January 2016 FAQs

January 2016 FAQs Heading link

What data are available comparing liposomal bupivacaine to other agents?

Introduction

Local anesthetics, non-steroidal anti-inflammatory drugs (NSAIDs) and/or opioids may be used as part of a multidrug regimen to provide adequate analgesia after surgical procedures.¹^,² The selection of a particular local anesthetic is based on the onset and duration of the anesthetic, its adverse effects, the type of procedure, and level of anticipated pain.³ Of the currently available local anesthetics, ropivacaine and bupivacaine are long-acting agents that are used for local infiltration. In October 2011, liposomal formulation of bupivacaine (Exparel) was approved by the Food and Drug Administration (FDA) for local infiltration of the surgical site for postsurgical anesthesia with dose recommendations only for two procedures, bunionectomy and hemorrhoidectomy.^4,5 On December 14, 2015, the manufacturer changed labeling to expand dosing recommendations to other surgical procedures.^5,6 The new label states that the dose of this agent may depend on size of surgical site, needed volume, and individual patient factors. The maximum dose should not exceed 266 mg, and the dosing for bunionectomy and hemorrhoidectomy are provided as examples. Liposomal bupivacaine may theoretically prolong the duration of action of bupivacaine because the slow release of bupivacaine from the liposome has been shown to maintain systemic plasma concentrations over 96 hours.⁶ This formulation is intended to provide analgesia through the postoperative period to reduce the need for opioids and, thereby, minimize opioid-related adverse effects. This review will summarize the current data on the comparative efficacy and safety.

Literature review

The table below summarizes the currently published comparative trials of liposomal bupivacaine and does not include placebo-controlled trials. Most trials compared liposomal bupivacaine to bupivacaine hydrochloride, patient-controlled analgesia, or ropivacaine. Trials of liposomal bupivacaine in bunionectomy are placebo-controlled, and therefore, are not discussed in this review.

