Outcomes Research in Review

Study Overview

Objective. To determine the effects of intra-articular triamcinolone acetonide at a dose of 40 mg administered at 3-month intervals on knee pain and progression of knee cartilage loss.

Design. Randomized, double-blind, placebo-controlled trial.

Setting and participants. 140 patients with ultrasonic features of synovitis and symptomatic knee osteoarthritis were selected from the patient pool at Tufts Medical Center in Boston, Massachusetts, between June 2011 and January 2015. Patients selected were age 45 years or older and met American College of Rheumatology osteoarthritis diagnostic criteria. Western Ontario and McMaster Universities (WOMAC) pain scores were between 2 and 8 on weight-bearing questions. Tibiofemoral osteoarthritis on posteroanterior weight bearing semi-flexed radiographs was evident in participants at a Kellegren-Lawrence grade 2 or 3. Eligible patients also had ultra-sonographic evidence of synovitis with an effusion larger than 2 mm in the study knee. Participants were excluded if they had undergone any trauma to the study joint such as osteonecrosis or a poorly controlled systemic illness. If the patient had used antibiotics, hyaluronic acid, glucosamine, chondroitin or had undergone recent intra-articular steroids in 3 months or fewer prior to the enrollment period the patient was excluded from the study. Further, patients were excluded if they were unable to undergo an MRI. Prior to pain assessments, patients were to discontinue any analgesics for 48 hours with the exception of acetaminophen if needed. The mean age of patients in this study was 58 years and the mean body mass index was 30. Half of patients had malalignment of the knee joint.

Intervention. 40 mg of a preparation of 40 mg/mL (total volume 1 mL) was injected into the intervention patients’ affected knees while 1 mL of 0.9% sodium chloride (saline solution) was injected into the control patients’ affected knees. Local anesthetic was not used. If present, synovial fluid was aspirated from the knee prior to injection. Injections were administered every 12 weeks for 2 years. Needle placement by ultrasound was utilized to ensure accurate injections, however, the probe was removed prior to injection. The injecting clinician was not involved in measuring outcomes in the study. Both intervention solutions were in identical syringes and were masked so the patient was blinded to which intervention he or she may have received.

Main outcome measure. Cartilage loss, pain, articular structural damage and physical function were the main outcome measures. Cartilage loss and structural damage were determined by MRI using validated quantitative and semi-quantitative assessments. Pain was measured with WOMAC scores and physical function was assessed using the 20-m walk test and the chair stand test. Patients were assessed during 9 scheduled visits at 3-month intervals when subjective data, blood pressure, and hemoglobin A1c levels were obtained. At 6-month intervals, patients underwent objective measures of function measured by a timed 20-m walk and chair stand testing. Evaluation of quantitative measures of cartilage analysis, semi-quantitative assessment of cartilage damage, bone marrow lesion and effusion volume measurement by MRI were done at time zero, 12 months and 24 months. The 36-Item Short-Form Health Survey was administered at these times as well. Results were computed with intention-to-treat analysis for all outcomes.

Main results. 140 patients were randomized out of 445 patients who were assessed for eligibility. Ten patients in the saline arm and 11 in the glucocorticoid arm were lost to follow-up. Groups were similar in age, BMI, varus or valgus malalignment, ultrasound measures, pain, and function measures. The group injected with triamcinolone had a higher rate of cartilage loss than the group injected with saline (–0.21 mm vs. –0.10 mm, P = 0.01) and had a higher rate of cartilage damage (–133.66 vs –72.41, P = 0.048). Cartilage denudation, bone marrow lesions, trabecular morphology and effusion volumes were not significantly different between groups. WOMAC pain measure differences from baseline in the groups were similar (–1.2 for triamcinolone group vs. –1.9 for the saline group, P = 0.17). There were also no differences between groups for the Visual Analog Scale pain score, stiffness, the 20-m walk test, or the chair stand test. Adverse events were similar between groups. At the end of the study protocol, only 45% of patients were able to correctly identify the group to which they were assigned.

Conclusion. In patients meeting American College of Rheumatology diagnostic criteria for osteoarthritis and evidence of inflammation in the affected joint, 40 mg of triamcinolone administered intra-articularly is no more effective in relieving pain or physical functioning after 2 years of injections every 3 months than normal saline. Injecting 40 mg of triamcinolone may hasten cartilage loss and damage as measured by MRI.

