight, cohost and producer of Mental Health Consult; Dr. Lorenzo Norris, editorial board member of Clinical Psychiatry News and cohost of Mental Health Consult, and an assistant professor of psychiatry and behavioral sciences, assistant dean of student affairs, and the medical director of psychiatric and behavioral services at George Washington University Hospital, Washington; Dr. Lillian Beard, pediatrician with Children’s National Hospital Network, Washington, and a Pediatric News editorial board member; Dr. David Pickar, adjunct professor of psychiatry at Johns Hopkins University School of Medicine in Baltimore and at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Pickar: Psychosis is the hallmark of serious mental illness, whether it's schizophrenia, severe bipolar, or psychosis otherwise. It is one of the great tragedies of our medical system, and I'll come back to the primary doc who's out there. I want to talk to you about this. It is a tragedy. Whitney knows, I put together a little documentary, The Realities of Serious Mental Illness. I just couldn't stand the lack of information.

They're very quick to report the violence, and I know a lot about the violence. I worry about it all the time. There's a huge debate between civil liberties and safety that's going on in serious mental illness. Regardless, knowing about it is enormously important for all docs. More patients with serious mental illness, by far, are in jails than they are in mental hospitals. There is nothing for them. You talk about collaborative care.
 
Whitney: On the team in the primary care setting, who's treating what?

Dr. Pickar: I'm talking now myself. A family member brings in an 18-year-old to evaluate. Okay? I'm glad to see it. Of course, I've been around a while. I spent decades as a scientist in schizophrenia. I just close my eyes and hope that I'm not seeing a first break for a seriously mental ill patient. Not that we can't treat it. Not that we can't help, but I know what's entailed. Not unlike seeing an oncology presentation. We're there. We're docs. You don't give up on it, but you know what's ahead for that family.

What's fascinating is many of the first breaks occur, not necessarily quietly, but can be a little insidious. They can be brought to the primary care. It is not uncommon. “My 16-year-old's not doing well. I can't get him up.” But really, what's going on? The primary care doc needs to have a consciousness of that. Let me just say this: First things about serious mental illness, particularly in schizophrenia, 1% of the population has it. That makes it a very common disorder.

People in this video: Whitney McKnight, cohost and producer of Mental Health Consult; Dr. Lorenzo Norris, editorial board member of Clinical Psychiatry News and cohost of Mental Health Consult, and an assistant professor of psychiatry and behavioral sciences, assistant dean of student affairs, and the medical director of psychiatric and behavioral services at George Washington University Hospital, Washington; Dr. Lillian Beard, pediatrician with Children’s National Hospital Network, Washington, and a Pediatric News editorial board member; Dr. David Pickar, adjunct professor of psychiatry at Johns Hopkins University School of Medicine in Baltimore and at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Pickar: Psychosis is the hallmark of serious mental illness, whether it's schizophrenia, severe bipolar, or psychosis otherwise. It is one of the great tragedies of our medical system, and I'll come back to the primary doc who's out there. I want to talk to you about this. It is a tragedy. Whitney knows, I put together a little documentary, The Realities of Serious Mental Illness. I just couldn't stand the lack of information.

They're very quick to report the violence, and I know a lot about the violence. I worry about it all the time. There's a huge debate between civil liberties and safety that's going on in serious mental illness. Regardless, knowing about it is enormously important for all docs. More patients with serious mental illness, by far, are in jails than they are in mental hospitals. There is nothing for them. You talk about collaborative care.
 
Whitney: On the team in the primary care setting, who's treating what?

Dr. Pickar: I'm talking now myself. A family member brings in an 18-year-old to evaluate. Okay? I'm glad to see it. Of course, I've been around a while. I spent decades as a scientist in schizophrenia. I just close my eyes and hope that I'm not seeing a first break for a seriously mental ill patient. Not that we can't treat it. Not that we can't help, but I know what's entailed. Not unlike seeing an oncology presentation. We're there. We're docs. You don't give up on it, but you know what's ahead for that family.

What's fascinating is many of the first breaks occur, not necessarily quietly, but can be a little insidious. They can be brought to the primary care. It is not uncommon. “My 16-year-old's not doing well. I can't get him up.” But really, what's going on? The primary care doc needs to have a consciousness of that. Let me just say this: First things about serious mental illness, particularly in schizophrenia, 1% of the population has it. That makes it a very common disorder.