Table. Comparative liposomal bupivacaine studies.^7-19

Study	Design/ duration	Population	Key interventions	Primary/secondary endpoints	Outcomes
*Breast Augmentation*
Smoot 2012⁷	Phase 3 randomized, multicenter, double-blind 72 h	N=136 patients undergoing breast augmentation with ASA^a physical status of 1 to 4 who received general anesthesia	Liposomal bupivacaine 600 mg (n=66) Bupivacaine HCl 200 mg with epinephrine 1: 200,000 (n=70)	Primary outcome: Cumulative pain score using NRS-A through 72 h after drug administration Secondary outcomes: Cumulative pain scores at each time point Total opioid use Proportion of patients receiving no opioid Quality of life Patient satisfaction Time to return to normal activity Adverse events	The mean cumulative pain score was not significantly different in the liposomal bupivacaine group compared with the bupivacaine HCl group (441.5 vs. 468.2, p=0.3999). Significant results for secondary outcomes included: NRS-A pain scores at 8 and 12 h were significantly lower with liposomal bupivacaine than bupivacaine HCl. Total amount of opioid consumed was significantly lower at 24 and 48 h with liposomal bupivacaine but not at other time points. No significant difference in rates of opioid rescue. Most common adverse events in both groups were nausea, constipation, vomiting, and muscle spasm.
*Colectomy and/or Ileostomy Reversal*
Vogel 2013⁸	Phase 4, prospective, single-center, open-label 30 d	N=43 patients undergoing ileostomy reversal	Liposomal bupivacaine 266 mg + ketorolac 30 mg IV + acetaminophen (IV or oral) 1000 mg every 6 h for 72 h + ibuprofen (oral) 600 mg every 6 h for 72 h (n=23) Opioid PCA using IV morphine or hydromorphone (n=20) All medications were initiated immediately after surgery.	Primary outcomes: Opioid use (morphine equivalents) Length of stay Hospital costs Secondary outcomes: Time to first rescue opioid use Patient satisfaction Adverse events	Mean opioid use for patients who received liposomal bupivacaine (38 mg) was significantly less compared with the PCA group (68 mg), p=0.004. Length of stay and cost were not found to be significantly different. Of the secondary outcomes, the time to first opioid use was statistically significantly longer with liposomal bupivacaine compared to PCA (1.1 h vs. 0.7 h, p=0.035). No significant differences in adverse events and patient satisfaction were observed.
Marcet 2013⁹	Phase 4 prospective, multicenter, open-label 30 d	N=27 patients undergoing ileostomy reversal	Liposomal bupivacaine 266 mg + ketorolac 30 mg IV + acetaminophen (IV or oral) 1000 mg every 6 h for 72 h + ibuprofen (oral) 600 mg every 6 h for 72 h (n=16) Opioid PCA (n=11)	Primary outcomes: Opioid use (morphine equivalents) Length of stay Hospital costs Secondary outcomes: Time to first opioid use Patient satisfaction Opioid-related adverse events	Mean opioid use for patients who received liposomal bupivacaine (20 mg) was significantly less compared with the PCA group (112 mg), p<0.01. Median duration of stay in the liposomal bupivacaine group was significantly shorter compared with the PCA group (3 d vs 5 d, respectively; p<0.001). Mean hospitalization cost was significantly less for patients who received liposomal bupivacaine compared to the PCA group ($6482 vs. $9282, p=0.01). Of the secondary outcomes, the time to first opioid use was statistically significantly longer with liposomal bupivacaine compared to PCA (2.9 h vs. 0.6 h, p=0.04). No significant difference in opioid-related adverse events and patient satisfaction was found between the 2 groups.
Cohen 2012¹⁰	Phase 4 open-label, single- center cohort 30 d	N=30 patients undergoing open colectomy	Liposomal bupivacaine 266 mg + ketorolac 30 mg IV + acetaminophen (IV or oral) 1000 mg every 6 h for 72 h + ibuprofen (oral) 600 mg every 6 h for 72 h (n=21) Opioid PCA using IV morphine and hydromorphone (n=18)	Primary outcomes: Opioid use (morphine equivalents) Length of stay Hospital costs Secondary outcomes: Patient satisfaction Hospital readmission and unplanned visits Adverse events	Mean opioid use (morphine equivalent) for patients who received liposomal bupivacaine was significantly less compared with the PCA group (57 mg vs. 115 mg), p=0.025. Median duration of stay in the liposomal bupivacaine group was significantly shorter compared with the PCA group (2 d vs. 4.9 d, respectively; p=0.004). Mean hospitalization cost was significantly less for patients who received liposomal bupivacaine compared to the PCA group ($8766 vs. $11,850, p=0.027). No differences between the 2 groups in any of the secondary outcomes were observed including opioid-related adverse events.
*Hemorrhoidectomy*
Haas 2012¹¹	Phase 2 randomized, double-blind, dose-ranging 72 h	N=100 patients undergoing hemorrhoid-ectomy with ASA^aphysical status of 1 to 2 who received general anesthesia and had a cumulative excisional length ≥ 3 cm	Liposomal bupivacaine 66 mg (n=24) Liposomal bupivacaine 199 mg (n=25) Liposomal bupivacaine 266 mg (n=25) Bupivacaine HCl 75 mg with epinephrine 1:200,000 (n=26)	Primary outcome: Cumulative pain score using NRS^b measured every 12 h up to 96 h after drug administration Secondary outcomes: Pain intensity with bowel movement Time to first bowel movement Number of patients not requiring an opioid Time to first use of opioid Total opioid consumption Provider satisfaction Discharge readiness Adverse events	Compared to bupivacaine HCl, cumulative pain scores at 96 h were statistically significantly lower with liposomal bupivacaine 199 mg (95% CI for difference -363 to -52, p=0.001) and 266 mg (95% CI -373 to -60, p<0.001). The median time to first opioid use was significantly longer in the liposomal bupivacaine 266 mg group compared to the bupivacaine HCl group (19 h vs. 8 h, respectively, p=0.005). Total opioid consumption between 48 and 96 h was significantly less with liposomal bupivacaine 266 mg compared to bupivacaine HCl. Provider satisfaction scores were significantly higher with liposomal bupivacaine 266 mg compared with bupivacaine HCl. The most common adverse events were constipation, nausea, and vomiting attributed to use of opioids. The incidence of these events was 4% with liposomal bupivacaine compared to 35% with bupivacaine HCl (p=0.006).
*Hysterectomy*
Gasanova 2015¹²	Prospective, randomized, observer-blinded 48 h	N=67 female patients scheduled for open total abdominal hysterectomy	Ultrasound-guided bilateral TAP blocks with bupivacaine 0.5% (20ml), acetaminophen 1000 mg IV, and ketorolac 30mg IV (n=29) Infiltration with liposomal bupivacaine 266 mg, acetaminophen 1000 mg IV, and ketorolac 30 mg IV (n=29)	Primary outcome: VAS pain scores upon coughing at 6 hours preoperatively Secondary outcomes: VAS pain scores at rest Opioid requirements Incidence of nausea and vomiting Need for rescue antiemetic for 48 hours postoperatively	Lower VAS pain score on coughing in the liposomal bupivacaine group compared with the TAP block group at 6 hours (p<0.0001). Lower VAS pain score at rest with liposomal bupivacaine (p<0.0001). Less morphine use in the liposomal bupivacaine group in the first 24 h (33.6 vs 47.7 mg; p=0.0497). Fewer hydrocodone-acetaminophen 5-325 mg tablets used in the liposomal bupivacaine group (1.90 vs 3.55; p=0.009). No difference in rates of reported nausea, vomiting, and need for rescue antiemetics.
Hutchins 2015¹³	Prospective, randomized, controlled, observer-blinded study 72 h	N=110 adult women undergoing elective robotic assisted hysterectomy	TAP block of 1.3% liposomal bupivacaine (n=30) TAP block of 0.25% bupivacaine HCl with 1:200,000 of epinephrine (n=30)	Primary outcome: Total opioid use 72 h post-operatively Secondary outcomes: Self-reported pain score Pain medication use Hospital LOS Nausea and vomiting Patient satisfaction	Total opioid use within the first 72 h was significantly lower in the liposomal bupivacaine arm compared with bupivacaine HCl arm (24.9 mg vs 51.7 mg of morphine equivalents, respectively; p=0.002). Pain score difference and opioid use not found to be statistically significant in all time intervals of the study period. Only maximum NRS pain scored remained statistically lower for liposomal bupivacaine group through various intervals (p from 0.006 to 0.47 based on different time interval). There was a significant reduction in nausea reported with liposomal bupivacaine compared with the control (25% vs 56.7%, respectively; p=0.014) No significant difference in LOS and patient reported pain control satisfaction was observed between the 2 treatment groups.
*Total Knee Arthroplasty*
Collis 2015¹⁴	Prospective, randomized, single-blind 6 weeks	N=105 patients undergoing primary TKA	Liposomal bupivacaine 20 ml (strength not specified) diluted to 40 ml (n=54) Modified Ranawat suspension (ropivacaine 246.25 mg, epinephrine 0.5 mg, ketorolac 30 mg, clonidine 0.08 mg, in 48.45 mL of saline) (n=51)	Pain levels a 24h, 48h, 72h, 2 weeks, and 6 weeks Total intravenous and oral analgesics for first 24 h Active range of motion Walking distance	No statistically significant differences in pain score at all time points, opioid use, range of motion and walking distance was found between the 2 treatment groups.
Schroer 2015¹⁵	Prospective, randomized, blinded 3 weeks	N=111 patients undergoing unilateral primary TKA	Periarticular injection (PAI) of liposomal bupivacaine 266 mg with 75 mg bupivacaine HCl (n=58) PAI of bupivacaine HCl 150 mg (n=53)	Primary outcome: VAS obtained twice a day prior to receiving physical therapy during hospitalization Secondary outcome: Hospital LOS Knee flexion at time of discharge and at three weeks Narcotic use during hospitalization	No difference in mean VAS was observed between the liposomal bupivacaine group and bupivacaine HCl group. Hospital LOS, knee flexion, and use of narcotic equivalents were not statistically different.
Surdam 2015¹⁶	Prospective, randomized 3 days	N=80 patients who underwent TKA	Liposomal bupivacaine 266mg (n=40) FNB consisting of 40 mL of 0.5% ropivacaine with 1:200,000 epinephrine, plus 30mg of 1% tetracaine (n=40)	Primary outcome: Self-reported pain on a 1-10 pain scale and the Wong-Baker pain faces scale Secondary outcomes: Range of motion Nausea and vomiting Opioid use Ambulation distance Hospital LOS	No difference in mean pain score between the liposomal bupivacaine group compared with the FNB group during the entire hospital stay (3.42 vs 2.92, respectively; p=0.07) Significantly better flexion in the FNB group compared with liposomal bupivacaine (101 degrees vs 94 degrees; p=0.001). No difference in rates of nausea and vomiting, total opioid use, and mean ambulation distance. Average LOS was less in the liposomal bupivacaine group versus FNB (2.36 days vs 2.65 days, respectively; p=0.03).
Bagsby 2014¹⁷	Single-center , retrospective cohort Length of hospital stay (approximately 3 days)	N=150 patients undergoing total knee arthroplasty	Peri-articular liposomal bupivacaine 266 mg (n=85) Traditional injection of peri-articular ropivacaine 400 mg, epinephrine 0.4 mg, and morphine 5 mg (n=65)	Mean pain score using VAS (0 to 10) Opioid use	Mean pain scores within 24 h after surgery were not significantly different between liposomal bupivacaine and traditional injection (1.94 vs. 1.93, respectively; p=1.0). During hospitalization, after the first 24 h until discharge, mean pain scores were found to be statistically significantly lower in the traditional injection group compared to liposomal bupivacaine (4.4 vs. 4.9, respectively, p=0.04). Opioid use and mean pain score at discharge were not significantly different.
Bramlett 2012¹⁸	Phase 2, randomized, multicenter, parallel-group, double-blind, dose-ranging study 96 h	N=138 patients undergoing total knee arthroplasty with ASA^a physical status of 1 to 3 who received general anesthesia	Liposomal bupivacaine 133 mg (n=28) Liposomal bupivacaine 266 mg (n=25) Liposomal bupivacaine 399 mg (n=26) Liposomal bupivacaine 532 mg (n=25) Bupivacaine HCl 150 mg with epinephrine 1:200,000 (n=34)	Primary outcome: Cumulative pain score using NRS-A measured through 96 h after drug administration Secondary outcomes: NRS-A and NRS-R at each time point Cumulative pain score for NRS-R Total opioid use Time to return to normal activity Adverse events	No significant difference between groups was observed in the primary outcome. Of the secondary outcomes, only the NRS-R scores were significantly lower for the liposomal bupivacaine 532 mg group compared to bupivacaine HCl. The most common adverse events were nausea, constipation, and pyrexia.
*Urologic Procedures*
Knight 2015¹⁹	Prospective, randomized, patient-blinded, controlled trial <3 days	N=206 adult patients who underwent laparoscopic urologic surgery	Liposomal bupivacaine 266mg (n=97) Bupivacaine 0.25%, weight based not to exceed 2 mg/kg or 150 mg, whichever was lowest (n=94)	Primary outcome: Total opioid consumption in morphine equivalents during the postoperative period Secondary outcome: Pain scores on Wong-Baker visual analog pain scale Hospital LOS Time to first opioid	Median morphine equivalent opioid consumption postoperatively did not differ between liposomal bupivacaine and bupivacaine (15 mg vs 17.3 mg, respectively; p=0.39). No differences were observed between the 2 treatment groups for secondary outcomes.
^aASA is a classification system to rate the overall status of a patient; status 1=normal healthy patient, status 2=mild systemic disease, status 3=severe systemic disease, status 4=severe systemic disease that is a constant threat to life. ^bNRS is a numeric rating scale with a range from 0 to 10 with higher score indicating greater pain. Abbreviations: ASA, American Society of Anesthesiologists; CI, confidence interval; HCl, hydrochloride; FNB, femoral nerve block; IV, intravenous; LOS, length of stay; NRS, numeric rating scale; NRS-A, pain with activity; NRS-R, pain at rest; PAI, periarticular injection; PCA, patient-controlled analgesia; TAP, transversus abdominis plane; TKA, total knee arthroplasty; VAS, visual analog scale.

