Take-Home Points

• IV-TXA significantly reduces intraoperative blood loss following TJA.
• Early mobilization correlates with reduced incidence of postoperative complications.
• IV-TXA minimizes postoperative anemia, facilitating improved early ambulation following TJA.
• IV-TXA significantly reduces the need for postoperative transfusions.
• IV-TXA is safe to use with no adverse events noted.

By the year 2020, use of primary total knee arthroplasty (TKA) in the United States will increase an estimated 110%, to 1.375 million procedures annually, and use of primary total hip arthroplasty (THA) will increase an estimated 75%, to more than 500,000 procedures.¹ Minimizing perioperative blood loss and improving early postoperative ambulation both correlate with reduced postoperative morbidity, allowing patients to return to their daily lives expeditiously. 

Tranexamic acid (TXA), a fibrinolytic inhibitor, competitively blocks lysine receptor binding sites of plasminogen, sustaining and stabilizing the fibrin architecture.² TXA must be present to occupy binding sites before plasminogen binds to fibrin, validating the need for preoperative administration so the drug is available early in the fibrinolytic cascade.³ Intravenous (IV) TXA diffuses rapidly into joint fluid and the synovial membrane.⁴ Drug concentration and elimination half-life in joint fluid are equivalent to those in serum. Elimination of TXA occurs by glomerular filtration, with about 30% of a 10-mg/kg dose removed in 1 hour, 55% over the first 3 hours, and 90% within 24 hours of IV administration.⁵

The efficacy of IV-TXA in minimizing total joint arthroplasty (TJA) perioperative blood loss has been proved in small studies and meta-analyses.^6-9 TXA-induced blood conservation decreases or eliminates the need for postoperative transfusion, which can impede valuable, early ambulation.10 In addition, the positive clinical safety profile of TXA supports routine use of TXA in TJA.^6,11-15

The benefits of early ambulation after TJA are well established. Getting patients to walk on the day of surgery is a key part of effective and rapid postoperative rehabilitation. Early mobilization correlates with reduced incidence of venous thrombosis and postoperative complications.¹⁶ In contrast to bed rest, sitting and standing promotes oxygen saturation, which improves tissue healing and minimizes adverse pulmonary events. Oxygen saturation also preserves muscle strength and blood flow, reducing the risk of venous thromboembolism and ulcers. Muscle strength must be maintained so normal gait can be regained.¹⁷ Compared with rehabilitation initiated 48 to 72 hours after TKA, rehabilitation initiated within 24 hours reduced the number of sessions needed to achieve independence and normal gait; in addition, early mobilization improved patient reports of pain after surgery.¹⁸ An evaluation of Denmark registry data revealed that mobilization to walking and use of crutches or canes was achieved earlier when ambulation was initiated on day of surgery.¹⁹ Finally, mobilization on day of surgery and during the immediate postoperative period improved long-term quality of life after TJA.²⁰

We conducted a retrospective cohort study to determine if use of IV-TXA improves early ambulation and reduces blood loss after TKA and anterior and posterior THA. We hypothesized that IV-TXA use would reduce postoperative anemia and improve early ambulation and outcomes without producing adverse events during the immediate postoperative period. TXA reduces bleeding, and reduced incidence of hemarthrosis, wound swelling, and anemia could facilitate ambulation, reduce complications, and shorten recovery in patients who undergo TJA.

Patients and Methods

In February 2014, this retrospective cohort study received Institutional Review Board approval to compare the safety and efficacy of IV-TXA (vs no TXA) in patients who underwent TKA, anterior THA, and posterior THA.

In March 2012, multidisciplinary protocols were standardized to ensure a uniform hospital course for patients at our institution. All patients underwent preoperative testing and evaluation by a nurse practitioner and an anesthesiologist. In March 2013, IV-TXA became our standard of care. TXA use was contraindicated in patients with thromboembolic disease or with hypersensitivity to TXA. Patients without a contraindication were given two 10-mg/kg IV-TXA doses, each administered over 15 to 30 minutes; the first dose was administered before incision, and the second was infused at case close and/or at least 60 minutes after the first dose. Most TKA patients received regional (femoral) anesthesia and analgesia, and most THA patients received spinal or epidural anesthesia and analgesia. In a small percentage of cases, IV analgesia was patient-controlled, as determined by the pain service. There were no significant differences in anesthesia/analgesia modality between the 2 study groups—patients who received TXA and those who did not. Patients were then transitioned to oral opioids for pain management, unless otherwise contraindicated, and were ambulated 4 hours after end of surgery, unless medically unstable. Hematology and chemistry laboratory values were monitored daily during admission.

Patients underwent physical therapy (PT) after surgery and until hospital discharge. Physical therapists blinded to patients’ intraoperative use or no use of TXA measured ambulation. After initial evaluation on postoperative day 0 (POD-0), patients were ambulated twice daily. The daily ambulation distance used for the study was the larger of the 2 daily PT distances (occasionally, patients were unable to participate fully in both sessions). Patients received either enoxaparin or rivaroxaban for postoperative thromboprophylaxis (the anticoagulant used was based on surgeon preference). Enoxaparin was subcutaneously administered at 30 mg every 12 hours for TKA, 40 mg once daily for THA, 30 mg once daily for calculated creatinine clearance under 30 mL/min, or 40 mg every 12 hours for body mass index (BMI) 40 or above. With enoxaparin, therapy duration was 14 days. Oral rivaroxaban was administered at 10 mg once daily for 12 days for TKA and 35 days for THA unless contraindicated.

The primary outcome variables were ambulation measured on POD-1 and POD-2 and intraoperative blood loss. In addition, hemoglobin and hematocrit were measured on POD-0, POD-1, and POD-2. Ambulation was defined as number of feet walked during postoperative hospitalization. To calculate intraoperative blood loss, the anesthesiologist subtracted any saline irrigation volume from the total volume in the suction canister. Also noted were postoperative transfusions and any diagnosis of postoperative venous thromboembolism—specifically, deep vein thrombosis (DVT) or pulmonary embolism (PE).

Demographic and clinical characteristics of the TXA and no-TXA groups were compared using either 2-sample t test (for continuous variables) or χ2 test (for categorical variables).

The ambulation outcome was log-transformed to meet standard assumptions of Gaussian residuals and equality of variance. Means and 95% confidence intervals (CIs) were calculated on the log scale and were anti-logged so the results could be presented in their original units. 

A linear mixed model was used to model intraoperative blood loss as a function of group (TXA, no TXA), procedure (TKA, anterior THA, posterior THA), and potential confounders (age, sex, BMI, operative time).

Linear mixed models for repeated measures were used to compare outcomes (hemoglobin, hematocrit) between groups (TXA, no TXA) and procedures (TKA, anterior THA, posterior THA) and to compare changes in outcomes over time. Group, procedure, and operative time interactions were explored. Potential confounders (age, sex, BMI, operative time) were included in the model as well.

A χ2 test was used to compare the groups (TXA, no TXA) on postoperative blood transfusion (yes, no). Given the smaller number of events, a more complex model accounting for clustered data and potential confounders was not used. Need for transfusion was clinically assessed case by case. Symptomatic anemia (dyspnea on exertion, headaches, tachycardia) was used as the primary indication for transfusion once hemoglobin fell below 8 g/dL or hematocrit below 24%. Number of patients with a postoperative thrombus formation was minimal. Therefore, this outcome was described with summary statistics and was not formally analyzed.

Results

Of the 477 patients who underwent TJAs (275 TKAs, 98 anterior THAs, 104 posterior THAs; all unilateral), 111 did not receive TXA (June 2012-February 2013), and 366 received TXA (March 2013-January 2014). Other than for the addition of IV-TXA, the same standardized protocols instituted in March 2012 continued throughout the study period. The difference in sample size between the TXA and no-TXA groups was not statistically significant and did not influence the outcome measures.

Ambulation

There was a significant (P = .0066) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P < .0001), sex (P < .0001), BMI (P < .0001), and operative time (P = .8308). Regarding TKA, mean ambulation was higher for the TXA group than for the no-TXA group at POD-1 (8.36 vs 3.40 feet; P < .0001) and POD-2 (25.81 vs 18.75 feet; P = .0054). The same was true for anterior THA at POD-1 (10.86 vs 3.33 feet; P < .0001) and POD-2 (27.24 vs 13.19 feet; P < .0001) and posterior THA at POD-1 (10.64 vs 3.37 feet; P < .0001) and POD-2 (24.68 vs 12.93 feet; P = .0002). See Table 3.

Intraoperative Blood Loss

There was a significant 3-way interaction of TXA, procedure (P < .0053), and operative time (P < .0001) after adjusting for age (P < .6136), sex (P = .1147), and BMI (P = .6180). Regarding TKA, mean intraoperative blood loss was significantly lower for the TXA group than for the no-TXA group (241.58 vs 287.81 mL; P = .0004). The same was true for anterior THA (352.91 vs 533.79 mL; P < .0001). Regarding posterior THA, there was no significant difference between the TXA and no-TXA groups (326.00 vs 350.16 mL; P = .3246). See Table 4. 