Commentary

In the current study, the rate of cartilage loss in the saline group was on par with prior studies examining the natural history of cartilage loss, suggesting that intra-articular steroid may actually be hastening the loss of cartilage observed in this study. The effect size was deemed moderate by the authors, though clinically significant minimal change has not been determined. Intra-articular cartilage loss is positively correlated with arthroplasty rates [1]. While this study was not designed to investigate the rate of joint replacement after intra-articular corticosteroid measurement, this may be an area for future study. Interestingly, pain and function scores were not significantly different between the 2 groups, despite the changes in cartilage. Of note, prior studies have shown the largest gains in pain relief occur during the first 4 weeks after an injection and pain measurements in this study were performed 3 months after the injections. While helpful for determining the long-term effects of intra-articular glucocorticoid administration, short-term benefits were not measured.

The Osteoarthritis Research Society International guidelines for the nonpharmacologic management of knee osteoarthritis recommend intra-articular steroids for short-term pain management based on meta-analysis of randomized controlled trials [2]. Guidelines set forth by the American College of Rheumatology in 2012 for management of osteoarthritis of the knee also recommend intra-articular steroids [3]. Intra-articular corticosteroid injections were listed as interchangeable, in the absence of comorbid conditions leading to contraindications, with oral acetaminophen, oral and topical NSAIDs, and tramadol.

Hemoglobin A1c and blood pressure were not negatively affected by intra-articular steroids in this study.

Applications for Clinical Practice

While this study overall showed hastening of cartilage loss/damage without long-term pain relief benefit, there are instances where intra-articular steroid injection may still be appropriate. For example, in patients for whom joint replacement therapy has been scheduled and temporary pain relief is needed prior to surgery, intra-articular steroids may provide the pain relief desired without cartilage loss being a clinical concern. Further, if a patient is in need of temporary pain relief to attend an important event and is at a level of marginal functional status due to pain, the benefit may outweigh the risk of hastening cartilage damage/loss to that particular patient. In light of the knowledge gained by this study, any time an intra-articular steroid injection is offered to a patient it should be made clear that the pain relief gained may be temporary and could result in faster deterioration of the cartilage.

Nonpharmacologic therapies for osteoarthritis, including water-based and land-based physical therapy and weight reduction, should be utilized before offering intra-articular corticosteroid injections. These interventions not only have a positive effect on knee osteoarthritis [2] but also promote general health and well-being.

—Christina Downey, MD, Geisinger Medical Center, Danville, PA

Study Overview

Objective. To determine the effects of intra-articular triamcinolone acetonide at a dose of 40 mg administered at 3-month intervals on knee pain and progression of knee cartilage loss.

Design. Randomized, double-blind, placebo-controlled trial.

Setting and participants. 140 patients with ultrasonic features of synovitis and symptomatic knee osteoarthritis were selected from the patient pool at Tufts Medical Center in Boston, Massachusetts, between June 2011 and January 2015. Patients selected were age 45 years or older and met American College of Rheumatology osteoarthritis diagnostic criteria. Western Ontario and McMaster Universities (WOMAC) pain scores were between 2 and 8 on weight-bearing questions. Tibiofemoral osteoarthritis on posteroanterior weight bearing semi-flexed radiographs was evident in participants at a Kellegren-Lawrence grade 2 or 3. Eligible patients also had ultra-sonographic evidence of synovitis with an effusion larger than 2 mm in the study knee. Participants were excluded if they had undergone any trauma to the study joint such as osteonecrosis or a poorly controlled systemic illness. If the patient had used antibiotics, hyaluronic acid, glucosamine, chondroitin or had undergone recent intra-articular steroids in 3 months or fewer prior to the enrollment period the patient was excluded from the study. Further, patients were excluded if they were unable to undergo an MRI. Prior to pain assessments, patients were to discontinue any analgesics for 48 hours with the exception of acetaminophen if needed. The mean age of patients in this study was 58 years and the mean body mass index was 30. Half of patients had malalignment of the knee joint.