Study

Design/

duration

Population

Key interventions

Primary/secondary endpoints

Outcomes

Breast Augmentation

Smoot 2012⁷

Phase 3 randomized, multicenter, double-blind

72 h

N=136 patients undergoing breast augmentation with ASA^a physical status of 1 to 4 who received general anesthesia

Liposomal bupivacaine 600 mg (n=66)

Bupivacaine HCl 200 mg with epinephrine 1: 200,000 (n=70)

Primary outcome:

Cumulative pain score using NRS-A through 72 h after drug administration

Secondary outcomes:

Cumulative pain scores at each time point
Total opioid use
Proportion of patients receiving no opioid
Quality of life
Patient satisfaction
Time to return to normal activity
Adverse events

The mean cumulative pain score was not significantly different in the liposomal bupivacaine group compared with the bupivacaine HCl group (441.5 vs. 468.2, p=0.3999).

Significant results for secondary outcomes included:

NRS-A pain scores at 8 and 12 h were significantly lower with liposomal bupivacaine than bupivacaine HCl.
Total amount of opioid consumed was significantly lower at 24 and 48 h with liposomal bupivacaine but not at other time points.
No significant difference in rates of opioid rescue.
Most common adverse events in both groups were nausea, constipation, vomiting, and muscle spasm.

Colectomy and/or Ileostomy Reversal

Vogel 2013⁸

Phase 4, prospective, single-center, open-label

30 d

N=43 patients undergoing ileostomy reversal

Liposomal bupivacaine 266 mg + ketorolac 30 mg IV + acetaminophen (IV or oral) 1000 mg every 6 h for 72 h + ibuprofen (oral) 600 mg every 6 h for 72 h

(n=23)

Opioid PCA using IV morphine or hydromorphone (n=20)

All medications were initiated immediately after surgery.

Primary outcomes:

Opioid use (morphine equivalents)
Length of stay
Hospital costs

Secondary outcomes:

Time to first rescue opioid use
Patient satisfaction
Adverse events

Mean opioid use for patients who received liposomal bupivacaine (38 mg) was significantly less compared with the PCA group (68 mg), p=0.004.

Length of stay and cost were not found to be significantly different.

Of the secondary outcomes, the time to first opioid use was statistically significantly longer with liposomal bupivacaine compared to PCA (1.1 h vs. 0.7 h, p=0.035).

No significant differences in adverse events and patient satisfaction were observed.

Marcet 2013⁹

Phase 4 prospective, multicenter, open-label

30 d

N=27 patients undergoing ileostomy reversal

Liposomal bupivacaine 266 mg + ketorolac 30 mg IV + acetaminophen (IV or oral) 1000 mg every 6 h for 72 h + ibuprofen (oral) 600 mg every 6 h for 72 h

(n=16)

Opioid PCA (n=11)

Primary outcomes:

Opioid use (morphine equivalents)
Length of stay
Hospital costs

Secondary outcomes:

Time to first opioid use
Patient satisfaction
Opioid-related adverse events

Mean opioid use for patients who received liposomal bupivacaine (20 mg) was significantly less compared with the PCA group (112 mg), p<0.01.

Median duration of stay in the liposomal bupivacaine group was significantly shorter compared with the PCA group (3 d vs 5 d, respectively; p<0.001).

Mean hospitalization cost was significantly less for patients who received liposomal bupivacaine compared to the PCA group ($6482 vs. $9282, p=0.01).

Of the secondary outcomes, the time to first opioid use was statistically significantly longer with liposomal bupivacaine compared to PCA (2.9 h vs. 0.6 h, p=0.04).

No significant difference in opioid-related adverse events and patient satisfaction was found between the 2 groups.

Cohen 2012¹⁰

Phase 4 open-label, single- center cohort

30 d

N=30 patients undergoing open colectomy

Liposomal bupivacaine 266 mg + ketorolac 30 mg IV + acetaminophen (IV or oral) 1000 mg every 6 h for 72 h + ibuprofen (oral) 600 mg every 6 h for 72 h (n=21)

Opioid PCA using IV morphine and hydromorphone (n=18)

Primary outcomes:

Opioid use (morphine equivalents)
Length of stay
Hospital costs

Secondary outcomes:

Patient satisfaction
Hospital readmission and unplanned visits
Adverse events

Mean opioid use (morphine equivalent) for patients who received liposomal bupivacaine was significantly less compared with the PCA group (57 mg vs. 115 mg), p=0.025.

Median duration of stay in the liposomal bupivacaine group was significantly shorter compared with the PCA group (2 d vs. 4.9 d, respectively; p=0.004).

Mean hospitalization cost was significantly less for patients who received liposomal bupivacaine compared to the PCA group ($8766 vs. $11,850, p=0.027).

No differences between the 2 groups in any of the secondary outcomes were observed including opioid-related adverse events.

Hemorrhoidectomy

Haas 2012¹¹

Phase 2 randomized, double-blind, dose-ranging

72 h

N=100 patients undergoing hemorrhoid-ectomy with ASA^aphysical status of 1 to 2 who received general anesthesia and had a cumulative excisional length ≥ 3 cm

Liposomal bupivacaine 66 mg (n=24)

Liposomal bupivacaine 199 mg (n=25)

Liposomal bupivacaine 266 mg (n=25)

Bupivacaine HCl 75 mg with epinephrine 1:200,000 (n=26)

Primary outcome:

Cumulative pain score using NRS^b measured every 12 h up to 96 h after drug administration

Secondary outcomes:

Pain intensity with bowel movement
Time to first bowel movement
Number of patients not requiring an opioid
Time to first use of opioid
Total opioid consumption
Provider satisfaction
Discharge readiness
Adverse events

Compared to bupivacaine HCl, cumulative pain scores at 96 h were statistically significantly lower with liposomal bupivacaine 199 mg (95% CI for difference -363 to -52, p=0.001) and 266 mg (95% CI

-373 to -60, p<0.001).

The median time to first opioid use was significantly longer in the liposomal bupivacaine 266 mg group compared to the bupivacaine HCl group (19 h vs. 8 h, respectively, p=0.005).

Total opioid consumption between 48 and 96 h was significantly less with liposomal bupivacaine 266 mg compared to bupivacaine HCl.

Provider satisfaction scores were significantly higher with liposomal bupivacaine 266 mg compared with bupivacaine HCl.

The most common adverse events were constipation, nausea, and vomiting attributed to use of opioids. The incidence of these events was 4% with liposomal bupivacaine compared to 35% with bupivacaine HCl (p=0.006).

Hysterectomy

Gasanova 2015¹²

Prospective, randomized, observer-blinded

48 h

N=67 female patients scheduled for open total abdominal hysterectomy

Ultrasound-guided bilateral TAP blocks with bupivacaine 0.5% (20ml), acetaminophen 1000 mg IV, and ketorolac 30mg IV (n=29)

Infiltration with liposomal bupivacaine 266 mg, acetaminophen 1000 mg IV, and ketorolac 30 mg IV (n=29)

Primary outcome:

VAS pain scores upon coughing at 6 hours preoperatively

Secondary outcomes:

VAS pain scores at rest
Opioid requirements
Incidence of nausea and vomiting
Need for rescue antiemetic for 48 hours postoperatively

Lower VAS pain score on coughing in the liposomal bupivacaine group compared with the TAP block group at 6 hours (p<0.0001).

Lower VAS pain score at rest with liposomal bupivacaine
(p<0.0001).

Less morphine use in the liposomal bupivacaine group in the first 24 h (33.6 vs 47.7 mg; p=0.0497).

Fewer hydrocodone-acetaminophen 5-325 mg tablets used in the liposomal bupivacaine group (1.90 vs 3.55; p=0.009).