Hemoglobin

There was a significant (P = .0008) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P = .0174), sex (P < .0001), BMI (P = .0007), and operative time (P = .0002). Regarding TKA, postoperative hemoglobin levels were higher for the TXA group than for the no-TXA group at POD-0 (12.10 vs 11.68 g/dL; P = .0135), POD-1 (11.62 vs 10.67 g/dL; P < .0001), and POD-2 (11.02 vs 10.11 g/dL; P < .0001). The same was true for anterior THA at POD-1 (11.03 vs 10.19 g/dL; P = .0034) and POD-2 (10.57 vs 9.64 g/dL; P = .0009) and posterior THA at POD-2 (11.04 vs 10.16 g/dL; P = .0003). See Table 5.

Hematocrit

There was a significant (P < .0006) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P = .1597), sex (P < .0001), BMI (P < .0001), and operative time (P = .0003). Regarding TKA, postoperative hematocrit levels were higher for the TXA group than for the no-TXA group at POD-0 (36.52% vs 34.65%; P < .0001), POD-1 (34.62% vs 31.83%; P < .0001), and POD-2 (33.01% vs 30.20%; P < .0001). The same was true for anterior THA at POD-1 (32.82% vs 30.59%; P = .0037) and POD-2 (31.58% vs 28.61%; P = .0004) and posterior THA at POD-2 (32.93% vs 30.17%; P < .0001). See Table 6.

Postoperative Transfusions 

Of the 477 patients, 25 (5.24%) required a postoperative transfusion. Postoperative transfusions were less likely (P < .0001) required in the TXA group (1.64%, 6/366) than in the no-TXA group (17.12%, 19/111). Given the smaller number of events, a more complex model accounting for clustered data and potential confounders was not used, and the different procedures were not evaluated separately.

Deep Vein Thrombosis and Pulmonary Embolism

Of the 477 patients, 2 developed a DVT, and 5 developed a PE. Both DVTs occurred in the TXA group (2/366, 0.55%; 95% CI, 0.07%-1.96%). Of the 5 PEs, 4 occurred in the TXA group (4/366, 1.09%; 95% CI, 0.30%-2.77%), and 1 occurred in the no-TXA group (1/111, 0.90%; 95% CI, 0.02%-4.92%). Given the exceedingly small number of events, no statistical significance was noted between groups.

Discussion

Orthopedic surgeons carefully balance patient expectations, societal needs, and regulatory mandates while providing excellent care and working under payers’ financial restrictions. The Centers for Medicare & Medicaid Services announced that, starting in 2016, TJAs will be reimbursed in total as a single bundled payment, adding to the need to provide optimal care in a fiscally responsible manner.²¹ Standardized protocols implementing multimodal therapies are pivotal in achieving favorable postoperative outcomes.

Our study results showed that IV-TXA use minimized hemoglobin and hematocrit reductions after TKA, anterior THA, and posterior THA. Postoperative anemia correlates with decreased ambulation ability and performance during the early postoperative period. In general, higher postoperative hemoglobin and hematocrit levels result in improved motor performance and shorter recovery.²² In addition, early ambulation is a validated predictor of favorable TJA outcomes. In our study, for TKA, anterior THA, and posterior THA, ambulation on POD-1 and POD-2 was significantly better for patients who received TXA than for patients who did not.

Transfusion rates were markedly lower for our TXA group than for our no-TXA group (1.64% vs 17.12%), confirming the findings of numerous other studies on outcomes of TJA with TXA.^{2,3,6-12,14,15} Transfusions impede physical therapy and affect hospitalization costs.

Although potential thrombosis-related adverse events remain an endpoint in studies involving TXA, we found a comparably low incidence of postoperative venous thrombosis in our TXA and no-TXA groups (1.09% and 0.90%, respectively). In addition, no patient in either group developed a postoperative arterial thrombosis.

This is the largest single-center study of TXA use in TKA, anterior THA, and posterior THA. The effect of TXA use on postoperative ambulation was not previously found with TJA.

This study had its limitations. First, it was not prospective, randomized, or double-blinded. However, the physical therapists who mobilized patients and recorded ambulation data were blinded to the study and its hypothesis and followed a standardized protocol for all patients. In addition, intraoperative blood loss was recorded by an anesthesiologist using a standardized protocol, and patients received TXA per orthopedic protocol and surgeon preference, without selection bias. Another limitation was that ambulation data were captured only for POD-1 and POD-2 (most patients were discharged by POD-3). However, a goal of the study was to capture immediate postoperative data in order to determine the efficacy of intraoperative TXA. Subsequent studies can determine if this early benefit leads to long-term clinical outcome improvements.

In reducing blood loss and transfusion rates, intra-articular TXA is as efficacious as IV-TXA.^23-25 We anticipate that the improved clinical outcomes found with IV-TXA in our study will be similar with intra-articular TXA, but more study is needed to confirm this hypothesis.

Conclusion

This retrospective cohort study found that use of IV-TXA in TJA improved early ambulation and clinical outcomes (reduced anemia, fewer transfusions) in the initial postoperative period, without producing adverse events.

Take-Home Points

• IV-TXA significantly reduces intraoperative blood loss following TJA.
• Early mobilization correlates with reduced incidence of postoperative complications.
• IV-TXA minimizes postoperative anemia, facilitating improved early ambulation following TJA.
• IV-TXA significantly reduces the need for postoperative transfusions.
• IV-TXA is safe to use with no adverse events noted.

By the year 2020, use of primary total knee arthroplasty (TKA) in the United States will increase an estimated 110%, to 1.375 million procedures annually, and use of primary total hip arthroplasty (THA) will increase an estimated 75%, to more than 500,000 procedures.¹ Minimizing perioperative blood loss and improving early postoperative ambulation both correlate with reduced postoperative morbidity, allowing patients to return to their daily lives expeditiously. 

Tranexamic acid (TXA), a fibrinolytic inhibitor, competitively blocks lysine receptor binding sites of plasminogen, sustaining and stabilizing the fibrin architecture.² TXA must be present to occupy binding sites before plasminogen binds to fibrin, validating the need for preoperative administration so the drug is available early in the fibrinolytic cascade.³ Intravenous (IV) TXA diffuses rapidly into joint fluid and the synovial membrane.⁴ Drug concentration and elimination half-life in joint fluid are equivalent to those in serum. Elimination of TXA occurs by glomerular filtration, with about 30% of a 10-mg/kg dose removed in 1 hour, 55% over the first 3 hours, and 90% within 24 hours of IV administration.⁵

The efficacy of IV-TXA in minimizing total joint arthroplasty (TJA) perioperative blood loss has been proved in small studies and meta-analyses.^6-9 TXA-induced blood conservation decreases or eliminates the need for postoperative transfusion, which can impede valuable, early ambulation.10 In addition, the positive clinical safety profile of TXA supports routine use of TXA in TJA.^6,11-15

The benefits of early ambulation after TJA are well established. Getting patients to walk on the day of surgery is a key part of effective and rapid postoperative rehabilitation. Early mobilization correlates with reduced incidence of venous thrombosis and postoperative complications.¹⁶ In contrast to bed rest, sitting and standing promotes oxygen saturation, which improves tissue healing and minimizes adverse pulmonary events. Oxygen saturation also preserves muscle strength and blood flow, reducing the risk of venous thromboembolism and ulcers. Muscle strength must be maintained so normal gait can be regained.¹⁷ Compared with rehabilitation initiated 48 to 72 hours after TKA, rehabilitation initiated within 24 hours reduced the number of sessions needed to achieve independence and normal gait; in addition, early mobilization improved patient reports of pain after surgery.¹⁸ An evaluation of Denmark registry data revealed that mobilization to walking and use of crutches or canes was achieved earlier when ambulation was initiated on day of surgery.¹⁹ Finally, mobilization on day of surgery and during the immediate postoperative period improved long-term quality of life after TJA.²⁰

We conducted a retrospective cohort study to determine if use of IV-TXA improves early ambulation and reduces blood loss after TKA and anterior and posterior THA. We hypothesized that IV-TXA use would reduce postoperative anemia and improve early ambulation and outcomes without producing adverse events during the immediate postoperative period. TXA reduces bleeding, and reduced incidence of hemarthrosis, wound swelling, and anemia could facilitate ambulation, reduce complications, and shorten recovery in patients who undergo TJA.

Patients and Methods

In February 2014, this retrospective cohort study received Institutional Review Board approval to compare the safety and efficacy of IV-TXA (vs no TXA) in patients who underwent TKA, anterior THA, and posterior THA.

In March 2012, multidisciplinary protocols were standardized to ensure a uniform hospital course for patients at our institution. All patients underwent preoperative testing and evaluation by a nurse practitioner and an anesthesiologist. In March 2013, IV-TXA became our standard of care. TXA use was contraindicated in patients with thromboembolic disease or with hypersensitivity to TXA. Patients without a contraindication were given two 10-mg/kg IV-TXA doses, each administered over 15 to 30 minutes; the first dose was administered before incision, and the second was infused at case close and/or at least 60 minutes after the first dose. Most TKA patients received regional (femoral) anesthesia and analgesia, and most THA patients received spinal or epidural anesthesia and analgesia. In a small percentage of cases, IV analgesia was patient-controlled, as determined by the pain service. There were no significant differences in anesthesia/analgesia modality between the 2 study groups—patients who received TXA and those who did not. Patients were then transitioned to oral opioids for pain management, unless otherwise contraindicated, and were ambulated 4 hours after end of surgery, unless medically unstable. Hematology and chemistry laboratory values were monitored daily during admission.