Intervention. 40 mg of a preparation of 40 mg/mL (total volume 1 mL) was injected into the intervention patients’ affected knees while 1 mL of 0.9% sodium chloride (saline solution) was injected into the control patients’ affected knees. Local anesthetic was not used. If present, synovial fluid was aspirated from the knee prior to injection. Injections were administered every 12 weeks for 2 years. Needle placement by ultrasound was utilized to ensure accurate injections, however, the probe was removed prior to injection. The injecting clinician was not involved in measuring outcomes in the study. Both intervention solutions were in identical syringes and were masked so the patient was blinded to which intervention he or she may have received.

Main outcome measure. Cartilage loss, pain, articular structural damage and physical function were the main outcome measures. Cartilage loss and structural damage were determined by MRI using validated quantitative and semi-quantitative assessments. Pain was measured with WOMAC scores and physical function was assessed using the 20-m walk test and the chair stand test. Patients were assessed during 9 scheduled visits at 3-month intervals when subjective data, blood pressure, and hemoglobin A1c levels were obtained. At 6-month intervals, patients underwent objective measures of function measured by a timed 20-m walk and chair stand testing. Evaluation of quantitative measures of cartilage analysis, semi-quantitative assessment of cartilage damage, bone marrow lesion and effusion volume measurement by MRI were done at time zero, 12 months and 24 months. The 36-Item Short-Form Health Survey was administered at these times as well. Results were computed with intention-to-treat analysis for all outcomes.

Main results. 140 patients were randomized out of 445 patients who were assessed for eligibility. Ten patients in the saline arm and 11 in the glucocorticoid arm were lost to follow-up. Groups were similar in age, BMI, varus or valgus malalignment, ultrasound measures, pain, and function measures. The group injected with triamcinolone had a higher rate of cartilage loss than the group injected with saline (–0.21 mm vs. –0.10 mm, P = 0.01) and had a higher rate of cartilage damage (–133.66 vs –72.41, P = 0.048). Cartilage denudation, bone marrow lesions, trabecular morphology and effusion volumes were not significantly different between groups. WOMAC pain measure differences from baseline in the groups were similar (–1.2 for triamcinolone group vs. –1.9 for the saline group, P = 0.17). There were also no differences between groups for the Visual Analog Scale pain score, stiffness, the 20-m walk test, or the chair stand test. Adverse events were similar between groups. At the end of the study protocol, only 45% of patients were able to correctly identify the group to which they were assigned.

Conclusion. In patients meeting American College of Rheumatology diagnostic criteria for osteoarthritis and evidence of inflammation in the affected joint, 40 mg of triamcinolone administered intra-articularly is no more effective in relieving pain or physical functioning after 2 years of injections every 3 months than normal saline. Injecting 40 mg of triamcinolone may hasten cartilage loss and damage as measured by MRI.

Commentary

In the current study, the rate of cartilage loss in the saline group was on par with prior studies examining the natural history of cartilage loss, suggesting that intra-articular steroid may actually be hastening the loss of cartilage observed in this study. The effect size was deemed moderate by the authors, though clinically significant minimal change has not been determined. Intra-articular cartilage loss is positively correlated with arthroplasty rates [1]. While this study was not designed to investigate the rate of joint replacement after intra-articular corticosteroid measurement, this may be an area for future study. Interestingly, pain and function scores were not significantly different between the 2 groups, despite the changes in cartilage. Of note, prior studies have shown the largest gains in pain relief occur during the first 4 weeks after an injection and pain measurements in this study were performed 3 months after the injections. While helpful for determining the long-term effects of intra-articular glucocorticoid administration, short-term benefits were not measured.

The Osteoarthritis Research Society International guidelines for the nonpharmacologic management of knee osteoarthritis recommend intra-articular steroids for short-term pain management based on meta-analysis of randomized controlled trials [2]. Guidelines set forth by the American College of Rheumatology in 2012 for management of osteoarthritis of the knee also recommend intra-articular steroids [3]. Intra-articular corticosteroid injections were listed as interchangeable, in the absence of comorbid conditions leading to contraindications, with oral acetaminophen, oral and topical NSAIDs, and tramadol.

Hemoglobin A1c and blood pressure were not negatively affected by intra-articular steroids in this study.