No difference in rates of reported nausea, vomiting, and need for rescue antiemetics.

Hutchins 2015¹³

Prospective, randomized, controlled, observer-blinded study

72 h

N=110 adult women undergoing elective robotic assisted hysterectomy

TAP block of 1.3% liposomal bupivacaine (n=30)

TAP block of 0.25% bupivacaine HCl with 1:200,000 of epinephrine (n=30)

Primary outcome:

Total opioid use 72 h post-operatively

Secondary outcomes:

Self-reported pain score
Pain medication use
Hospital LOS
Nausea and vomiting
Patient satisfaction

Total opioid use within the first 72 h was significantly lower in the liposomal bupivacaine arm compared with bupivacaine HCl arm (24.9 mg vs 51.7 mg of morphine equivalents, respectively; p=0.002).

Pain score difference and opioid use not found to be statistically significant in all time intervals of the study period.

Only maximum NRS pain scored remained statistically lower for liposomal bupivacaine group through various intervals (p from 0.006 to 0.47 based on different time interval).

There was a significant reduction in nausea reported with liposomal bupivacaine compared with the control (25% vs 56.7%, respectively; p=0.014)

No significant difference in LOS and patient reported pain control satisfaction was observed between the 2 treatment groups.

Total Knee Arthroplasty

Collis 2015¹⁴

Prospective, randomized, single-blind

6 weeks

N=105 patients undergoing primary TKA

Liposomal bupivacaine 20 ml (strength not specified) diluted to 40 ml (n=54)

Modified Ranawat suspension (ropivacaine 246.25 mg, epinephrine 0.5 mg, ketorolac 30 mg, clonidine 0.08 mg, in 48.45 mL of saline) (n=51)

Pain levels a 24h, 48h, 72h, 2 weeks, and 6 weeks
Total intravenous and oral analgesics for first 24 h
Active range of motion
Walking distance

No statistically significant differences in pain score at all time points, opioid use, range of motion and walking distance was found between the 2 treatment groups.

Schroer 2015¹⁵

Prospective, randomized, blinded

3 weeks

N=111 patients undergoing unilateral primary TKA

Periarticular injection (PAI) of liposomal bupivacaine 266 mg with 75 mg bupivacaine HCl (n=58)

PAI of bupivacaine HCl 150 mg (n=53)

Primary outcome:

VAS obtained twice a day prior to receiving physical therapy during hospitalization

Secondary outcome:

Hospital LOS
Knee flexion at time of discharge and at three weeks
Narcotic use during hospitalization

No difference in mean VAS was observed between the liposomal bupivacaine group and bupivacaine HCl group.

Hospital LOS, knee flexion, and use of narcotic equivalents were not statistically different.

Surdam 2015¹⁶

Prospective, randomized

3 days

N=80 patients who underwent TKA

Liposomal bupivacaine 266mg (n=40)

FNB consisting of 40 mL of 0.5% ropivacaine with 1:200,000 epinephrine, plus 30mg of 1% tetracaine (n=40)

Primary outcome:

Self-reported pain on a 1-10 pain scale and the Wong-Baker pain faces scale

Secondary outcomes:

Range of motion
Nausea and vomiting
Opioid use
Ambulation distance
Hospital LOS

No difference in mean pain score between the liposomal bupivacaine group compared with the FNB group during the entire hospital stay (3.42 vs 2.92, respectively; p=0.07)

Significantly better flexion in the FNB group compared with liposomal bupivacaine (101 degrees vs 94 degrees; p=0.001).

No difference in rates of nausea and vomiting, total opioid use, and mean ambulation distance.

Average LOS was less in the liposomal bupivacaine group versus FNB (2.36 days vs 2.65 days, respectively; p=0.03).

Bagsby 2014¹⁷

Single-center , retrospective cohort

Length of hospital stay (approximately 3 days)

N=150 patients undergoing total knee arthroplasty

Peri-articular liposomal bupivacaine 266 mg (n=85)

Traditional injection of peri-articular ropivacaine 400 mg, epinephrine 0.4 mg, and morphine 5 mg (n=65)

Mean pain score using VAS (0 to 10)
Opioid use

Mean pain scores within 24 h after surgery were not significantly different between liposomal bupivacaine and traditional injection (1.94 vs. 1.93, respectively; p=1.0).

During hospitalization, after the first 24 h until discharge, mean pain scores were found to be statistically significantly lower in the traditional injection group compared to liposomal bupivacaine (4.4 vs. 4.9, respectively, p=0.04).

Opioid use and mean pain score at discharge were not significantly different.

Bramlett 2012¹⁸

Phase 2, randomized, multicenter, parallel-group, double-blind,

dose-ranging study

96 h

N=138 patients undergoing total knee arthroplasty with ASA^a physical status of 1 to 3 who received general anesthesia

Liposomal bupivacaine 133 mg (n=28)

Liposomal bupivacaine 266 mg (n=25)

Liposomal bupivacaine 399 mg (n=26)

Liposomal bupivacaine 532 mg (n=25)

Bupivacaine HCl 150 mg with epinephrine 1:200,000 (n=34)

Primary outcome:

Cumulative pain score using NRS-A measured through 96 h after drug administration

Secondary outcomes:

NRS-A and NRS-R at each time point
Cumulative pain score for NRS-R
Total opioid use
Time to return to normal activity
Adverse events

No significant difference between groups was observed in the primary outcome.

Of the secondary outcomes, only the NRS-R scores were significantly lower for the liposomal bupivacaine 532 mg group compared to bupivacaine HCl.

The most common adverse events were nausea, constipation, and pyrexia.

Urologic Procedures

Knight 2015¹⁹

Prospective, randomized, patient-blinded, controlled trial

<3 days

N=206 adult patients who underwent laparoscopic urologic surgery

Liposomal bupivacaine 266mg (n=97)

Bupivacaine 0.25%, weight based not to exceed 2 mg/kg or 150 mg, whichever was lowest (n=94)

Primary outcome:

Total opioid consumption in morphine equivalents during the postoperative period

Secondary outcome:

Pain scores on Wong-Baker visual analog pain scale
Hospital LOS
Time to first opioid

Median morphine equivalent opioid consumption postoperatively did not differ between liposomal bupivacaine and bupivacaine (15 mg vs 17.3 mg, respectively; p=0.39).

No differences were observed between the 2 treatment groups for secondary outcomes.

^aASA is a classification system to rate the overall status of a patient; status 1=normal healthy patient, status 2=mild systemic disease, status 3=severe systemic disease, status 4=severe systemic disease that is a constant threat to life.

^bNRS is a numeric rating scale with a range from 0 to 10 with higher score indicating greater pain.

Abbreviations: ASA, American Society of Anesthesiologists; CI, confidence interval; HCl, hydrochloride; FNB, femoral nerve block; IV, intravenous; LOS, length of stay; NRS, numeric rating scale; NRS-A, pain with activity; NRS-R, pain at rest; PAI, periarticular injection; PCA, patient-controlled analgesia; TAP, transversus abdominis plane; TKA, total knee arthroplasty; VAS, visual analog scale.

Liposomal bupivacaine shows different outcome trends depending on the indication for which it is used. In total knee arthroplasty (TKA), reported pain scores as well as other outcomes such as opioid use and adverse effects did not significantly differ between liposomal bupivacaine and comparator treatments.^14-18 More consistent benefits of liposomal bupivacaine over patient controlled analgesia (PCA) were observed when used for colectomy or ileostomy reversal.^8-10 These studies show that the use of liposomal bupivacaine consistently decreased the average opioid use compared with PCA use alone. Furthermore, the secondary outcomes in these trials showed benefits in reduction of hospital length of stay as well as overall costs. Liposomal bupivacaine showed an overall decrease in pain scores, opioid use, and adverse effects such as nausea, vomiting, and constipation compared to the bupivacaine HCl formulation when used for hemorrhoidectomy.¹¹ The use of liposomal bupivacaine for hysterectomy procedures revealed lower opioid use compared to transversus abdominis plane (TAP) blocks that contain regular bupivacaine but results were inconsistent regarding pain scores and adverse events.^12,13 Statistical differences between liposomal bupivacaine and regular bupivacaine groups were not observed when used for urologic procedures.¹⁹ In the study by Smoot which evaluated its use in breast augmentation, pain scores and opioid use were not found to be significantly different than in patients treated with the regular formulation.⁷ Most of these studies did not define consistent interventions or outcomes, and therefore, the comparative data must be interpreted cautiously.