Patients underwent physical therapy (PT) after surgery and until hospital discharge. Physical therapists blinded to patients’ intraoperative use or no use of TXA measured ambulation. After initial evaluation on postoperative day 0 (POD-0), patients were ambulated twice daily. The daily ambulation distance used for the study was the larger of the 2 daily PT distances (occasionally, patients were unable to participate fully in both sessions). Patients received either enoxaparin or rivaroxaban for postoperative thromboprophylaxis (the anticoagulant used was based on surgeon preference). Enoxaparin was subcutaneously administered at 30 mg every 12 hours for TKA, 40 mg once daily for THA, 30 mg once daily for calculated creatinine clearance under 30 mL/min, or 40 mg every 12 hours for body mass index (BMI) 40 or above. With enoxaparin, therapy duration was 14 days. Oral rivaroxaban was administered at 10 mg once daily for 12 days for TKA and 35 days for THA unless contraindicated.

The primary outcome variables were ambulation measured on POD-1 and POD-2 and intraoperative blood loss. In addition, hemoglobin and hematocrit were measured on POD-0, POD-1, and POD-2. Ambulation was defined as number of feet walked during postoperative hospitalization. To calculate intraoperative blood loss, the anesthesiologist subtracted any saline irrigation volume from the total volume in the suction canister. Also noted were postoperative transfusions and any diagnosis of postoperative venous thromboembolism—specifically, deep vein thrombosis (DVT) or pulmonary embolism (PE).

Demographic and clinical characteristics of the TXA and no-TXA groups were compared using either 2-sample t test (for continuous variables) or χ2 test (for categorical variables).

The ambulation outcome was log-transformed to meet standard assumptions of Gaussian residuals and equality of variance. Means and 95% confidence intervals (CIs) were calculated on the log scale and were anti-logged so the results could be presented in their original units. 

A linear mixed model was used to model intraoperative blood loss as a function of group (TXA, no TXA), procedure (TKA, anterior THA, posterior THA), and potential confounders (age, sex, BMI, operative time).

Linear mixed models for repeated measures were used to compare outcomes (hemoglobin, hematocrit) between groups (TXA, no TXA) and procedures (TKA, anterior THA, posterior THA) and to compare changes in outcomes over time. Group, procedure, and operative time interactions were explored. Potential confounders (age, sex, BMI, operative time) were included in the model as well.

A χ2 test was used to compare the groups (TXA, no TXA) on postoperative blood transfusion (yes, no). Given the smaller number of events, a more complex model accounting for clustered data and potential confounders was not used. Need for transfusion was clinically assessed case by case. Symptomatic anemia (dyspnea on exertion, headaches, tachycardia) was used as the primary indication for transfusion once hemoglobin fell below 8 g/dL or hematocrit below 24%. Number of patients with a postoperative thrombus formation was minimal. Therefore, this outcome was described with summary statistics and was not formally analyzed.

Results

Of the 477 patients who underwent TJAs (275 TKAs, 98 anterior THAs, 104 posterior THAs; all unilateral), 111 did not receive TXA (June 2012-February 2013), and 366 received TXA (March 2013-January 2014). Other than for the addition of IV-TXA, the same standardized protocols instituted in March 2012 continued throughout the study period. The difference in sample size between the TXA and no-TXA groups was not statistically significant and did not influence the outcome measures.

Ambulation

There was a significant (P = .0066) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P < .0001), sex (P < .0001), BMI (P < .0001), and operative time (P = .8308). Regarding TKA, mean ambulation was higher for the TXA group than for the no-TXA group at POD-1 (8.36 vs 3.40 feet; P < .0001) and POD-2 (25.81 vs 18.75 feet; P = .0054). The same was true for anterior THA at POD-1 (10.86 vs 3.33 feet; P < .0001) and POD-2 (27.24 vs 13.19 feet; P < .0001) and posterior THA at POD-1 (10.64 vs 3.37 feet; P < .0001) and POD-2 (24.68 vs 12.93 feet; P = .0002). See Table 3.

Intraoperative Blood Loss

There was a significant 3-way interaction of TXA, procedure (P < .0053), and operative time (P < .0001) after adjusting for age (P < .6136), sex (P = .1147), and BMI (P = .6180). Regarding TKA, mean intraoperative blood loss was significantly lower for the TXA group than for the no-TXA group (241.58 vs 287.81 mL; P = .0004). The same was true for anterior THA (352.91 vs 533.79 mL; P < .0001). Regarding posterior THA, there was no significant difference between the TXA and no-TXA groups (326.00 vs 350.16 mL; P = .3246). See Table 4. 

Hemoglobin

There was a significant (P = .0008) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P = .0174), sex (P < .0001), BMI (P = .0007), and operative time (P = .0002). Regarding TKA, postoperative hemoglobin levels were higher for the TXA group than for the no-TXA group at POD-0 (12.10 vs 11.68 g/dL; P = .0135), POD-1 (11.62 vs 10.67 g/dL; P < .0001), and POD-2 (11.02 vs 10.11 g/dL; P < .0001). The same was true for anterior THA at POD-1 (11.03 vs 10.19 g/dL; P = .0034) and POD-2 (10.57 vs 9.64 g/dL; P = .0009) and posterior THA at POD-2 (11.04 vs 10.16 g/dL; P = .0003). See Table 5.

Hematocrit

There was a significant (P < .0006) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P = .1597), sex (P < .0001), BMI (P < .0001), and operative time (P = .0003). Regarding TKA, postoperative hematocrit levels were higher for the TXA group than for the no-TXA group at POD-0 (36.52% vs 34.65%; P < .0001), POD-1 (34.62% vs 31.83%; P < .0001), and POD-2 (33.01% vs 30.20%; P < .0001). The same was true for anterior THA at POD-1 (32.82% vs 30.59%; P = .0037) and POD-2 (31.58% vs 28.61%; P = .0004) and posterior THA at POD-2 (32.93% vs 30.17%; P < .0001). See Table 6.

Postoperative Transfusions 

Of the 477 patients, 25 (5.24%) required a postoperative transfusion. Postoperative transfusions were less likely (P < .0001) required in the TXA group (1.64%, 6/366) than in the no-TXA group (17.12%, 19/111). Given the smaller number of events, a more complex model accounting for clustered data and potential confounders was not used, and the different procedures were not evaluated separately.

Deep Vein Thrombosis and Pulmonary Embolism

Of the 477 patients, 2 developed a DVT, and 5 developed a PE. Both DVTs occurred in the TXA group (2/366, 0.55%; 95% CI, 0.07%-1.96%). Of the 5 PEs, 4 occurred in the TXA group (4/366, 1.09%; 95% CI, 0.30%-2.77%), and 1 occurred in the no-TXA group (1/111, 0.90%; 95% CI, 0.02%-4.92%). Given the exceedingly small number of events, no statistical significance was noted between groups.

Discussion

Orthopedic surgeons carefully balance patient expectations, societal needs, and regulatory mandates while providing excellent care and working under payers’ financial restrictions. The Centers for Medicare & Medicaid Services announced that, starting in 2016, TJAs will be reimbursed in total as a single bundled payment, adding to the need to provide optimal care in a fiscally responsible manner.²¹ Standardized protocols implementing multimodal therapies are pivotal in achieving favorable postoperative outcomes.

Our study results showed that IV-TXA use minimized hemoglobin and hematocrit reductions after TKA, anterior THA, and posterior THA. Postoperative anemia correlates with decreased ambulation ability and performance during the early postoperative period. In general, higher postoperative hemoglobin and hematocrit levels result in improved motor performance and shorter recovery.²² In addition, early ambulation is a validated predictor of favorable TJA outcomes. In our study, for TKA, anterior THA, and posterior THA, ambulation on POD-1 and POD-2 was significantly better for patients who received TXA than for patients who did not.

Transfusion rates were markedly lower for our TXA group than for our no-TXA group (1.64% vs 17.12%), confirming the findings of numerous other studies on outcomes of TJA with TXA.^{2,3,6-12,14,15} Transfusions impede physical therapy and affect hospitalization costs.

Although potential thrombosis-related adverse events remain an endpoint in studies involving TXA, we found a comparably low incidence of postoperative venous thrombosis in our TXA and no-TXA groups (1.09% and 0.90%, respectively). In addition, no patient in either group developed a postoperative arterial thrombosis.

This is the largest single-center study of TXA use in TKA, anterior THA, and posterior THA. The effect of TXA use on postoperative ambulation was not previously found with TJA.