Applications for Clinical Practice

While this study overall showed hastening of cartilage loss/damage without long-term pain relief benefit, there are instances where intra-articular steroid injection may still be appropriate. For example, in patients for whom joint replacement therapy has been scheduled and temporary pain relief is needed prior to surgery, intra-articular steroids may provide the pain relief desired without cartilage loss being a clinical concern. Further, if a patient is in need of temporary pain relief to attend an important event and is at a level of marginal functional status due to pain, the benefit may outweigh the risk of hastening cartilage damage/loss to that particular patient. In light of the knowledge gained by this study, any time an intra-articular steroid injection is offered to a patient it should be made clear that the pain relief gained may be temporary and could result in faster deterioration of the cartilage.

Nonpharmacologic therapies for osteoarthritis, including water-based and land-based physical therapy and weight reduction, should be utilized before offering intra-articular corticosteroid injections. These interventions not only have a positive effect on knee osteoarthritis [2] but also promote general health and well-being.

—Christina Downey, MD, Geisinger Medical Center, Danville, PA

Study Overview

Objective. To determine the effects of intra-articular triamcinolone acetonide at a dose of 40 mg administered at 3-month intervals on knee pain and progression of knee cartilage loss.

Design. Randomized, double-blind, placebo-controlled trial.

Setting and participants. 140 patients with ultrasonic features of synovitis and symptomatic knee osteoarthritis were selected from the patient pool at Tufts Medical Center in Boston, Massachusetts, between June 2011 and January 2015. Patients selected were age 45 years or older and met American College of Rheumatology osteoarthritis diagnostic criteria. Western Ontario and McMaster Universities (WOMAC) pain scores were between 2 and 8 on weight-bearing questions. Tibiofemoral osteoarthritis on posteroanterior weight bearing semi-flexed radiographs was evident in participants at a Kellegren-Lawrence grade 2 or 3. Eligible patients also had ultra-sonographic evidence of synovitis with an effusion larger than 2 mm in the study knee. Participants were excluded if they had undergone any trauma to the study joint such as osteonecrosis or a poorly controlled systemic illness. If the patient had used antibiotics, hyaluronic acid, glucosamine, chondroitin or had undergone recent intra-articular steroids in 3 months or fewer prior to the enrollment period the patient was excluded from the study. Further, patients were excluded if they were unable to undergo an MRI. Prior to pain assessments, patients were to discontinue any analgesics for 48 hours with the exception of acetaminophen if needed. The mean age of patients in this study was 58 years and the mean body mass index was 30. Half of patients had malalignment of the knee joint.

Intervention. 40 mg of a preparation of 40 mg/mL (total volume 1 mL) was injected into the intervention patients’ affected knees while 1 mL of 0.9% sodium chloride (saline solution) was injected into the control patients’ affected knees. Local anesthetic was not used. If present, synovial fluid was aspirated from the knee prior to injection. Injections were administered every 12 weeks for 2 years. Needle placement by ultrasound was utilized to ensure accurate injections, however, the probe was removed prior to injection. The injecting clinician was not involved in measuring outcomes in the study. Both intervention solutions were in identical syringes and were masked so the patient was blinded to which intervention he or she may have received.

Main outcome measure. Cartilage loss, pain, articular structural damage and physical function were the main outcome measures. Cartilage loss and structural damage were determined by MRI using validated quantitative and semi-quantitative assessments. Pain was measured with WOMAC scores and physical function was assessed using the 20-m walk test and the chair stand test. Patients were assessed during 9 scheduled visits at 3-month intervals when subjective data, blood pressure, and hemoglobin A1c levels were obtained. At 6-month intervals, patients underwent objective measures of function measured by a timed 20-m walk and chair stand testing. Evaluation of quantitative measures of cartilage analysis, semi-quantitative assessment of cartilage damage, bone marrow lesion and effusion volume measurement by MRI were done at time zero, 12 months and 24 months. The 36-Item Short-Form Health Survey was administered at these times as well. Results were computed with intention-to-treat analysis for all outcomes.