In a 2012 analysis of published studies and abstracts, Dasta and colleagues compared the pooled efficacy and safety of liposomal bupivacaine to bupivacaine hydrochloride.²⁰ Included studies were double-blind, active or placebo-controlled trials using a single dose of ≤266 mg liposomal bupivacaine injected into the surgical site before the end of surgery. Outcome measures included the 72-hour cumulative pain score as measured by the 11-point numeric rating scale (NRS), time to first use of opioid rescue medication, total opioid consumption (expressed as morphine equivalents) in 72 hours, overall adverse events, and opioid-related adverse events (pruritus, respiratory depression, vomiting, and urinary retention). Results of 9 studies were evaluated with 505 patients in the liposomal bupivacaine group and 406 in the bupivacaine hydrochloride group. Surgical procedures included inguinal hernia repair, knee arthroplasty, hemorrhoidectomy, breast augmentation, and bunionectomy. The mean area under the curve (AUC) of NRS scores through 72 hours was significantly lower with liposomal bupivacaine compared to bupivacaine hydrochloride (283 vs. 329, respectively, p=0.039). Median time to opioid administration was significantly longer with liposomal bupivacaine compared to bupivacaine hydrochloride (2.7 h vs. 9.9 h, respectively, p<0.0001). Patients receiving liposomal bupivacaine consumed a lower average amount of opioids (12.2 mg) compared to patients in the bupivacaine hydrochloride group (19 mg, p<0.0001). Common adverse events observed in both groups included nausea, constipation, vomiting, pyrexia, pruritus, and dizziness. Significantly more patients reported opioid-related adverse effects in the bupivacaine hydrochloride group (36%) compared to patients in the liposomal bupivacaine group (20%, p<0.0001). The authors concluded that liposomal bupivacaine can provide longer analgesia with less opioid consumption compared to bupivacaine hydrochloride. Of note, this analysis included 2 placebo-controlled studies and results of another pooled analysis. It is unknown whether exclusion of these studies would affect the results of this analysis.

Conclusion

The comparative data currently available for liposomal bupivacaine are limited to comparisons to bupivacaine hydrochloride, opioid PCA, continuous epidural, and ropivacaine. Majority of the studies remain relatively small with about 50 to 150 patients enrolled in each trial. Liposomal bupivacaine is showing trends for potential benefits in certain indications but these results are difficult to interpret and compare due to varying designs, interventions utilized, and measured primary and/or secondary outcomes among the trials. Larger, prospective, randomized trials comparing liposomal bupivacaine to bupivacaine hydrochloride and other analgesic regimens can help further define its role in postsurgical analgesia and whether its use translates to a reduction in opioid-related adverse effects, shorter length of stay, and reduced hospitalization costs.

References

1. Slevin KA, Ballantyne JC. Management of acute postoperative pain. In: Longnecker DE, Brown DL, Newman MF, Zapol WM. eds. Anesthesiology. 2nd ed. New York, NY: McGraw-Hill; 2012. http://accessanesthesiology.mhmedical.com/content.aspx?bookid=490&Sectionid=4011476. Accessed May 20, 2014.

2. Simopoulos TT. Preemptive analgesia. In: Warfield CA, Bajwa ZH. eds. Principles and Practice of Pain Medicine. 2nd ed. New York, NY: McGraw-Hill; 2004. http://accessanesthesiology.mhmedical.com/content.aspx?bookid=411&Sectionid=4042983. Accessed May 20, 2014.

3. Tsai T, Gadsden J, Connery C. Local infiltration anesthesia. In: Hadzic A. ed. NYSORA Textbook of Regional Anesthesia and Acute Pain Management. New York, NY: McGraw-Hill; 2007. http://accessanesthesiology.mhmedical.com/content.aspx?bookid=413&Sectionid=3982815. Accessed May 20, 2014.

4. Exparel [package insert]. San Diego, CA: Pacira Pharmaceuticals; October 2011.

5. Exparel. Drugs@FDA. US Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo. Accessed December 21, 2015.

6. Exparel [package insert]. San Diego, CA; Pacira Pharmaceuticals; December 2015.

7. Smoot JD, Bergese SD, Onel E, Williams HT, Hedden W. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty: a randomized, double-blind, active-control study. Aesthet Surg J. 2012;32(1):69-76.

8. Vogel JD. Liposome bupivacaine (EXPAREL(R)) for extended pain relief in patients undergoing ileostomy reversal at a single institution with a fast-track discharge protocol: an IMPROVE Phase IV health economics trial. J Pain Res. 2013;6:605-610.

9. Marcet JE, Nfonsam VN, Larach S. An extended paIn relief trial utilizing the infiltration of a long-acting Multivesicular liPosome foRmulation Of bupiVacaine, EXPAREL (IMPROVE): a Phase IV health economic trial in adult patients undergoing ileostomy reversal. J Pain Res. 2013;6:549-555.

10. Cohen SM. Extended pain relief trial utilizing infiltration of Exparel®, a long-acting multivesicular liposome formulation of bupivacaine: a Phase IV health economic trial in adult patients undergoing open colectomy. J Pain Res 2012;5:567-572.

11. Haas E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg. 2012;78(5):574-581.

12. Gasanova I, Alexander J, Ogunnaike B, et al. Transversus Abdominis Plane Block Versus Surgical Site Infiltration for Pain Management After Open Total Abdominal Hysterectomy. Anesth Analg. 2015;121(5):1383-1388.

13. Hutchins J, Delaney D, Vogel RI, et al. Ultrasound guided subcostal transversus abdominis plane (TAP) infiltration with liposomal bupivacaine for patients undergoing robotic assisted hysterectomy: A prospective randomized controlled study. Gynecol Oncol. 2015;138(3):609-613.

14. Collis PN, Hunter AM, Vaughn MD, Carreon LY, Huang J, Malkani AL. Periarticular injection after total knee arthroplasty using liposomal bupivacaine vs a modified Ranawat suspension: a prospective, randomized study. J Arthroplasty. 2015: doi: 10.1016/j.arth.2015.09.025.

15. Schroer WC, Diesfeld PG, LeMarr AR, Morton DJ, Reedy ME. Does extended-release liposomal bupivacaine better control pain than bupivacaine after total knee arthroplasty (TKA)? a prospective, randomized clinical trial. J Arthroplasty. 2015;30(9 Suppl):64-67.

16. Surdam JW, Licini DJ, Baynes NT, Arce BR. The use of exparel (liposomal bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients. J Arthroplasty. 2015;30(2):325-329.

17. Bagsby DT, Ireland PH, Meneghini RM. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J Arthroplasty. 2014;29(8):1687-1690.

18. Bramlett K, Onel E, Viscusi ER, Jones K. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee. 2012;19(5):530-536.

19. Knight RB, Walker PW, Keegan KA, et al. A randomized controlled rrial for pain control in laparoscopic urologic surgery: 0.25% bupivacaine versus long-acting liposomal bupivacaine. J Endourol. 2015;29(9):1019-1024.

20. Dasta J, Ramamoorthy S, Patou G, Sinatra R. Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting. Curr Med Res Opin. 2012;28(10):1609-1615.

Prepared by:
Vincent Soriano, PharmD
PGY1 Pharmacy Resident
College of Pharmacy
University of Illinois at Chicago

January 2016

The literature presented is current as of November 15, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Return to Top

Can estimated patient weight be safely used for dosing of alteplase for acute ischemic stroke?