This study had its limitations. First, it was not prospective, randomized, or double-blinded. However, the physical therapists who mobilized patients and recorded ambulation data were blinded to the study and its hypothesis and followed a standardized protocol for all patients. In addition, intraoperative blood loss was recorded by an anesthesiologist using a standardized protocol, and patients received TXA per orthopedic protocol and surgeon preference, without selection bias. Another limitation was that ambulation data were captured only for POD-1 and POD-2 (most patients were discharged by POD-3). However, a goal of the study was to capture immediate postoperative data in order to determine the efficacy of intraoperative TXA. Subsequent studies can determine if this early benefit leads to long-term clinical outcome improvements.

In reducing blood loss and transfusion rates, intra-articular TXA is as efficacious as IV-TXA.^23-25 We anticipate that the improved clinical outcomes found with IV-TXA in our study will be similar with intra-articular TXA, but more study is needed to confirm this hypothesis.

Conclusion

This retrospective cohort study found that use of IV-TXA in TJA improved early ambulation and clinical outcomes (reduced anemia, fewer transfusions) in the initial postoperative period, without producing adverse events.

Take-Home Points

• IV-TXA significantly reduces intraoperative blood loss following TJA.
• Early mobilization correlates with reduced incidence of postoperative complications.
• IV-TXA minimizes postoperative anemia, facilitating improved early ambulation following TJA.
• IV-TXA significantly reduces the need for postoperative transfusions.
• IV-TXA is safe to use with no adverse events noted.

By the year 2020, use of primary total knee arthroplasty (TKA) in the United States will increase an estimated 110%, to 1.375 million procedures annually, and use of primary total hip arthroplasty (THA) will increase an estimated 75%, to more than 500,000 procedures.¹ Minimizing perioperative blood loss and improving early postoperative ambulation both correlate with reduced postoperative morbidity, allowing patients to return to their daily lives expeditiously. 

Tranexamic acid (TXA), a fibrinolytic inhibitor, competitively blocks lysine receptor binding sites of plasminogen, sustaining and stabilizing the fibrin architecture.² TXA must be present to occupy binding sites before plasminogen binds to fibrin, validating the need for preoperative administration so the drug is available early in the fibrinolytic cascade.³ Intravenous (IV) TXA diffuses rapidly into joint fluid and the synovial membrane.⁴ Drug concentration and elimination half-life in joint fluid are equivalent to those in serum. Elimination of TXA occurs by glomerular filtration, with about 30% of a 10-mg/kg dose removed in 1 hour, 55% over the first 3 hours, and 90% within 24 hours of IV administration.⁵

The efficacy of IV-TXA in minimizing total joint arthroplasty (TJA) perioperative blood loss has been proved in small studies and meta-analyses.^6-9 TXA-induced blood conservation decreases or eliminates the need for postoperative transfusion, which can impede valuable, early ambulation.10 In addition, the positive clinical safety profile of TXA supports routine use of TXA in TJA.^6,11-15

The benefits of early ambulation after TJA are well established. Getting patients to walk on the day of surgery is a key part of effective and rapid postoperative rehabilitation. Early mobilization correlates with reduced incidence of venous thrombosis and postoperative complications.¹⁶ In contrast to bed rest, sitting and standing promotes oxygen saturation, which improves tissue healing and minimizes adverse pulmonary events. Oxygen saturation also preserves muscle strength and blood flow, reducing the risk of venous thromboembolism and ulcers. Muscle strength must be maintained so normal gait can be regained.¹⁷ Compared with rehabilitation initiated 48 to 72 hours after TKA, rehabilitation initiated within 24 hours reduced the number of sessions needed to achieve independence and normal gait; in addition, early mobilization improved patient reports of pain after surgery.¹⁸ An evaluation of Denmark registry data revealed that mobilization to walking and use of crutches or canes was achieved earlier when ambulation was initiated on day of surgery.¹⁹ Finally, mobilization on day of surgery and during the immediate postoperative period improved long-term quality of life after TJA.²⁰

We conducted a retrospective cohort study to determine if use of IV-TXA improves early ambulation and reduces blood loss after TKA and anterior and posterior THA. We hypothesized that IV-TXA use would reduce postoperative anemia and improve early ambulation and outcomes without producing adverse events during the immediate postoperative period. TXA reduces bleeding, and reduced incidence of hemarthrosis, wound swelling, and anemia could facilitate ambulation, reduce complications, and shorten recovery in patients who undergo TJA.

Patients and Methods

In February 2014, this retrospective cohort study received Institutional Review Board approval to compare the safety and efficacy of IV-TXA (vs no TXA) in patients who underwent TKA, anterior THA, and posterior THA.

In March 2012, multidisciplinary protocols were standardized to ensure a uniform hospital course for patients at our institution. All patients underwent preoperative testing and evaluation by a nurse practitioner and an anesthesiologist. In March 2013, IV-TXA became our standard of care. TXA use was contraindicated in patients with thromboembolic disease or with hypersensitivity to TXA. Patients without a contraindication were given two 10-mg/kg IV-TXA doses, each administered over 15 to 30 minutes; the first dose was administered before incision, and the second was infused at case close and/or at least 60 minutes after the first dose. Most TKA patients received regional (femoral) anesthesia and analgesia, and most THA patients received spinal or epidural anesthesia and analgesia. In a small percentage of cases, IV analgesia was patient-controlled, as determined by the pain service. There were no significant differences in anesthesia/analgesia modality between the 2 study groups—patients who received TXA and those who did not. Patients were then transitioned to oral opioids for pain management, unless otherwise contraindicated, and were ambulated 4 hours after end of surgery, unless medically unstable. Hematology and chemistry laboratory values were monitored daily during admission.

Patients underwent physical therapy (PT) after surgery and until hospital discharge. Physical therapists blinded to patients’ intraoperative use or no use of TXA measured ambulation. After initial evaluation on postoperative day 0 (POD-0), patients were ambulated twice daily. The daily ambulation distance used for the study was the larger of the 2 daily PT distances (occasionally, patients were unable to participate fully in both sessions). Patients received either enoxaparin or rivaroxaban for postoperative thromboprophylaxis (the anticoagulant used was based on surgeon preference). Enoxaparin was subcutaneously administered at 30 mg every 12 hours for TKA, 40 mg once daily for THA, 30 mg once daily for calculated creatinine clearance under 30 mL/min, or 40 mg every 12 hours for body mass index (BMI) 40 or above. With enoxaparin, therapy duration was 14 days. Oral rivaroxaban was administered at 10 mg once daily for 12 days for TKA and 35 days for THA unless contraindicated.

The primary outcome variables were ambulation measured on POD-1 and POD-2 and intraoperative blood loss. In addition, hemoglobin and hematocrit were measured on POD-0, POD-1, and POD-2. Ambulation was defined as number of feet walked during postoperative hospitalization. To calculate intraoperative blood loss, the anesthesiologist subtracted any saline irrigation volume from the total volume in the suction canister. Also noted were postoperative transfusions and any diagnosis of postoperative venous thromboembolism—specifically, deep vein thrombosis (DVT) or pulmonary embolism (PE).

Demographic and clinical characteristics of the TXA and no-TXA groups were compared using either 2-sample t test (for continuous variables) or χ2 test (for categorical variables).

The ambulation outcome was log-transformed to meet standard assumptions of Gaussian residuals and equality of variance. Means and 95% confidence intervals (CIs) were calculated on the log scale and were anti-logged so the results could be presented in their original units. 

A linear mixed model was used to model intraoperative blood loss as a function of group (TXA, no TXA), procedure (TKA, anterior THA, posterior THA), and potential confounders (age, sex, BMI, operative time).

Linear mixed models for repeated measures were used to compare outcomes (hemoglobin, hematocrit) between groups (TXA, no TXA) and procedures (TKA, anterior THA, posterior THA) and to compare changes in outcomes over time. Group, procedure, and operative time interactions were explored. Potential confounders (age, sex, BMI, operative time) were included in the model as well.

A χ2 test was used to compare the groups (TXA, no TXA) on postoperative blood transfusion (yes, no). Given the smaller number of events, a more complex model accounting for clustered data and potential confounders was not used. Need for transfusion was clinically assessed case by case. Symptomatic anemia (dyspnea on exertion, headaches, tachycardia) was used as the primary indication for transfusion once hemoglobin fell below 8 g/dL or hematocrit below 24%. Number of patients with a postoperative thrombus formation was minimal. Therefore, this outcome was described with summary statistics and was not formally analyzed.

Results

Of the 477 patients who underwent TJAs (275 TKAs, 98 anterior THAs, 104 posterior THAs; all unilateral), 111 did not receive TXA (June 2012-February 2013), and 366 received TXA (March 2013-January 2014). Other than for the addition of IV-TXA, the same standardized protocols instituted in March 2012 continued throughout the study period. The difference in sample size between the TXA and no-TXA groups was not statistically significant and did not influence the outcome measures.

Ambulation

There was a significant (P = .0066) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P < .0001), sex (P < .0001), BMI (P < .0001), and operative time (P = .8308). Regarding TKA, mean ambulation was higher for the TXA group than for the no-TXA group at POD-1 (8.36 vs 3.40 feet; P < .0001) and POD-2 (25.81 vs 18.75 feet; P = .0054). The same was true for anterior THA at POD-1 (10.86 vs 3.33 feet; P < .0001) and POD-2 (27.24 vs 13.19 feet; P < .0001) and posterior THA at POD-1 (10.64 vs 3.37 feet; P < .0001) and POD-2 (24.68 vs 12.93 feet; P = .0002). See Table 3.