Main results. 140 patients were randomized out of 445 patients who were assessed for eligibility. Ten patients in the saline arm and 11 in the glucocorticoid arm were lost to follow-up. Groups were similar in age, BMI, varus or valgus malalignment, ultrasound measures, pain, and function measures. The group injected with triamcinolone had a higher rate of cartilage loss than the group injected with saline (–0.21 mm vs. –0.10 mm, P = 0.01) and had a higher rate of cartilage damage (–133.66 vs –72.41, P = 0.048). Cartilage denudation, bone marrow lesions, trabecular morphology and effusion volumes were not significantly different between groups. WOMAC pain measure differences from baseline in the groups were similar (–1.2 for triamcinolone group vs. –1.9 for the saline group, P = 0.17). There were also no differences between groups for the Visual Analog Scale pain score, stiffness, the 20-m walk test, or the chair stand test. Adverse events were similar between groups. At the end of the study protocol, only 45% of patients were able to correctly identify the group to which they were assigned.

Conclusion. In patients meeting American College of Rheumatology diagnostic criteria for osteoarthritis and evidence of inflammation in the affected joint, 40 mg of triamcinolone administered intra-articularly is no more effective in relieving pain or physical functioning after 2 years of injections every 3 months than normal saline. Injecting 40 mg of triamcinolone may hasten cartilage loss and damage as measured by MRI.

Commentary

In the current study, the rate of cartilage loss in the saline group was on par with prior studies examining the natural history of cartilage loss, suggesting that intra-articular steroid may actually be hastening the loss of cartilage observed in this study. The effect size was deemed moderate by the authors, though clinically significant minimal change has not been determined. Intra-articular cartilage loss is positively correlated with arthroplasty rates [1]. While this study was not designed to investigate the rate of joint replacement after intra-articular corticosteroid measurement, this may be an area for future study. Interestingly, pain and function scores were not significantly different between the 2 groups, despite the changes in cartilage. Of note, prior studies have shown the largest gains in pain relief occur during the first 4 weeks after an injection and pain measurements in this study were performed 3 months after the injections. While helpful for determining the long-term effects of intra-articular glucocorticoid administration, short-term benefits were not measured.

The Osteoarthritis Research Society International guidelines for the nonpharmacologic management of knee osteoarthritis recommend intra-articular steroids for short-term pain management based on meta-analysis of randomized controlled trials [2]. Guidelines set forth by the American College of Rheumatology in 2012 for management of osteoarthritis of the knee also recommend intra-articular steroids [3]. Intra-articular corticosteroid injections were listed as interchangeable, in the absence of comorbid conditions leading to contraindications, with oral acetaminophen, oral and topical NSAIDs, and tramadol.

Hemoglobin A1c and blood pressure were not negatively affected by intra-articular steroids in this study.

Applications for Clinical Practice

While this study overall showed hastening of cartilage loss/damage without long-term pain relief benefit, there are instances where intra-articular steroid injection may still be appropriate. For example, in patients for whom joint replacement therapy has been scheduled and temporary pain relief is needed prior to surgery, intra-articular steroids may provide the pain relief desired without cartilage loss being a clinical concern. Further, if a patient is in need of temporary pain relief to attend an important event and is at a level of marginal functional status due to pain, the benefit may outweigh the risk of hastening cartilage damage/loss to that particular patient. In light of the knowledge gained by this study, any time an intra-articular steroid injection is offered to a patient it should be made clear that the pain relief gained may be temporary and could result in faster deterioration of the cartilage.

Nonpharmacologic therapies for osteoarthritis, including water-based and land-based physical therapy and weight reduction, should be utilized before offering intra-articular corticosteroid injections. These interventions not only have a positive effect on knee osteoarthritis [2] but also promote general health and well-being.

—Christina Downey, MD, Geisinger Medical Center, Danville, PA

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine the effect of navigation for older cancer patients by lay persons on health care use and Medicare costs.

Design. Observational cohort study using propensity score–matched controls.

Setting and participants. The study was conducted at the University of Alabama at Birmingham Health System Cancer Community Network, which consists of 2 academic and 10 community cancer centers across Alabama, Georgia, Florida, Mississippi and Tennessee. Participants were Medicare beneficiaries who received care at these facilities from 1 Jan 2012 to 31 Dec 2015. The patient population includes Medicare beneficiaries age 65 years or older with primary Medicare Part A and B insurance and a cancer diagnosis from 2012 to 2015, and excludes those with Medicare health maintenance organization coverage. Only patients with 1 quarter of observation prior to receiving patient navigation and those with 2 quarters of observation after initiation of navigation services were included in the sample. Propensity score matching method was used to establish a matched group of patients without patient navigation. Covariates included in the propensity score matching include age at diagnosis, race, sex, cancer acuity, phase of care, comorbidity score, cost of care, treatment with chemotherapy and emergency department (ED) and intensive care unit use at baseline.