Background

The treatment guideline for acute ischemic stroke from the American Heart Association/American Stroke Association recommends fibrinolytic therapy with alteplase for qualified patients, starting no more than 4.5 hours after stroke onset.¹ The recommended intravenous dose is 0.9 mg/kg (maximum of 90 mg) with 10% of the dose administered as a bolus over 1 minute and the remainder of the dose infused over 60 minutes.^1,2Dose-finding studies and the landmark National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study support the efficacy and safety of the 0.9 mg/kg dose.³

However, accurate dosing in clinical practice is limited by the availability of patient weight information. Stroke-related functional impairment may prevent patients from giving weight information to clinicians and family members may not be available or may not know the patient’s weight. It may not be possible to obtain an actual patient weight depending on the clinical circumstances, the availability of scales that are logistically feasible for the patient to use, or timing since stroke onset. Methods for estimating patient weight using anthropometric measurements have been proposed but obtaining anthropometric measurements may be just as impractical as obtaining patient weights.^4-6 Therefore, many clinicians rely on their own estimates of patient weight for alteplase dosing despite reports of inaccuracy with the practice of using estimated weights in acute care settings.^7,8

Use of inaccurate alteplase doses could have serious clinical implications. If estimated patient weight is too high, the patient may receive a dose >0.9 mg/kg and be at risk for bleeding complications including intracranial hemorrhage (ICH). If estimated patient weight is too low, the patient may receive a dose <0.9 mg/kg and potentially not experience the full therapeutic benefit of the medication. This article summarizes the available studies on the use of estimated weight for alteplase dosing in the setting of acute ischemic stroke, with the aim of assessing outcomes and patient safety when estimated weights are used.

Studies that support using estimated weight for alteplase dosing

Three studies support the use of estimated patient weights for dosing alteplase for acute ischemic stroke.^9-11 The largest study was a subanalysis of the NINDS rt-PA Stoke Study.¹⁰The actual weight, estimated weight, and alteplase dose were compared for 311 patients. Estimated weight was provided by the patient, family member, or a clinician. Patient weight was overestimated by ≥10% in 32 patients (10.4%) which resulted in overdose in 11 patients (3.6%). Patient weight was underestimated by ≥10% in 14 patients (4.5%) which resulted in underdose in 6 patients (2%). A multivariate logistic regression that compared the highest dose quintile (median dose 0.99 mg/kg) to the lower dose quintiles (median dose 0.9 mg/kg) did not reveal any association between dose and risk of ICH (p=0.31). There was no difference in the risk of ICH between patients who received an overdose and patients who did not. After adjusting for age, baseline National Institutes of Health Stroke Scale (NIHSS) score, and time to treatment, the likelihood of a good outcome (modified Rankin scale score of 0 or 1 at 90 days) did not differ among dose quintiles. The authors concluded that the use of estimated patient weight for dosing of alteplase is a reasonable practice and did not affect patient efficacy or safety.

Two additional retrospective studies describe the real-world effects of alteplase dosed on estimated patient weight. In a retrospective analysis of prospectively collected data from 3 stroke centers in the United States and the Czech Republic (n=272), alteplase dosing ranged from 0.59 to 1.17 mg/kg.¹¹ Weight estimates were reported by the patients or estimated by emergency physicians. Estimated weight discrepancies of >10% resulted overdose in 11% of patients and underdose in 9% of patients. Although parenchymal hemorrhage was numerically more prevalent in patients who received higher alteplase doses, there was no statistically significant difference in parenchymal hemorrhage between dose groups. There were also no significant differences in favorable outcome (modified Rankin scale score of 0 or 1 at 90 days). The authors concluded that dosing alteplase based on estimated patient weight is an acceptable practice. A single-center retrospective study evaluated the dosing accuracy of 26 patients who received alteplase for acute ischemic stroke based on estimated body weight, with estimated weights provided by nurses, physicians, family members, or patients.⁹The study used a dose error threshold of 10% and a dose cap of 90 mg for patients weighing >100 kg. Mean estimated and actual weights differed by 1.4 kg. Four patients had an estimated weight discrepancy of at least 5 kg; none of these weight discrepancies resulted in dose errors. Similarly, there were no dose errors among 11 patients with underestimated weights of <5 kg and 9 patients with overestimated weights of <5 kg. Two patients experienced an ICH; neither received an alteplase overdose. Despite the similarity between estimated and actual weights in this study and the lack of significant findings, the authors concluded that the use of actual patient weight is optimal for alteplase dosing.

Studies that do not support using estimated weight for alteplase dosing

A total of 5 studies suggest that the use of estimated patient weight may cause harm or decreased efficacy of alteplase.^12-16 The largest (and earliest) study was a post-hoc analysis of the Multicenter rt-PA Acute Stroke Survey, which was a retrospective review of 1205 patients from multiple stroke data sets.¹²The alteplase dose was compared to actual patient weight for 769 patients, then linear regression was used to correlate the dose to the risk of ICH or good outcome (modified Rankin score of 0 or 1). Overall, the mean dose was 0.89 ± 0.09 mg/kg; 59 patients received the maximum dose of alteplase due to weight >100 kg. Seven percent and 5% of patients received alteplase doses based on weight over- and underestimated by >10%, respectively. There was no association between dose and the achievement of a good outcome (p=0.57). There was no association between dose and the risk of ICH (p=0.57), which occurred in 11% of patients. Patients in the highest dose quintile (>0.919 mg/kg) had a numerically higher rate of ICH compared to the lower quintiles (15.8% vs. 11%). Although this was not statistically significant, the authors concluded that small drug overdoses due to overestimated patient weight could be harmful.

Two prospective studies were published in 2015 that attempt to provide real-world estimations of risk with use of alteplase dosed with estimated patient weight.^13-14 The first was a single-center, observational study of 242 patients with acute stroke in London.¹³Dosing weight was estimated for all patients by stroke specialist nurses and attending physicians at the time of presentation; actual weight was measured the next day. Estimated weights were significantly lower than actual weights by a mean of 1.13 kg (p<0.05). This resulted in 11.5% of patients receiving an underdose and 8.1% of patients receiving an overdose. Dosing errors had no effect on favorable outcome (modified Rankin scale between 0 and 1, p-value not given) or ICH rates (p=0.66). Exclusion of 17 patients who received a capped dose due to patient weight >100 kg did not change these results. Patients who received appropriate doses had greater improvements in NIHSS scores compared to those who received inappropriate doses. The authors concluded that weights of heavier patients tend to be underestimated and weights of lighter patients tend to be overestimated, which could lead to worse outcomes. Another single-center, observational study of 97 patients with acute stroke in Spain found that incorrect estimated weights were reported in 22.7% of patients, with overestimation of weight (by a mean of 2.182 kg) being more common than underestimation.¹⁴Healthcare providers were more likely to estimate patient weight incorrectly compared to family members or patients. The mean alteplase dose was 0.927 mg/kg, with 17.5% and 5.1% of patients receiving an overdose or underdose of ≥10%, respectively, after exclusion of patients who received a capped dose due to weights >100 kg. The mean alteplase dose was significantly higher in patients who had an ICH compared to patients who did not have an ICH (0.96 vs. 0.92, p=0.02). A univariate regression analysis found that for each 10% increase in alteplase dose above 0.9 mg/kg the odds ratio for ICH was 2.68 (95% confidence interval 1.12 to 6.42, p=0.026), and alteplase dose was the only independent risk factor for ICH in a multivariate regression analysis. Alteplase doses between patients with good/poor functional outcomes or death/survival were not significantly different. The authors concluded that overestimated weights are common and that alteplase doses higher than 0.9 mg/kg occurring from overestimated patient weight could increase the risk of ICH.