Intraoperative Blood Loss

There was a significant 3-way interaction of TXA, procedure (P < .0053), and operative time (P < .0001) after adjusting for age (P < .6136), sex (P = .1147), and BMI (P = .6180). Regarding TKA, mean intraoperative blood loss was significantly lower for the TXA group than for the no-TXA group (241.58 vs 287.81 mL; P = .0004). The same was true for anterior THA (352.91 vs 533.79 mL; P < .0001). Regarding posterior THA, there was no significant difference between the TXA and no-TXA groups (326.00 vs 350.16 mL; P = .3246). See Table 4. 

Hemoglobin

There was a significant (P = .0008) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P = .0174), sex (P < .0001), BMI (P = .0007), and operative time (P = .0002). Regarding TKA, postoperative hemoglobin levels were higher for the TXA group than for the no-TXA group at POD-0 (12.10 vs 11.68 g/dL; P = .0135), POD-1 (11.62 vs 10.67 g/dL; P < .0001), and POD-2 (11.02 vs 10.11 g/dL; P < .0001). The same was true for anterior THA at POD-1 (11.03 vs 10.19 g/dL; P = .0034) and POD-2 (10.57 vs 9.64 g/dL; P = .0009) and posterior THA at POD-2 (11.04 vs 10.16 g/dL; P = .0003). See Table 5.

Hematocrit

There was a significant (P < .0006) 3-way interaction of TXA, procedure, and operative time after adjusting for age (P = .1597), sex (P < .0001), BMI (P < .0001), and operative time (P = .0003). Regarding TKA, postoperative hematocrit levels were higher for the TXA group than for the no-TXA group at POD-0 (36.52% vs 34.65%; P < .0001), POD-1 (34.62% vs 31.83%; P < .0001), and POD-2 (33.01% vs 30.20%; P < .0001). The same was true for anterior THA at POD-1 (32.82% vs 30.59%; P = .0037) and POD-2 (31.58% vs 28.61%; P = .0004) and posterior THA at POD-2 (32.93% vs 30.17%; P < .0001). See Table 6.

Postoperative Transfusions 

Of the 477 patients, 25 (5.24%) required a postoperative transfusion. Postoperative transfusions were less likely (P < .0001) required in the TXA group (1.64%, 6/366) than in the no-TXA group (17.12%, 19/111). Given the smaller number of events, a more complex model accounting for clustered data and potential confounders was not used, and the different procedures were not evaluated separately.

Deep Vein Thrombosis and Pulmonary Embolism

Of the 477 patients, 2 developed a DVT, and 5 developed a PE. Both DVTs occurred in the TXA group (2/366, 0.55%; 95% CI, 0.07%-1.96%). Of the 5 PEs, 4 occurred in the TXA group (4/366, 1.09%; 95% CI, 0.30%-2.77%), and 1 occurred in the no-TXA group (1/111, 0.90%; 95% CI, 0.02%-4.92%). Given the exceedingly small number of events, no statistical significance was noted between groups.

Discussion

Orthopedic surgeons carefully balance patient expectations, societal needs, and regulatory mandates while providing excellent care and working under payers’ financial restrictions. The Centers for Medicare & Medicaid Services announced that, starting in 2016, TJAs will be reimbursed in total as a single bundled payment, adding to the need to provide optimal care in a fiscally responsible manner.²¹ Standardized protocols implementing multimodal therapies are pivotal in achieving favorable postoperative outcomes.

Our study results showed that IV-TXA use minimized hemoglobin and hematocrit reductions after TKA, anterior THA, and posterior THA. Postoperative anemia correlates with decreased ambulation ability and performance during the early postoperative period. In general, higher postoperative hemoglobin and hematocrit levels result in improved motor performance and shorter recovery.²² In addition, early ambulation is a validated predictor of favorable TJA outcomes. In our study, for TKA, anterior THA, and posterior THA, ambulation on POD-1 and POD-2 was significantly better for patients who received TXA than for patients who did not.

Transfusion rates were markedly lower for our TXA group than for our no-TXA group (1.64% vs 17.12%), confirming the findings of numerous other studies on outcomes of TJA with TXA.^{2,3,6-12,14,15} Transfusions impede physical therapy and affect hospitalization costs.

Although potential thrombosis-related adverse events remain an endpoint in studies involving TXA, we found a comparably low incidence of postoperative venous thrombosis in our TXA and no-TXA groups (1.09% and 0.90%, respectively). In addition, no patient in either group developed a postoperative arterial thrombosis.

This is the largest single-center study of TXA use in TKA, anterior THA, and posterior THA. The effect of TXA use on postoperative ambulation was not previously found with TJA.

This study had its limitations. First, it was not prospective, randomized, or double-blinded. However, the physical therapists who mobilized patients and recorded ambulation data were blinded to the study and its hypothesis and followed a standardized protocol for all patients. In addition, intraoperative blood loss was recorded by an anesthesiologist using a standardized protocol, and patients received TXA per orthopedic protocol and surgeon preference, without selection bias. Another limitation was that ambulation data were captured only for POD-1 and POD-2 (most patients were discharged by POD-3). However, a goal of the study was to capture immediate postoperative data in order to determine the efficacy of intraoperative TXA. Subsequent studies can determine if this early benefit leads to long-term clinical outcome improvements.

In reducing blood loss and transfusion rates, intra-articular TXA is as efficacious as IV-TXA.^23-25 We anticipate that the improved clinical outcomes found with IV-TXA in our study will be similar with intra-articular TXA, but more study is needed to confirm this hypothesis.

Conclusion

This retrospective cohort study found that use of IV-TXA in TJA improved early ambulation and clinical outcomes (reduced anemia, fewer transfusions) in the initial postoperative period, without producing adverse events.

A study comparing parental attitudes of the human papillomavirus (HPV) vaccine in three countries indicates both low and high HPV knowledge may be associated with lower rates of vaccination, and parents’ country and gender also impact the likelihood of adolescents being immunized, reported Brooke Nickel, of the University of Sydney, and associates.

Of 179 parents with a daughter aged 9-17 years from the United States, United Kingdom, or Australia who took part in an online HPV vaccine opinion survey in 2011, 59% reported that their daughters had received HPV vaccination – 43% in the United States cohort, 63% in the United Kingdom cohort, and 76% in the Australian cohort.

Choreograph/Thinkstock

cnellist@frontlinemedcom.com

A study comparing parental attitudes of the human papillomavirus (HPV) vaccine in three countries indicates both low and high HPV knowledge may be associated with lower rates of vaccination, and parents’ country and gender also impact the likelihood of adolescents being immunized, reported Brooke Nickel, of the University of Sydney, and associates.

Of 179 parents with a daughter aged 9-17 years from the United States, United Kingdom, or Australia who took part in an online HPV vaccine opinion survey in 2011, 59% reported that their daughters had received HPV vaccination – 43% in the United States cohort, 63% in the United Kingdom cohort, and 76% in the Australian cohort.

Choreograph/Thinkstock

cnellist@frontlinemedcom.com

A study comparing parental attitudes of the human papillomavirus (HPV) vaccine in three countries indicates both low and high HPV knowledge may be associated with lower rates of vaccination, and parents’ country and gender also impact the likelihood of adolescents being immunized, reported Brooke Nickel, of the University of Sydney, and associates.

Of 179 parents with a daughter aged 9-17 years from the United States, United Kingdom, or Australia who took part in an online HPV vaccine opinion survey in 2011, 59% reported that their daughters had received HPV vaccination – 43% in the United States cohort, 63% in the United Kingdom cohort, and 76% in the Australian cohort.

Choreograph/Thinkstock

cnellist@frontlinemedcom.com

Opportunities to give the human papillomavirus (HPV) vaccine were missed, especially during well-adolescent and vaccine-related visits, in a study of more than 14,000 fully insured teen girls, reported Claudia M. Espinosa, MD, of the division of pediatric infectious diseases, University of Louisville (Ky.), and her associates.

In a study of 14,588 girls in a fully insured commercial or Medicaid plan who turned 11 years old between Jan. 1, 2010, and Sept. 31, 2015, it was documented whether or not the girls received an HPV vaccine when they were given another adolescent vaccine – one or more doses of the Tdap vaccine and/or one or more doses of the 4-valent meningococcal conjugate vaccine (MenACWY vaccine).

luiscar/Thinkstock

cnellist@frontlinemedcom.com

Opportunities to give the human papillomavirus (HPV) vaccine were missed, especially during well-adolescent and vaccine-related visits, in a study of more than 14,000 fully insured teen girls, reported Claudia M. Espinosa, MD, of the division of pediatric infectious diseases, University of Louisville (Ky.), and her associates.