Patients were identified to receive patient navigation through review of patient census in the ED and hospital, clinical referral, and self-referral. High-risk patients were prioritized to receive navigation; this included patients with metastatic disease, cancers that have high morbidity, chronic diseases that have high morbidity, or a history of recent acute care utilization.

Navigation program. The patient navigation program was started in 2013 as an innovation project funded by the Center for Medicare and Medicaid Services. Implementation began in March 2013 and all sites started to enroll patients for patient navigation by October 2013. Patient navigation was conducted by lay navigators who were hired from within the community. Navigators were required to have a bachelor’s degree but were not licensed clinicians such as a nurse or social worker. Patient navigators aimed to proactively identify patient needs, connect patient with resources, coordinate patient care, and empower patients to take an active role in their own care. Navigators performed distress screenings that assessed patients’ practical, information, financial, familial, emotional, spiritual and physical concerns. Assistance was given to patients at patients’ request and algorithms were used to guide frequency of contact.

Main outcome measures. The main outcome measure was Medicare costs per beneficiary per quarter; these costs include all amounts paid by Medicare for all care received but exclude Medicare Part D prescription drug costs. Other outcomes included source of costs and resource utilization defined by number of ED visits, hospitalizations, and intensive care unit admissions per quarter. The return on investment was also examined with the investment defined by salaries for the patient navigators, including fringe benefits; each navigator had a mean caseload of 152 patients per quarter. The return on investment was calculated as reduced Medicare costs of navigated patients compared with non-navigated patients multiplied by the number of patients served.

Main results. A total of 6214 matched pairs of navigated and non-navigated patients were included in the analysis. The mean age of the patients was 75 (SD ± 7) and 12% were African American. Medicare costs declined faster among those with navigation compared to the control group by $781 more per quarter per navigated patient. Inpatient and outpatient costs had the largest decline at $294 and $275 respectively. Resource use decreased in the navigated group more so than the non-navigated group, with a 6% more decrease per quarter in ED visits, 8% more decrease in hospitalization, and 11% more decrease in intensive care unit admissions. The return on investment was estimated at 1:10 with a $475,024 reduction in Medicare cost per navigator annually.

Conclusion. Navigation by lay persons among older Medicare beneficiaries with cancer is associated with a decrease in Medicare costs and resource utilization. There is substantial return on investment when considering the salaries of navigator staff against the Medicare savings associated with care navigation. Lay navigation appears to have benefits of reducing health care costs and resource use.

Commentary

The U.S. health care system is often difficult to navigate for older persons, particularly those with complex health care needs. Older adults with chronic disease, including cancer, may utilize care in multiple settings and with multiple providers and teams, making it challenging to organize and obtain needed care. In this study, the authors examined the impact of a patient navigation program on older patients with cancer and found that the use of lay navigation is associated with reduced costs and resource use for the health care system. Prior studies have examined the use of care navigation in complex chronic disease management, such as HIV infection and cancer [1,2] and have often found positive impacts on patient satisfaction, adherence to treatments, and reducing care disparities in vulnerable populations [3]. Care navigation has been performed using clinical staff, such as nursing, but with lay persons as well [4]. Lay persons offer the benefit of reduced costs, and if they are able to perform the care navigation tasks well with training, clinical staff use may not be necessary.

This study uses alternative methods to randomization to generate a balanced non-navigated control group for comparison to determine the impact of care navigation. The limitation is that the propensity score method used may balance potential confounders that are specified but unmeasured confounders were not accounted for in the analysis [5]. Another limitation is that the comparison group may not be concurrent, because non-navigated patients prior to the initiation of the navigation program were included in the control group. As care delivery often changes over time, non-concurrent comparison may introduce bias in the study. Nonetheless, the effect that is found on costs and resource utilization appear to be a strong one and is consistent with prior studies on the effects of care navigation.