Another prospective, observational, single-center study (WAIST) of 109 patients with acute ischemic stroke in Germany compared outcomes between visually estimated weights, anthropometrically estimated weights, and actual weights.¹⁵ Patient weights were visually estimated independently by 2 physicians, 2 emergency nurses, and the neuroradiology technician. Anthropometrically estimated weights followed the method by Lorenz et al.⁴ The mean alteplase dose was 0.904 mg/kg. Using a 10% error threshold, body weights were overestimated and underestimated by 20.8% and 12.8% of physician teams, 11.3% and 9.4% of patients, 7.4% and 18.5% of relatives, and 17.9% and 2.1% of anthropometric estimates, respectively. After excluding patients who received a capped dose due to weight >100 kg, 17% of patients received an overdose and 12% of patients received an underdose. Fewer patients who received an underdose experienced favorable and independent outcomes (modified Rankin Scale 0 to 2), and underdose was an independent predictor of dependency or death (modified Rankin Scale 3 to 6) in a multivariate regression analysis (odds ratio 5.87, 95% confidence interval 1.26 to 27.34, p=0.024). Only 10 patients experienced an ICH (8 correct dose, 1 underdose, 1 overdose), so no trends between ICH and dose could be determined. The authors concluded that dosing errors are common and underdosing of alteplase may adversely affect patient outcomes.

Lastly, a retrospective, observational, single-center study of 140 patients with acute ischemic stroke in Canada found that 6.1% of patients received an alteplase underdose (≤0.8 mg/kg) and 9.8% received an alteplase overdose (≥1.0 mg/kg).¹⁶Patients who received an overdose had a lower likelihood of good functional outcome (modified Rankin scale score of 0 to 2 at discharge, 34% vs. 0%, p=0.009) and numerically higher mortality (15% vs. 6%) compared to patients who did not receive an overdose. Patients who were not weighed had a significantly increased mortality compared to patients who were weighed (21% vs. 7%, p=0.019); it is unknown whether incorrect alteplase doses affected mortality in these patients. Overall, 17.9% of patients experienced a hemorrhagic transformation of their ischemic stroke; there was a nonsignificantly higher rate of transformation in patients who received an overdose (n=4, 31%) compared to patients who received lower doses (n=21, 16.3%, p=0.16). The authors concluded that alteplase overdoses were associated with worse functional outcomes compared to correct doses.

Conclusion

Overall, the available studies have not clearly demonstrated whether estimated patient weights can be safely used to determine alteplase doses for acute ischemic stroke. The largest study that assessed alteplase doses based on estimated weight found no association between incorrect doses and good outcomes.¹² There was a trend toward increased rates of ICH with higher doses in this study but this finding was not significant. The 3 studies that did not find significant differences in patient outcomes with the use of alteplase dosed on estimated patient weight were limited by their retrospective nature and small sample sizes.^9-11 None of these studies were powered to detect a difference in dosing groups based on patient weight so the possibility of efficacy or safety differences cannot be ruled out.

Prospective observational studies suggest that patients who receive inappropriate alteplase doses may have less improvement in NIHSS scores and worse functional outcomes.^13,15In addition, a retrospective study found significantly decreased functional outcomes, numerically higher mortality, and numerically higher rates of hemorrhagic transformation in patients who received an overdose.¹⁶Only 1 prospective study has observed a significantly increased risk of ICH with alteplase overdose.¹⁴

Despite the lack of consensus in the literature, the prospective findings of worse functional outcomes with inappropriate alteplase doses and increased ICH with alteplase overdoses should prompt clinicians to pursue strategies for quickly and accurately measuring actual weights of patients with acute ischemic stroke. Although accurate dosing was very common in all studies, both overdose and underdose occurred. Clinicians should be aware that most studies in this population/setting reported higher rates of weight overestimation and subsequent overdose. Therefore, conservative estimation of patient weight and conservative alteplase dosing may be more appropriate than more aggressive strategies.

References

Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
Activase [package insert]. Genentech, Inc: South San Francisco, CA; 2015.
Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-1587.
Lorenz MW, Graf M, Henke C, et al. Anthropometric approximation of body weight in unresponsive stroke patients. J Neurol Neurosurg Psychiatry. 2007;78(12):1331-1336.
Lin BW, Yoshida D, Quinn J, Strehlow M. A better way to estimate adult patients' weights. Am J Emerg Med. 2009;27(9):1060-1064.
Buckley RG, Stehman CR, Dos Santos FL, et al. Bedside method to estimate actual body weight in the emergency department. J Emerg Med. 2012;42(1):100-104.
Kahn CA, Oman JA, Rudkin SE, Anderson CL, Sultani D. Can ED staff accurately estimate the weight of adult patients? Am J Emerg Med. 2007;25(3):307-312.
Determann RM, Wolthuis EK, Spronk PE, et al. Reliability of height and weight estimates in patients acutely admitted to intensive care units. Crit Care Nurse. 2007;27(5):48-55.
Graves A, VerHage A, Richlik B, Makic MB. Estimated versus actual weight when dosing rt-PA in acute ischemic stroke: is there a difference? J Neurosci Nurs. 2013 Aug;45(4):180-5.
Messé SR, Kasner SE, Cucchiara BL, et al; NINDS t-PA Stroke Study Group. Dosing errors did not have a major impact on outcome in the NINDS t-PA stroke study. J Stroke Cerebrovasc Dis. 2011;20(3):236-240.
Aulicky P, Rabinstein A, Seet RC, Neumann J, Mikulik R. Dosing of tissue plasminogen activator often differs from 0.9 mg/kg, but does not affect the outcome. J Stroke Cerebrovasc Dis. 2013;22(8):1293-1297.
Messé SR, Tanne D, Demchuk AM, Cucchiara BL, Levine SR, Kasner SE; Multicenter rt-PA Stroke Survey Group. Dosing errors may impact the risk of rt-PA for stroke: the Multicenter rt-PA Acute Stroke Survey. J Stroke Cerebrovasc Dis. 2004;13(1):35-40.
Barrow T, Khan MS, Halse O, Bentley P, Sharma P. Estimating weight of patients with acute stroke when dosing for thrombolysis. Stroke. 2015 Nov 10. pii: STROKEAHA.115.011436. [Epub ahead of print]
García-Pastor A, Díaz-Otero F, Funes-Molina C, et al. Tissue plasminogen activator for acute ischemic stroke: calculation of dose based on estimated patient weight can increase the risk of cerebral bleeding. J Thromb Thrombolysis. 2015;40(3):347-352.
Breuer L, Nowe T, Huttner HB, et al. Weight approximation in stroke before thrombolysis: the WAIST-Study: a prospective observational "dose-finding" study. Stroke. 2010;41(12):2867-2871.
Sahlas DJ, Gould L, Swartz RH, et al. Tissue plasminogen activator overdose in acute ischemic stroke patients linked to poorer functional outcomes. J Stroke Cerebrovasc Dis. 2014;23(1):155-159.

January 2016

The information presented is current as of December 9, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Return to Top

What are the key features of the new rheumatoid arthritis guidelines?

What are the key features of the new rheumatoid arthritis guidelines?

Introduction

Rheumatoid arthritis is the most common form of chronic inflammatory arthritis and affects an estimated 0.5% to 1% of adults globally.¹ The etiology of rheumatoid arthritis is unknown; however, genetics and environmental factors, such as cigarette smoking and potentially certain viral infections, may play a role in its development and progression. Diagnosis of rheumatoid arthritis is primarily based on signs and symptoms. Patients with the disease will often present with increased nonspecific inflammatory markers (i.e., erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)). The presence of rheumatoid factor (RF) and cyclic citrullinated peptides (CCP) aids clinicians in differentiating rheumatoid arthritis form other polyarticular diseases. Other options in the diagnostic toolbox include synovial fluid analysis revealing an elevated white blood cell count and joint imaging including x-rays, magnetic resonance imaging (MRI), and ultrasound techniques. The clinical course of patients with rheumatoid arthritis is difficult to predict; however, the majority of patients will experience persistent, progressive disease activity that waxes and wanes in intensity over time. Rheumatoid arthritis can eventually result in irreversible joint damage and physical disability. Patients with rheumatoid arthritis have an overall mortality rate that is 2 times greater than the general population. Ischemic heart disease is the most common cause of death for patients with rheumatoid arthritis followed by infection.

In November 2015, the American College of Rheumatology (ACR) released a new guideline for the treatment of rheumatoid arthritis.² The guideline was last updated in 2012.³ This frequently asked question focuses on the key features of the new guideline with an emphasis on pharmacologic management options.