In a study of 14,588 girls in a fully insured commercial or Medicaid plan who turned 11 years old between Jan. 1, 2010, and Sept. 31, 2015, it was documented whether or not the girls received an HPV vaccine when they were given another adolescent vaccine – one or more doses of the Tdap vaccine and/or one or more doses of the 4-valent meningococcal conjugate vaccine (MenACWY vaccine).

luiscar/Thinkstock

cnellist@frontlinemedcom.com

Opportunities to give the human papillomavirus (HPV) vaccine were missed, especially during well-adolescent and vaccine-related visits, in a study of more than 14,000 fully insured teen girls, reported Claudia M. Espinosa, MD, of the division of pediatric infectious diseases, University of Louisville (Ky.), and her associates.

In a study of 14,588 girls in a fully insured commercial or Medicaid plan who turned 11 years old between Jan. 1, 2010, and Sept. 31, 2015, it was documented whether or not the girls received an HPV vaccine when they were given another adolescent vaccine – one or more doses of the Tdap vaccine and/or one or more doses of the 4-valent meningococcal conjugate vaccine (MenACWY vaccine).

luiscar/Thinkstock

cnellist@frontlinemedcom.com

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DALLAS – Patients with heart failure with preserved ejection fraction who were hospitalized for acute decompensation had a significantly smaller rise in serum creatinine when treated with intermittent, bolus doses of furosemide, compared with patients who received a continuous furosemide infusion in a single-center, randomized trial with 90 patients.

Intermittent furosemide also resulted in many fewer episodes of worsening renal function. In the trial, 12% of patients who received bolus furosemide doses developed worsening renal function during hospitalization compared with 36% of patients treated with a continuous furosemide infusion, Kavita Sharma, MD, said at the annual scientific meeting of the Heart Failure Society of America.

While acknowledging that this finding is preliminary because it was made in a relatively small, single-center study, “I’d be cautious about continuous infusion” in acute decompensated patients with heart failure with preserved ejection fraction (HFpEF); “bolus is preferred,” Dr. Sharma said in a video interview.

Results from the prior Diuretic Optimization Strategies Evaluation (DOSE) trial, published in 2011, had shown no significant difference in renal function in hospitalized heart failure patients randomized to receive either bolus or continuous furosemide, but that study largely enrolled patients with heart failure with reduced ejection fraction (HFrEF) (N Engl J Med. 2011 Mar 3;364[9]:797-805).

“When patients with HFpEF are hospitalized with acute heart failure there is a high rate of kidney injury, that often results in slowing diuresis leading to longer hospital stays. With adjustment for changes in blood pressure and volume of diuresis we saw a fourfold increase in worsening renal failure [with continuous infusion], so you should think twice before using continuous dosing,” said Dr. Sharma, a heart failure cardiologist at Johns Hopkins Medicine in Baltimore.

She presented results from Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction (ROPA-DOP), which randomized 90 hospitalized heart failure patients with a left ventricular ejection fraction of at least 50% and an estimated glomerular filtration rate of more than 15 mL/min/1.73 m². The enrolled patients averaged 66 years old, 61% were women, their average body mass index was 41 kg/m², and their average estimated glomerular filtration rate was 58 mL/min/1.73 m^2.

The study’s primary endpoint was percent change in creatinine during hospitalization, which rose by an average 5% in the patients who received intermittent bolus furosemide and by an average 16% in patient who received a continuous infusion, a statistically significant difference. In a regression analysis that controlled for between-group differences in patient’s age, sex, race, body mass index, smoking status, changes in systolic blood pressure, heart rate, fluid balance after 72 hours, and other variables, patients treated with continuous furosemide infusion averaged an 11% greater increase in serum creatinine, Dr. Sharma reported. After similar adjustments, the secondary endpoint rate of worsening renal function was more than four times more likely to occur in the patients on continuous infusion compared with those who received intermittent bolus treatment, she said.

A second aspect of the ROPA-DOP trial randomized the same patients to received either low dose (3 mcg/kg per min) dopamine or placebo during hospitalization. The results showed that low-dose dopamine had no significant impact on either change in creatinine levels or on the incidence of worsening renal function compared with placebo, though dopamine treatment did link with a nonsignificant trend toward somewhat greater diuresis. These results were consistent with prior findings in the Renal Optimization Strategies Evaluation (ROSE) trial (JAMA. 2013 Nov 18;310[23]:2533-43), which used a mixed population of patients with HFpEF or HFrEF but predominantly patients with HFrEF, Dr. Sharma noted.

“It was a neutral finding [for dopamine in ROPA-DOP], and while there was no harm from dopamine there was clearly no benefit,” she said. It is possible that HFpEF patients with right ventricular dysfunction secondary to pulmonary hypertension might benefit from low-dose dopamine, but this needs further study, Dr. Sharma said.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

DALLAS – Patients with heart failure with preserved ejection fraction who were hospitalized for acute decompensation had a significantly smaller rise in serum creatinine when treated with intermittent, bolus doses of furosemide, compared with patients who received a continuous furosemide infusion in a single-center, randomized trial with 90 patients.

Intermittent furosemide also resulted in many fewer episodes of worsening renal function. In the trial, 12% of patients who received bolus furosemide doses developed worsening renal function during hospitalization compared with 36% of patients treated with a continuous furosemide infusion, Kavita Sharma, MD, said at the annual scientific meeting of the Heart Failure Society of America.

While acknowledging that this finding is preliminary because it was made in a relatively small, single-center study, “I’d be cautious about continuous infusion” in acute decompensated patients with heart failure with preserved ejection fraction (HFpEF); “bolus is preferred,” Dr. Sharma said in a video interview.

Results from the prior Diuretic Optimization Strategies Evaluation (DOSE) trial, published in 2011, had shown no significant difference in renal function in hospitalized heart failure patients randomized to receive either bolus or continuous furosemide, but that study largely enrolled patients with heart failure with reduced ejection fraction (HFrEF) (N Engl J Med. 2011 Mar 3;364[9]:797-805).

“When patients with HFpEF are hospitalized with acute heart failure there is a high rate of kidney injury, that often results in slowing diuresis leading to longer hospital stays. With adjustment for changes in blood pressure and volume of diuresis we saw a fourfold increase in worsening renal failure [with continuous infusion], so you should think twice before using continuous dosing,” said Dr. Sharma, a heart failure cardiologist at Johns Hopkins Medicine in Baltimore.

She presented results from Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction (ROPA-DOP), which randomized 90 hospitalized heart failure patients with a left ventricular ejection fraction of at least 50% and an estimated glomerular filtration rate of more than 15 mL/min/1.73 m². The enrolled patients averaged 66 years old, 61% were women, their average body mass index was 41 kg/m², and their average estimated glomerular filtration rate was 58 mL/min/1.73 m^2.

The study’s primary endpoint was percent change in creatinine during hospitalization, which rose by an average 5% in the patients who received intermittent bolus furosemide and by an average 16% in patient who received a continuous infusion, a statistically significant difference. In a regression analysis that controlled for between-group differences in patient’s age, sex, race, body mass index, smoking status, changes in systolic blood pressure, heart rate, fluid balance after 72 hours, and other variables, patients treated with continuous furosemide infusion averaged an 11% greater increase in serum creatinine, Dr. Sharma reported. After similar adjustments, the secondary endpoint rate of worsening renal function was more than four times more likely to occur in the patients on continuous infusion compared with those who received intermittent bolus treatment, she said.

A second aspect of the ROPA-DOP trial randomized the same patients to received either low dose (3 mcg/kg per min) dopamine or placebo during hospitalization. The results showed that low-dose dopamine had no significant impact on either change in creatinine levels or on the incidence of worsening renal function compared with placebo, though dopamine treatment did link with a nonsignificant trend toward somewhat greater diuresis. These results were consistent with prior findings in the Renal Optimization Strategies Evaluation (ROSE) trial (JAMA. 2013 Nov 18;310[23]:2533-43), which used a mixed population of patients with HFpEF or HFrEF but predominantly patients with HFrEF, Dr. Sharma noted.

“It was a neutral finding [for dopamine in ROPA-DOP], and while there was no harm from dopamine there was clearly no benefit,” she said. It is possible that HFpEF patients with right ventricular dysfunction secondary to pulmonary hypertension might benefit from low-dose dopamine, but this needs further study, Dr. Sharma said.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

DALLAS – Patients with heart failure with preserved ejection fraction who were hospitalized for acute decompensation had a significantly smaller rise in serum creatinine when treated with intermittent, bolus doses of furosemide, compared with patients who received a continuous furosemide infusion in a single-center, randomized trial with 90 patients.

Intermittent furosemide also resulted in many fewer episodes of worsening renal function. In the trial, 12% of patients who received bolus furosemide doses developed worsening renal function during hospitalization compared with 36% of patients treated with a continuous furosemide infusion, Kavita Sharma, MD, said at the annual scientific meeting of the Heart Failure Society of America.

While acknowledging that this finding is preliminary because it was made in a relatively small, single-center study, “I’d be cautious about continuous infusion” in acute decompensated patients with heart failure with preserved ejection fraction (HFpEF); “bolus is preferred,” Dr. Sharma said in a video interview.