People in this video: Whitney McKnight, cohost and producer of Mental Health Consult; Dr. Lorenzo Norris, editorial board member of Clinical Psychiatry News and cohost of Mental Health Consult, and an assistant professor of psychiatry and behavioral sciences, assistant dean of student affairs, and the medical director of psychiatric and behavioral services at George Washington University Hospital, Washington; Dr. Lillian Beard, pediatrician with Children’s National Hospital Network, Washington, and a Pediatric News editorial board member; Dr. David Pickar, adjunct professor of psychiatry at Johns Hopkins University School of Medicine in Baltimore and at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Pickar: Psychosis is the hallmark of serious mental illness, whether it's schizophrenia, severe bipolar, or psychosis otherwise. It is one of the great tragedies of our medical system, and I'll come back to the primary doc who's out there. I want to talk to you about this. It is a tragedy. Whitney knows, I put together a little documentary, The Realities of Serious Mental Illness. I just couldn't stand the lack of information.

They're very quick to report the violence, and I know a lot about the violence. I worry about it all the time. There's a huge debate between civil liberties and safety that's going on in serious mental illness. Regardless, knowing about it is enormously important for all docs. More patients with serious mental illness, by far, are in jails than they are in mental hospitals. There is nothing for them. You talk about collaborative care.
 
Whitney: On the team in the primary care setting, who's treating what?

Dr. Pickar: I'm talking now myself. A family member brings in an 18-year-old to evaluate. Okay? I'm glad to see it. Of course, I've been around a while. I spent decades as a scientist in schizophrenia. I just close my eyes and hope that I'm not seeing a first break for a seriously mental ill patient. Not that we can't treat it. Not that we can't help, but I know what's entailed. Not unlike seeing an oncology presentation. We're there. We're docs. You don't give up on it, but you know what's ahead for that family.

What's fascinating is many of the first breaks occur, not necessarily quietly, but can be a little insidious. They can be brought to the primary care. It is not uncommon. “My 16-year-old's not doing well. I can't get him up.” But really, what's going on? The primary care doc needs to have a consciousness of that. Let me just say this: First things about serious mental illness, particularly in schizophrenia, 1% of the population has it. That makes it a very common disorder.

SAN DIEGO – The Neck Disability Index–10 did not perform as well as the Neck Disability Index–5 in assessing patient-reported outcomes in cervical spine patients – and neither was as good as the PROMIS physical function domain delivered by computerized adaptive testing.

Those are the key findings from an analysis of data from more than 500 cervical spine patients treated at University of Utah Health Care in Salt Lake City.

“Previous studies by us and others have shown problems with the NDI [Neck Disability Index] as it is commonly administered” in 10 questions, lead study author Dr. Darrel S. Brodke said in an interview in advance of the annual meeting of the Cervical Spine Research Society. “It has a very poor floor effect, meaning that it does not differentiate between minimally disabled patients, and the scores cannot be appropriately handled with the kinds of statistics that we normally use – though because few of us know this, we still use it as a standard parametric measure.”

In what he said is the first study of its kind, Dr. Brodke, professor of orthopedics at the University of Utah, and his associates set out to compare the psychometric performance of the National Institutes of Health–funded PROMIS (Patient Reported Outcomes Measurement Information System) physical function (PF) domain, administered by computerized adaptive testing, with the standard NDI-10, the NDI-5, and the 36-Item Short Form physical function domain (SF-36 PFD).

In all, 566 patients completed the NDI and PROMIS PF computerized adaptive testing assessments, while 490 also completed the SF-36 PFD.

On average, the NDI-10 took the longest to complete (10 questions in a mean of 183 seconds), followed by the SF-36 PFD (5 questions in a mean of 123 seconds), the NDI-5 (5 questions in a mean of 99 seconds), and the PROMIS PF computerized adaptive testing (between 4 and 12 questions in a mean of 62 seconds).

The psychometric properties of the PROMIS PF computerized adaptive testing were superior to the other outcome measurement tools studied, Dr. Brodke reported. Specifically, the ceiling and floor effects were “excellent” for the PROMIS PF computerized adaptive testing (1.94% and 4.06%, respectively), while the ceiling effects were “fine” for the NDI-10 (4.77%), NDI-5 (7.60%), and SF-36 PFD (11.84%), he said.

However, the floor effects of these three instruments were poor (45.58%, 48.59% and 21.55%, respectively). “The NDI-10 also has the additional challenge of extremely poor raw score to measure correlation,” the researchers noted in their abstract.