Key Features

The new guideline summarizes treatment recommendations for patients with early rheumatoid arthritis (duration < 6 months) versus those with established disease.² Table 1 provides an overview of recommendations for those patients with early rheumatoid arthritis. Recommendations for patients with established disease are presented in Table 2.

Table 1. Treatment recommendations for patients with early rheumatoid arthritis.²

Recommendation

Level of evidence*

A treat-to-target approach (i.e., obtaining sustained remission or sustained low disease activity) should be utilized for these patients

Low quality evidence

Strong recommendation from the Guideline Panel

If disease activity is low, in patients who have never taken a DMARD:

Use DMARD monotherapy (with methotrexate as the preferred agent) over double or triple therapy

Low quality evidence

Strong recommendation from the Guideline Panel

If disease activity is moderate or high, in patients who have never taken a DMARD:

Use DMARD monotherapy over double or triple therapy

Moderate quality evidence for monotherapy over double therapy

High quality evidence for monotherapy over triple therapy

Conditional recommendation from the Guideline Panel

If disease activity remains moderate or high despite DMARD monotherapy (with or without glucocorticoids), use combination DMARDs or a TNF inhibitor or a non-TNF biologic (all choices with or without methotrexate, in no particular order of preference), versus continuing DMARD monotherapy alone

Low quality evidence

Strong recommendation from the Guideline Panel

If disease activity remains moderate or high despite DMARDs:

Use a TNF inhibitor monotherapy over tofacitinib monotherapy
Use a TNF inhibitor + methotrexate over tofacitinib + methotrexate

Low quality evidence for both recommendations

Conditional recommendation from the Guideline Panel

If disease activity remains moderate or high despite DMARD or biologic therapies, add low-dose glucocorticoids

Moderate quality evidence for DMARD

Low quality evidence for biologic therapies

Conditional recommendation from the Guideline Panel

If disease flares, add short-term glucocorticoids at the lowest possible dose and for the shortest possible duration

Very low quality evidence

Conditional recommendation from the Guideline Panel

Abbreviations: DMARD(s)=disease-modifying antirheumatic drug(s); TNF=tumor necrosis factor.

Strong recommendations = panel is confident that the desirable effects of following the recommendation outweigh the undesirable effects (or vice versa); the course of action would apply to most patients.

Conditional recommendations = desirable effects of following the recommendation probably outweigh the undesirable effects; the course of action would apply to the majority of patients, but some may not want to follow the recommendation.

Table 2. Treatment recommendations for patients with established rheumatoid arthritis.²

Recommendation

Level of evidence*

A treat-to-target approach (i.e., obtaining sustained remission or sustained low disease activity) should be utilized for these patients

Moderate quality evidence

Strong recommendation from the Guideline Panel

If disease activity is low, in patients who have never taken a DMARD:

Use DMARD monotherapy (with methotrexate as the preferred agent) over a TNF inhibitor

Low quality evidence

Strong recommendation from the Guideline Panel

If disease activity is moderate or high, in patients who have never taken a DMARD:

Use DMARD monotherapy over tofacitinib or combination DMARD therapy

High quality evidence for DMARD over tofacitinib

Moderate quality evidence for DMARD monotherapy over combination therapy

Conditional recommendation from the Guideline Panel

If disease activity remains moderate or high despite DMARD monotherapy, use combination traditional DMARDs or add a TNF inhibitor or a non-TNF biologic or tofacitinib (all choices with or without methotrexate, in no particular order of preference), versus continuing DMARD monotherapy alone

Moderate to very low quality evidence

Strong recommendation from the Guideline Panel

If disease activity remains moderate or high despite TNF inhibitor therapy in patients who are currently not on DMARDs, add one or two DMARDs to TNF inhibitor therapy versus continuing TNF inhibitor therapy alone

High quality evidence

Strong recommendation from the Guideline Panel

If disease activity remains moderate or high despite use of a single TNF inhibitor:

Use a non-TNF biologic, with or without methotrexate, over another TNF inhibitor with or without methotrexate
Use a non-TNF biologic, with or without methotrexate, over tofacitinib with or without methotrexate

Low to very low quality evidence for a non-TNF biologic, with or without methotrexate, over another TNF inhibitor

Very low quality evidence for a non-TNF biologic, with or without methotrexate, over tofacitinib

Conditional recommendation from the Guideline Panel

If disease activity remains moderate or high despite use of a single non-TNF biologic, use another non-TNF biologic, with or without methotrexate, over tofacitinib, with or without methotrexate

Very low quality evidence

Conditional recommendation from the Guideline Panel

If disease activity remains moderate or high despite use of multiple (2+) sequential TNF inhibitor therapies, first use a non-TNF biologic, with or without methotrexate, over another TNF inhibitor or tofacitinib (with or without methotrexate)

Very low quality evidence

Conditional recommendation from the Guideline Panel

If disease activity still remains moderate or high despite the use of multiple TNF inhibitor therapies, use tofacitinib, with or without methotrexate, over another TNF inhibitor, with or without methotrexate, if use of a non-TNF biologic is not an option

Low quality evidence

Conditional recommendation from the Guideline Panel

If disease activity remains moderate or high despite use of at least one TNF inhibitor and at least one non-TNF-biologic:

First use another non-TNF biologic, with or without methotrexate, over tofacitinib
If disease activity remains moderate or high, use tofacitinib, with or without methotrexate, over another TNF inhibitor

Very low quality evidence for both recommendations

Conditional recommendation from the Guideline Panel

If disease activity remains moderate or high despite use of DMARD, TNF inhibitor, or non-TNF biologic therapy, add short-term, low dose glucocorticoids

High to moderate quality evidence

Conditional recommendation from the Guideline Panel

If disease flares in patients on DMARD, TNF inhibitor, or non-TNF biologic therapy, add short-term glucocorticoids at the lowest possible dose and the shortest possible duration

Very low quality evidence

Conditional recommendation from the Guideline Panel

If the patient is in remission:

Taper DMARD therapy
Taper TNF inhibitor, non-TNF biologic, or tofacitinib

Low quality evidence for tapering DMARD therapy

Moderate to very low quality evidence for tapering other therapies

Conditional recommendation from the Guideline Panel

If disease activity is low:

Continue DMARD therapy
Continue TNF inhibitor, non-TNF biologic, or tofacitinib rather than discontinuing respective medication

Moderate quality evidence for continuing DMARD therapy

High to very low quality evidence for continuing other therapies

Strong recommendation from the Guideline Panel

If the patient’s disease is in remission, do not discontinue all therapies for rheumatoid arthritis

Very low quality evidence

Strong recommendation from the Guideline Panel

Abbreviations: DMARD(s)=disease-modifying antirheumatic drug(s); TNF=tumor necrosis factor.

Beyond these pharmacologic-focused recommendations, the new guideline provides recommendations for laboratory monitoring, tuberculosis (TB) screening, patients with high-risk comorbidities (such as heart failure, hepatitis B, hepatitis C, and malignancy), and the use of vaccines.²

Summary

Rheumatoid arthritis is a chronic, debilitating disease for many individuals that significantly affects quality of life and the ability to complete activities of daily living. The new ACR guideline on the treatment of rheumatoid arthritis offers clinicians multiple therapeutic recommendations for both patients with early and established disease based on a review of published evidence and recommendations from a guideline panel. Implementation of these recommendations in clinical practice may result in favorable efficacy and safety results for most patients with rheumatoid disease.

References

1. Shah A, St. Clair EW. Rheumatoid arthritis. In: Kasper DL, Fauci AS, Hauser S, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com/content.aspx?sectionid=79750035&bookid=1130&Resultclick=2&q=rheumatoid+arthritis. Accessed December 19, 2015.

2. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2015 Nov 6. doi: 10.1002/art.39480. [Epub ahead of print].

3. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5):625-639.

January 2016

The information presented is current as of December 18, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Return to Top

Drug Information Group

Retzky College of Pharmacy - Chicago | Rockford

January 2016 FAQs