Results from the prior Diuretic Optimization Strategies Evaluation (DOSE) trial, published in 2011, had shown no significant difference in renal function in hospitalized heart failure patients randomized to receive either bolus or continuous furosemide, but that study largely enrolled patients with heart failure with reduced ejection fraction (HFrEF) (N Engl J Med. 2011 Mar 3;364[9]:797-805).

“When patients with HFpEF are hospitalized with acute heart failure there is a high rate of kidney injury, that often results in slowing diuresis leading to longer hospital stays. With adjustment for changes in blood pressure and volume of diuresis we saw a fourfold increase in worsening renal failure [with continuous infusion], so you should think twice before using continuous dosing,” said Dr. Sharma, a heart failure cardiologist at Johns Hopkins Medicine in Baltimore.

She presented results from Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction (ROPA-DOP), which randomized 90 hospitalized heart failure patients with a left ventricular ejection fraction of at least 50% and an estimated glomerular filtration rate of more than 15 mL/min/1.73 m². The enrolled patients averaged 66 years old, 61% were women, their average body mass index was 41 kg/m², and their average estimated glomerular filtration rate was 58 mL/min/1.73 m^2.

The study’s primary endpoint was percent change in creatinine during hospitalization, which rose by an average 5% in the patients who received intermittent bolus furosemide and by an average 16% in patient who received a continuous infusion, a statistically significant difference. In a regression analysis that controlled for between-group differences in patient’s age, sex, race, body mass index, smoking status, changes in systolic blood pressure, heart rate, fluid balance after 72 hours, and other variables, patients treated with continuous furosemide infusion averaged an 11% greater increase in serum creatinine, Dr. Sharma reported. After similar adjustments, the secondary endpoint rate of worsening renal function was more than four times more likely to occur in the patients on continuous infusion compared with those who received intermittent bolus treatment, she said.

A second aspect of the ROPA-DOP trial randomized the same patients to received either low dose (3 mcg/kg per min) dopamine or placebo during hospitalization. The results showed that low-dose dopamine had no significant impact on either change in creatinine levels or on the incidence of worsening renal function compared with placebo, though dopamine treatment did link with a nonsignificant trend toward somewhat greater diuresis. These results were consistent with prior findings in the Renal Optimization Strategies Evaluation (ROSE) trial (JAMA. 2013 Nov 18;310[23]:2533-43), which used a mixed population of patients with HFpEF or HFrEF but predominantly patients with HFrEF, Dr. Sharma noted.

“It was a neutral finding [for dopamine in ROPA-DOP], and while there was no harm from dopamine there was clearly no benefit,” she said. It is possible that HFpEF patients with right ventricular dysfunction secondary to pulmonary hypertension might benefit from low-dose dopamine, but this needs further study, Dr. Sharma said.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

PARIS – Low physical activity in childhood and adolescence was independently associated with later development of schizophrenia and other nonaffective psychotic disorders in the large, prospective, population-based Cardiovascular Risk in Young Finns cohort study, Jarmo Hietala, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.

The key question now: Is this risk factor remediable? That is, will a pediatric exercise intervention that results in improved physical fitness also reduce the risk of later nonaffective psychosis? Given that there are really no downsides to physical activity, the Finnish data make a strong case for including exercise and physical activity interventions in investigational psychosis prevention programs targeting high-risk youth, according to Dr. Hietala, professor of psychiatry at the University of Turku (Finland).

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com
 

PARIS – Low physical activity in childhood and adolescence was independently associated with later development of schizophrenia and other nonaffective psychotic disorders in the large, prospective, population-based Cardiovascular Risk in Young Finns cohort study, Jarmo Hietala, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.

The key question now: Is this risk factor remediable? That is, will a pediatric exercise intervention that results in improved physical fitness also reduce the risk of later nonaffective psychosis? Given that there are really no downsides to physical activity, the Finnish data make a strong case for including exercise and physical activity interventions in investigational psychosis prevention programs targeting high-risk youth, according to Dr. Hietala, professor of psychiatry at the University of Turku (Finland).

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com
 

PARIS – Low physical activity in childhood and adolescence was independently associated with later development of schizophrenia and other nonaffective psychotic disorders in the large, prospective, population-based Cardiovascular Risk in Young Finns cohort study, Jarmo Hietala, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.

The key question now: Is this risk factor remediable? That is, will a pediatric exercise intervention that results in improved physical fitness also reduce the risk of later nonaffective psychosis? Given that there are really no downsides to physical activity, the Finnish data make a strong case for including exercise and physical activity interventions in investigational psychosis prevention programs targeting high-risk youth, according to Dr. Hietala, professor of psychiatry at the University of Turku (Finland).

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com
 

On Oct. 6, the Trump administration rolled back a crucial piece of the Affordable Care Act so that any employer can now claim a moral or religious objection to providing contraception coverage, thus denying their employees access to critical health care – contraception.

Nearly all women – 99% – who have had sex have used some form of contraception at some point during their reproductive lives, regardless of faith or religion (National health statistics reports. 2013 Feb 14[62]). Most women spend the majority of their fertile life span, approximately 35-40 years, avoiding pregnancy, and only a few years actively trying to become pregnant. A desired pregnancy is a gift, but unplanned pregnancies may have a negative impact on women, families, and society.

In the United States, our rising maternal mortality ratio is currently at 26.4 per 100,000 live births (Lancet. 2016 Oct 8;388[10053]:1775-812). Given the risks of pregnancy, especially to those with medical conditions that make pregnancy more dangerous, women need access to methods to avoid pregnancy until they actively seek it. If employers of for-profit businesses now choose to claim a moral or religious objection to providing coverage for contraception, millions of women could become unable to access affordable, effective contraception.

Dr. Prager is associate professor of obstetrics and gynecology at the University of Washington, Seattle. She is also the director of the family planning division and family planning fellowship. Dr. Prager is an unpaid trainer for Nexplanon (Merck). Dr. Espey is professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque. Dr. Espey reported having no relevant disclosures.

On Oct. 6, the Trump administration rolled back a crucial piece of the Affordable Care Act so that any employer can now claim a moral or religious objection to providing contraception coverage, thus denying their employees access to critical health care – contraception.

Nearly all women – 99% – who have had sex have used some form of contraception at some point during their reproductive lives, regardless of faith or religion (National health statistics reports. 2013 Feb 14[62]). Most women spend the majority of their fertile life span, approximately 35-40 years, avoiding pregnancy, and only a few years actively trying to become pregnant. A desired pregnancy is a gift, but unplanned pregnancies may have a negative impact on women, families, and society.

In the United States, our rising maternal mortality ratio is currently at 26.4 per 100,000 live births (Lancet. 2016 Oct 8;388[10053]:1775-812). Given the risks of pregnancy, especially to those with medical conditions that make pregnancy more dangerous, women need access to methods to avoid pregnancy until they actively seek it. If employers of for-profit businesses now choose to claim a moral or religious objection to providing coverage for contraception, millions of women could become unable to access affordable, effective contraception.

Dr. Prager is associate professor of obstetrics and gynecology at the University of Washington, Seattle. She is also the director of the family planning division and family planning fellowship. Dr. Prager is an unpaid trainer for Nexplanon (Merck). Dr. Espey is professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque. Dr. Espey reported having no relevant disclosures.

On Oct. 6, the Trump administration rolled back a crucial piece of the Affordable Care Act so that any employer can now claim a moral or religious objection to providing contraception coverage, thus denying their employees access to critical health care – contraception.

Nearly all women – 99% – who have had sex have used some form of contraception at some point during their reproductive lives, regardless of faith or religion (National health statistics reports. 2013 Feb 14[62]). Most women spend the majority of their fertile life span, approximately 35-40 years, avoiding pregnancy, and only a few years actively trying to become pregnant. A desired pregnancy is a gift, but unplanned pregnancies may have a negative impact on women, families, and society.

In the United States, our rising maternal mortality ratio is currently at 26.4 per 100,000 live births (Lancet. 2016 Oct 8;388[10053]:1775-812). Given the risks of pregnancy, especially to those with medical conditions that make pregnancy more dangerous, women need access to methods to avoid pregnancy until they actively seek it. If employers of for-profit businesses now choose to claim a moral or religious objection to providing coverage for contraception, millions of women could become unable to access affordable, effective contraception.

Dr. Prager is associate professor of obstetrics and gynecology at the University of Washington, Seattle. She is also the director of the family planning division and family planning fellowship. Dr. Prager is an unpaid trainer for Nexplanon (Merck). Dr. Espey is professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque. Dr. Espey reported having no relevant disclosures.

The combination of glecaprevir and pibrentasvir has been found to be both safe and effective as a treatment for hepatitis C virus (HCV) infection in patients with end-stage kidney disease, according to a paper published in the New England Journal of Medicine.

There are few treatment options available for these patients, as ribavirin can accumulate systemically in patients with severe renal impairment with serious adverse consequences such as hemolytic anemia and pruritus, and interferon has a negative side-effect profile in this population.

s-c-s/Thinkstock

The combination of glecaprevir and pibrentasvir has been found to be both safe and effective as a treatment for hepatitis C virus (HCV) infection in patients with end-stage kidney disease, according to a paper published in the New England Journal of Medicine.