“The legacy scale scores significantly predicted the PROMIS PF CAT scores (P less than .0001), with fair correlation for the PF CAT and NDI-10 (0.53) and good correlation of PF CAT and SF-36 PFD (0.62), allowing use of conversion equations to predict scores, which were generated,” the investigators explained.

PROMIS PF computerized adaptive testing “does much better than the NDI or the SF-36 physical function domain at characterizing patients’ physical function, with much better coverage,” Dr. Brodke said. “Not only this, but it is also much faster to fill out, so less burdensome to the patient and the clinic.”

One limitation of the study is that the researchers did not measure the responsiveness aspect of PROMIS performance. “We did not have enough pre- and posttreatment scores to do this measurement yet,” Dr. Brodke said. “The other thing is that minimum clinically important difference [MCID] is not yet worked out for PROMIS in this patient population, though we can infer an MCID as one-half of a standard deviation. More to come in future studies.”

Dr. Brodke reported having no financial disclosures.

[email protected]

SAN DIEGO – The Neck Disability Index–10 did not perform as well as the Neck Disability Index–5 in assessing patient-reported outcomes in cervical spine patients – and neither was as good as the PROMIS physical function domain delivered by computerized adaptive testing.

Those are the key findings from an analysis of data from more than 500 cervical spine patients treated at University of Utah Health Care in Salt Lake City.

“Previous studies by us and others have shown problems with the NDI [Neck Disability Index] as it is commonly administered” in 10 questions, lead study author Dr. Darrel S. Brodke said in an interview in advance of the annual meeting of the Cervical Spine Research Society. “It has a very poor floor effect, meaning that it does not differentiate between minimally disabled patients, and the scores cannot be appropriately handled with the kinds of statistics that we normally use – though because few of us know this, we still use it as a standard parametric measure.”

In what he said is the first study of its kind, Dr. Brodke, professor of orthopedics at the University of Utah, and his associates set out to compare the psychometric performance of the National Institutes of Health–funded PROMIS (Patient Reported Outcomes Measurement Information System) physical function (PF) domain, administered by computerized adaptive testing, with the standard NDI-10, the NDI-5, and the 36-Item Short Form physical function domain (SF-36 PFD).

In all, 566 patients completed the NDI and PROMIS PF computerized adaptive testing assessments, while 490 also completed the SF-36 PFD.

On average, the NDI-10 took the longest to complete (10 questions in a mean of 183 seconds), followed by the SF-36 PFD (5 questions in a mean of 123 seconds), the NDI-5 (5 questions in a mean of 99 seconds), and the PROMIS PF computerized adaptive testing (between 4 and 12 questions in a mean of 62 seconds).

The psychometric properties of the PROMIS PF computerized adaptive testing were superior to the other outcome measurement tools studied, Dr. Brodke reported. Specifically, the ceiling and floor effects were “excellent” for the PROMIS PF computerized adaptive testing (1.94% and 4.06%, respectively), while the ceiling effects were “fine” for the NDI-10 (4.77%), NDI-5 (7.60%), and SF-36 PFD (11.84%), he said.

However, the floor effects of these three instruments were poor (45.58%, 48.59% and 21.55%, respectively). “The NDI-10 also has the additional challenge of extremely poor raw score to measure correlation,” the researchers noted in their abstract.

“The legacy scale scores significantly predicted the PROMIS PF CAT scores (P less than .0001), with fair correlation for the PF CAT and NDI-10 (0.53) and good correlation of PF CAT and SF-36 PFD (0.62), allowing use of conversion equations to predict scores, which were generated,” the investigators explained.

PROMIS PF computerized adaptive testing “does much better than the NDI or the SF-36 physical function domain at characterizing patients’ physical function, with much better coverage,” Dr. Brodke said. “Not only this, but it is also much faster to fill out, so less burdensome to the patient and the clinic.”

One limitation of the study is that the researchers did not measure the responsiveness aspect of PROMIS performance. “We did not have enough pre- and posttreatment scores to do this measurement yet,” Dr. Brodke said. “The other thing is that minimum clinically important difference [MCID] is not yet worked out for PROMIS in this patient population, though we can infer an MCID as one-half of a standard deviation. More to come in future studies.”

Dr. Brodke reported having no financial disclosures.

[email protected]

SAN DIEGO – The Neck Disability Index–10 did not perform as well as the Neck Disability Index–5 in assessing patient-reported outcomes in cervical spine patients – and neither was as good as the PROMIS physical function domain delivered by computerized adaptive testing.