There are few treatment options available for these patients, as ribavirin can accumulate systemically in patients with severe renal impairment with serious adverse consequences such as hemolytic anemia and pruritus, and interferon has a negative side-effect profile in this population.

s-c-s/Thinkstock

The combination of glecaprevir and pibrentasvir has been found to be both safe and effective as a treatment for hepatitis C virus (HCV) infection in patients with end-stage kidney disease, according to a paper published in the New England Journal of Medicine.

There are few treatment options available for these patients, as ribavirin can accumulate systemically in patients with severe renal impairment with serious adverse consequences such as hemolytic anemia and pruritus, and interferon has a negative side-effect profile in this population.

s-c-s/Thinkstock

Patients with primary biliary cholangitis (PBC) have lower lumbar spine and hip bone mineral density (BMD) and are at an increased risk of osteoporosis and fracture, according to Junyu Fan, MD, and associates.

In a meta-analysis of 210 potentially relevant articles, only 8 met the study’s criteria. Of those, five studies were pooled and the overall relationship between PBC and osteoporosis risk was assessed. Results found a significant association between PBC (n = 504) and the prevalence of osteoporosis (P = .01), compared with the control group (n = 2,052).

©eranicle/Thinkstock

llaubach@frontlinemedcom.com

Patients with primary biliary cholangitis (PBC) have lower lumbar spine and hip bone mineral density (BMD) and are at an increased risk of osteoporosis and fracture, according to Junyu Fan, MD, and associates.

In a meta-analysis of 210 potentially relevant articles, only 8 met the study’s criteria. Of those, five studies were pooled and the overall relationship between PBC and osteoporosis risk was assessed. Results found a significant association between PBC (n = 504) and the prevalence of osteoporosis (P = .01), compared with the control group (n = 2,052).

©eranicle/Thinkstock

llaubach@frontlinemedcom.com

Patients with primary biliary cholangitis (PBC) have lower lumbar spine and hip bone mineral density (BMD) and are at an increased risk of osteoporosis and fracture, according to Junyu Fan, MD, and associates.

In a meta-analysis of 210 potentially relevant articles, only 8 met the study’s criteria. Of those, five studies were pooled and the overall relationship between PBC and osteoporosis risk was assessed. Results found a significant association between PBC (n = 504) and the prevalence of osteoporosis (P = .01), compared with the control group (n = 2,052).

©eranicle/Thinkstock

llaubach@frontlinemedcom.com

SAN FRANCISCO – Routine testing for minimal residual disease is probably not of value in acute myeloid leukemia, as there is no evidence that changing treatment based on MRD status currently makes a difference in patient outcomes, experts said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

“If we find minimal residual disease, we don’t always have a better therapy to offer our patients,” Jessica Altman, MD, associate professor of hematology and oncology at the Northwestern University Feinberg School of Medicine, said.

Beyond that therapeutic reality, there are no clear guidelines and standards for MRD testing. The optimal timing for MRD testing and a standard threshold for an MRD classification are not yet established, she said.

“Having MRD is bad, not having it is better,” Richard Stone, MD, PhD, clinical director of the adult leukemia program at the Dana-Farber Cancer Institute, said. The problem in AML, he said, is, “So?” There is no reliable “MRD eraser” in AML, he said. Until then, there is not much point in knowing whether a patient is MRD positive or not.

A recent survey conducted by researchers at Moffitt Cancer Center, Tampa, addressed MRD testing at 13 major cancer centers. While most centers reported that they test for MRD, many physicians said that they are unsure about what to do with the results.

A 2013 study by the HOVON group found that patients who were in complete remission but MRD positive after their first course of therapy, subsequently became MRD negative after their second course of therapy. But the second regimen would not have been different based on knowledge of MRD status, according to the HOVON/SAKK AML 42A study (J Clin Oncol. 2013; 31:3889-97).

The AML community is awaiting guidelines on MRD use from the NCCN and other groups, Dr. Altman said. An option for using NPM1 mutations to assess MRD should be available soon, and could be an improvement on existing options (N Engl J Med 2016; 374:422-33).

Given the treatment limitations, knowing about MRD status can have a negative mental toll on patients, Dr. Stone said. “I would not underplay the psychological burden.” Nevertheless, MRD should be measured in clinical trials, and it could be a valuable surrogate marker by which to compare drug efficacy.

One of the biggest hopes is that MRD status could eventually be useful in determining the need for allogeneic stem cell transplant in patients deemed intermediate risk, Dr. Altman said. “I think we are finally on the brink of this being actionable.”

Dr. Altman reports financial relationships with Astellas, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Syros. Dr. Stone reports financial relationships with AbbVie, Actinium, Agios, Amgen and many other companies.

SAN FRANCISCO – Routine testing for minimal residual disease is probably not of value in acute myeloid leukemia, as there is no evidence that changing treatment based on MRD status currently makes a difference in patient outcomes, experts said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

“If we find minimal residual disease, we don’t always have a better therapy to offer our patients,” Jessica Altman, MD, associate professor of hematology and oncology at the Northwestern University Feinberg School of Medicine, said.

Beyond that therapeutic reality, there are no clear guidelines and standards for MRD testing. The optimal timing for MRD testing and a standard threshold for an MRD classification are not yet established, she said.

“Having MRD is bad, not having it is better,” Richard Stone, MD, PhD, clinical director of the adult leukemia program at the Dana-Farber Cancer Institute, said. The problem in AML, he said, is, “So?” There is no reliable “MRD eraser” in AML, he said. Until then, there is not much point in knowing whether a patient is MRD positive or not.

A recent survey conducted by researchers at Moffitt Cancer Center, Tampa, addressed MRD testing at 13 major cancer centers. While most centers reported that they test for MRD, many physicians said that they are unsure about what to do with the results.

A 2013 study by the HOVON group found that patients who were in complete remission but MRD positive after their first course of therapy, subsequently became MRD negative after their second course of therapy. But the second regimen would not have been different based on knowledge of MRD status, according to the HOVON/SAKK AML 42A study (J Clin Oncol. 2013; 31:3889-97).

The AML community is awaiting guidelines on MRD use from the NCCN and other groups, Dr. Altman said. An option for using NPM1 mutations to assess MRD should be available soon, and could be an improvement on existing options (N Engl J Med 2016; 374:422-33).

Given the treatment limitations, knowing about MRD status can have a negative mental toll on patients, Dr. Stone said. “I would not underplay the psychological burden.” Nevertheless, MRD should be measured in clinical trials, and it could be a valuable surrogate marker by which to compare drug efficacy.

One of the biggest hopes is that MRD status could eventually be useful in determining the need for allogeneic stem cell transplant in patients deemed intermediate risk, Dr. Altman said. “I think we are finally on the brink of this being actionable.”

Dr. Altman reports financial relationships with Astellas, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Syros. Dr. Stone reports financial relationships with AbbVie, Actinium, Agios, Amgen and many other companies.

SAN FRANCISCO – Routine testing for minimal residual disease is probably not of value in acute myeloid leukemia, as there is no evidence that changing treatment based on MRD status currently makes a difference in patient outcomes, experts said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

“If we find minimal residual disease, we don’t always have a better therapy to offer our patients,” Jessica Altman, MD, associate professor of hematology and oncology at the Northwestern University Feinberg School of Medicine, said.

Beyond that therapeutic reality, there are no clear guidelines and standards for MRD testing. The optimal timing for MRD testing and a standard threshold for an MRD classification are not yet established, she said.

“Having MRD is bad, not having it is better,” Richard Stone, MD, PhD, clinical director of the adult leukemia program at the Dana-Farber Cancer Institute, said. The problem in AML, he said, is, “So?” There is no reliable “MRD eraser” in AML, he said. Until then, there is not much point in knowing whether a patient is MRD positive or not.

A recent survey conducted by researchers at Moffitt Cancer Center, Tampa, addressed MRD testing at 13 major cancer centers. While most centers reported that they test for MRD, many physicians said that they are unsure about what to do with the results.

A 2013 study by the HOVON group found that patients who were in complete remission but MRD positive after their first course of therapy, subsequently became MRD negative after their second course of therapy. But the second regimen would not have been different based on knowledge of MRD status, according to the HOVON/SAKK AML 42A study (J Clin Oncol. 2013; 31:3889-97).

The AML community is awaiting guidelines on MRD use from the NCCN and other groups, Dr. Altman said. An option for using NPM1 mutations to assess MRD should be available soon, and could be an improvement on existing options (N Engl J Med 2016; 374:422-33).

Given the treatment limitations, knowing about MRD status can have a negative mental toll on patients, Dr. Stone said. “I would not underplay the psychological burden.” Nevertheless, MRD should be measured in clinical trials, and it could be a valuable surrogate marker by which to compare drug efficacy.

One of the biggest hopes is that MRD status could eventually be useful in determining the need for allogeneic stem cell transplant in patients deemed intermediate risk, Dr. Altman said. “I think we are finally on the brink of this being actionable.”

Dr. Altman reports financial relationships with Astellas, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Syros. Dr. Stone reports financial relationships with AbbVie, Actinium, Agios, Amgen and many other companies.