Those are the key findings from an analysis of data from more than 500 cervical spine patients treated at University of Utah Health Care in Salt Lake City.

“Previous studies by us and others have shown problems with the NDI [Neck Disability Index] as it is commonly administered” in 10 questions, lead study author Dr. Darrel S. Brodke said in an interview in advance of the annual meeting of the Cervical Spine Research Society. “It has a very poor floor effect, meaning that it does not differentiate between minimally disabled patients, and the scores cannot be appropriately handled with the kinds of statistics that we normally use – though because few of us know this, we still use it as a standard parametric measure.”

In what he said is the first study of its kind, Dr. Brodke, professor of orthopedics at the University of Utah, and his associates set out to compare the psychometric performance of the National Institutes of Health–funded PROMIS (Patient Reported Outcomes Measurement Information System) physical function (PF) domain, administered by computerized adaptive testing, with the standard NDI-10, the NDI-5, and the 36-Item Short Form physical function domain (SF-36 PFD).

In all, 566 patients completed the NDI and PROMIS PF computerized adaptive testing assessments, while 490 also completed the SF-36 PFD.

On average, the NDI-10 took the longest to complete (10 questions in a mean of 183 seconds), followed by the SF-36 PFD (5 questions in a mean of 123 seconds), the NDI-5 (5 questions in a mean of 99 seconds), and the PROMIS PF computerized adaptive testing (between 4 and 12 questions in a mean of 62 seconds).

The psychometric properties of the PROMIS PF computerized adaptive testing were superior to the other outcome measurement tools studied, Dr. Brodke reported. Specifically, the ceiling and floor effects were “excellent” for the PROMIS PF computerized adaptive testing (1.94% and 4.06%, respectively), while the ceiling effects were “fine” for the NDI-10 (4.77%), NDI-5 (7.60%), and SF-36 PFD (11.84%), he said.

However, the floor effects of these three instruments were poor (45.58%, 48.59% and 21.55%, respectively). “The NDI-10 also has the additional challenge of extremely poor raw score to measure correlation,” the researchers noted in their abstract.

“The legacy scale scores significantly predicted the PROMIS PF CAT scores (P less than .0001), with fair correlation for the PF CAT and NDI-10 (0.53) and good correlation of PF CAT and SF-36 PFD (0.62), allowing use of conversion equations to predict scores, which were generated,” the investigators explained.

PROMIS PF computerized adaptive testing “does much better than the NDI or the SF-36 physical function domain at characterizing patients’ physical function, with much better coverage,” Dr. Brodke said. “Not only this, but it is also much faster to fill out, so less burdensome to the patient and the clinic.”

One limitation of the study is that the researchers did not measure the responsiveness aspect of PROMIS performance. “We did not have enough pre- and posttreatment scores to do this measurement yet,” Dr. Brodke said. “The other thing is that minimum clinically important difference [MCID] is not yet worked out for PROMIS in this patient population, though we can infer an MCID as one-half of a standard deviation. More to come in future studies.”

Dr. Brodke reported having no financial disclosures.

[email protected]

Keeping up on medical literature is never easy. Time is limited between work and family. It’s often hard to know what to read. Most journals are a combination of research and practical information.

I’m not an academic and never will be. I have nothing against my colleagues who are, but it’s just not my personality type. I’m a happy-to-see-patients-all-day type of doctor.

I try to stick with reading things that have an immediate impact on how I practice: review articles, information about new diagnostic procedures and treatments, and news about the economics of medicine. That’s about it. If I can’t use it now or in the immediate future, it’s not relevant to my practice. My patients want to know what I can do for them today, not in 5-10 years. There’s enough to keep up on that’s relevant to current practice as it is.

Research in medicine is obviously crucial, since what we do is based on it. There is a lot of interesting and potentially game-changing research out there. But medical literature is full of small studies that show promise for something only to be shot down when larger investigations are done. It’s not practical or even good medicine to make treatment decisions based on small-scale preliminary data and anecdotal reports.

Even the oft-cited “green journal” – Neurology – isn’t on my reading list. I admit that it has its share of practical knowledge, but the last time I read it, the majority of pages were devoted to research that was promising, though not imminently applicable to patient care. That’s not for me.

Time is always at a premium in modern life. There’s no shortage of journals and interesting research to peruse, and so I try to stay with what’s practical for both me and my patients. I’ll leave the research to those who are good at it, and do my best to support the people who come to my office every day.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Keeping up on medical literature is never easy. Time is limited between work and family. It’s often hard to know what to read. Most journals are a combination of research and practical information.

I’m not an academic and never will be. I have nothing against my colleagues who are, but it’s just not my personality type. I’m a happy-to-see-patients-all-day type of doctor.

I try to stick with reading things that have an immediate impact on how I practice: review articles, information about new diagnostic procedures and treatments, and news about the economics of medicine. That’s about it. If I can’t use it now or in the immediate future, it’s not relevant to my practice. My patients want to know what I can do for them today, not in 5-10 years. There’s enough to keep up on that’s relevant to current practice as it is.

Research in medicine is obviously crucial, since what we do is based on it. There is a lot of interesting and potentially game-changing research out there. But medical literature is full of small studies that show promise for something only to be shot down when larger investigations are done. It’s not practical or even good medicine to make treatment decisions based on small-scale preliminary data and anecdotal reports.

Even the oft-cited “green journal” – Neurology – isn’t on my reading list. I admit that it has its share of practical knowledge, but the last time I read it, the majority of pages were devoted to research that was promising, though not imminently applicable to patient care. That’s not for me.

Time is always at a premium in modern life. There’s no shortage of journals and interesting research to peruse, and so I try to stay with what’s practical for both me and my patients. I’ll leave the research to those who are good at it, and do my best to support the people who come to my office every day.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Keeping up on medical literature is never easy. Time is limited between work and family. It’s often hard to know what to read. Most journals are a combination of research and practical information.

I’m not an academic and never will be. I have nothing against my colleagues who are, but it’s just not my personality type. I’m a happy-to-see-patients-all-day type of doctor.

I try to stick with reading things that have an immediate impact on how I practice: review articles, information about new diagnostic procedures and treatments, and news about the economics of medicine. That’s about it. If I can’t use it now or in the immediate future, it’s not relevant to my practice. My patients want to know what I can do for them today, not in 5-10 years. There’s enough to keep up on that’s relevant to current practice as it is.

Research in medicine is obviously crucial, since what we do is based on it. There is a lot of interesting and potentially game-changing research out there. But medical literature is full of small studies that show promise for something only to be shot down when larger investigations are done. It’s not practical or even good medicine to make treatment decisions based on small-scale preliminary data and anecdotal reports.

Even the oft-cited “green journal” – Neurology – isn’t on my reading list. I admit that it has its share of practical knowledge, but the last time I read it, the majority of pages were devoted to research that was promising, though not imminently applicable to patient care. That’s not for me.

Time is always at a premium in modern life. There’s no shortage of journals and interesting research to peruse, and so I try to stay with what’s practical for both me and my patients. I’ll leave the research to those who are good at it, and do my best to support the people who come to my office every day.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

An appeal from Martin Brotman, M.D., AGAF, Chair, AGA Research Foundation

Past Senior Vice President, Education, Research, and Philanthropy, CPMC Sutter Health

This holiday season is a good time to reflect on our many blessings and thank those who have helped make our lives and careers worthwhile, successful, and prosperous. What better way than to pass on something to those who will ensure that gastroenterology will advance in decades to come?

Progress in this lifesaving work is made possible by the generosity of many supporters, like you, who understand the devastating physical, emotional, and financial costs of digestive diseases. We simply cannot allow a slowdown in the pace of GI research, and we cannot afford to lose talent when research offers so much promise for the future.

What can you do to ensure the progress continues?

Show your support and give back.

Help close the gap in research funding and save lives. Make your tax-deductible donation online at www.gastro.org/donateonline.

The foundation funds promising young investigators who might not receive funding otherwise at crucial times in their early careers. The research of these individuals, while important to the field, if left unfunded, could end prematurely. That’s something the field can’t afford, and that’s why I’ve supported the AGA Research Foundation over the years through my donations. We must maintain a robust pipeline of research that will help safeguard the success of clinical medicine. I urge you to support the future of GI with a generous donation to the AGA Research Foundation endowment fund. Your donation of $250, $500, $1,000, $2,500, or any amount you can give today will keep giving for years to come.

May 2016 will mark the end of my tenure as chair of the AGA Research Foundation. I am proud of our accomplishments over these past years, and, while I will no longer occupy the chair at the head of the table, I will continue to be involved in the foundation’s important work. I am hoping that my last year at the helm of the foundation will be our most successful yet. A gift from you will be a vote of confidence in our work and will send a message that you share in our hopes for the future of digestive disease research.

Thank you in advance for support and best wishes for a happy, healthy holiday season and prosperous New Year.

Three easy ways to give

Online: www.gastro.org/contribute

Through the mail:

AGA Research Foundation

4930 Del Ray Avenue

Bethesda, MD 20814

Over the phone: 301-222-4002

All gifts are tax-deductible to the fullest extent of U.S. law.

An appeal from Martin Brotman, M.D., AGAF, Chair, AGA Research Foundation

Past Senior Vice President, Education, Research, and Philanthropy, CPMC Sutter Health

This holiday season is a good time to reflect on our many blessings and thank those who have helped make our lives and careers worthwhile, successful, and prosperous. What better way than to pass on something to those who will ensure that gastroenterology will advance in decades to come?

Progress in this lifesaving work is made possible by the generosity of many supporters, like you, who understand the devastating physical, emotional, and financial costs of digestive diseases. We simply cannot allow a slowdown in the pace of GI research, and we cannot afford to lose talent when research offers so much promise for the future.

What can you do to ensure the progress continues?

Show your support and give back.

Help close the gap in research funding and save lives. Make your tax-deductible donation online at www.gastro.org/donateonline.

The foundation funds promising young investigators who might not receive funding otherwise at crucial times in their early careers. The research of these individuals, while important to the field, if left unfunded, could end prematurely. That’s something the field can’t afford, and that’s why I’ve supported the AGA Research Foundation over the years through my donations. We must maintain a robust pipeline of research that will help safeguard the success of clinical medicine. I urge you to support the future of GI with a generous donation to the AGA Research Foundation endowment fund. Your donation of $250, $500, $1,000, $2,500, or any amount you can give today will keep giving for years to come.

May 2016 will mark the end of my tenure as chair of the AGA Research Foundation. I am proud of our accomplishments over these past years, and, while I will no longer occupy the chair at the head of the table, I will continue to be involved in the foundation’s important work. I am hoping that my last year at the helm of the foundation will be our most successful yet. A gift from you will be a vote of confidence in our work and will send a message that you share in our hopes for the future of digestive disease research.

Thank you in advance for support and best wishes for a happy, healthy holiday season and prosperous New Year.

Three easy ways to give

Online: www.gastro.org/contribute

Through the mail:

AGA Research Foundation

4930 Del Ray Avenue

Bethesda, MD 20814

Over the phone: 301-222-4002

All gifts are tax-deductible to the fullest extent of U.S. law.

An appeal from Martin Brotman, M.D., AGAF, Chair, AGA Research Foundation

Past Senior Vice President, Education, Research, and Philanthropy, CPMC Sutter Health

This holiday season is a good time to reflect on our many blessings and thank those who have helped make our lives and careers worthwhile, successful, and prosperous. What better way than to pass on something to those who will ensure that gastroenterology will advance in decades to come?

Progress in this lifesaving work is made possible by the generosity of many supporters, like you, who understand the devastating physical, emotional, and financial costs of digestive diseases. We simply cannot allow a slowdown in the pace of GI research, and we cannot afford to lose talent when research offers so much promise for the future.

What can you do to ensure the progress continues?

Show your support and give back.

Help close the gap in research funding and save lives. Make your tax-deductible donation online at www.gastro.org/donateonline.

The foundation funds promising young investigators who might not receive funding otherwise at crucial times in their early careers. The research of these individuals, while important to the field, if left unfunded, could end prematurely. That’s something the field can’t afford, and that’s why I’ve supported the AGA Research Foundation over the years through my donations. We must maintain a robust pipeline of research that will help safeguard the success of clinical medicine. I urge you to support the future of GI with a generous donation to the AGA Research Foundation endowment fund. Your donation of $250, $500, $1,000, $2,500, or any amount you can give today will keep giving for years to come.

May 2016 will mark the end of my tenure as chair of the AGA Research Foundation. I am proud of our accomplishments over these past years, and, while I will no longer occupy the chair at the head of the table, I will continue to be involved in the foundation’s important work. I am hoping that my last year at the helm of the foundation will be our most successful yet. A gift from you will be a vote of confidence in our work and will send a message that you share in our hopes for the future of digestive disease research.

Thank you in advance for support and best wishes for a happy, healthy holiday season and prosperous New Year.

Three easy ways to give

Online: www.gastro.org/contribute

Through the mail:

AGA Research Foundation

4930 Del Ray Avenue

Bethesda, MD 20814

Over the phone: 301-222-4002

All gifts are tax-deductible to the fullest extent of U.S. law.