Although this study spanned several clinical settings across a large geographic area, it is unclear if the program will offer similar benefits at other institutions. Additional studies that examine the impact of lay navigation on other patient outcomes such as satisfaction will be useful, as will studying the model at other institutions and in other settings to examine whether the program’s effects can be generalized.

Applications for Clinical Practice

In general, evidence suggests that patient navigation is an effective intervention for use in health care. Clinicians should consider assigning team members to help their patients with cancer navigate the health care system.

—William W. Hung, MD, MPH

Study Overview

Objective. To determine the effect of navigation for older cancer patients by lay persons on health care use and Medicare costs.

Design. Observational cohort study using propensity score–matched controls.

Setting and participants. The study was conducted at the University of Alabama at Birmingham Health System Cancer Community Network, which consists of 2 academic and 10 community cancer centers across Alabama, Georgia, Florida, Mississippi and Tennessee. Participants were Medicare beneficiaries who received care at these facilities from 1 Jan 2012 to 31 Dec 2015. The patient population includes Medicare beneficiaries age 65 years or older with primary Medicare Part A and B insurance and a cancer diagnosis from 2012 to 2015, and excludes those with Medicare health maintenance organization coverage. Only patients with 1 quarter of observation prior to receiving patient navigation and those with 2 quarters of observation after initiation of navigation services were included in the sample. Propensity score matching method was used to establish a matched group of patients without patient navigation. Covariates included in the propensity score matching include age at diagnosis, race, sex, cancer acuity, phase of care, comorbidity score, cost of care, treatment with chemotherapy and emergency department (ED) and intensive care unit use at baseline.

Patients were identified to receive patient navigation through review of patient census in the ED and hospital, clinical referral, and self-referral. High-risk patients were prioritized to receive navigation; this included patients with metastatic disease, cancers that have high morbidity, chronic diseases that have high morbidity, or a history of recent acute care utilization.

Navigation program. The patient navigation program was started in 2013 as an innovation project funded by the Center for Medicare and Medicaid Services. Implementation began in March 2013 and all sites started to enroll patients for patient navigation by October 2013. Patient navigation was conducted by lay navigators who were hired from within the community. Navigators were required to have a bachelor’s degree but were not licensed clinicians such as a nurse or social worker. Patient navigators aimed to proactively identify patient needs, connect patient with resources, coordinate patient care, and empower patients to take an active role in their own care. Navigators performed distress screenings that assessed patients’ practical, information, financial, familial, emotional, spiritual and physical concerns. Assistance was given to patients at patients’ request and algorithms were used to guide frequency of contact.

Main outcome measures. The main outcome measure was Medicare costs per beneficiary per quarter; these costs include all amounts paid by Medicare for all care received but exclude Medicare Part D prescription drug costs. Other outcomes included source of costs and resource utilization defined by number of ED visits, hospitalizations, and intensive care unit admissions per quarter. The return on investment was also examined with the investment defined by salaries for the patient navigators, including fringe benefits; each navigator had a mean caseload of 152 patients per quarter. The return on investment was calculated as reduced Medicare costs of navigated patients compared with non-navigated patients multiplied by the number of patients served.

Main results. A total of 6214 matched pairs of navigated and non-navigated patients were included in the analysis. The mean age of the patients was 75 (SD ± 7) and 12% were African American. Medicare costs declined faster among those with navigation compared to the control group by $781 more per quarter per navigated patient. Inpatient and outpatient costs had the largest decline at $294 and $275 respectively. Resource use decreased in the navigated group more so than the non-navigated group, with a 6% more decrease per quarter in ED visits, 8% more decrease in hospitalization, and 11% more decrease in intensive care unit admissions. The return on investment was estimated at 1:10 with a $475,024 reduction in Medicare cost per navigator annually.

Conclusion. Navigation by lay persons among older Medicare beneficiaries with cancer is associated with a decrease in Medicare costs and resource utilization. There is substantial return on investment when considering the salaries of navigator staff against the Medicare savings associated with care navigation. Lay navigation appears to have benefits of reducing health care costs and resource use.

Commentary

The U.S. health care system is often difficult to navigate for older persons, particularly those with complex health care needs. Older adults with chronic disease, including cancer, may utilize care in multiple settings and with multiple providers and teams, making it challenging to organize and obtain needed care. In this study, the authors examined the impact of a patient navigation program on older patients with cancer and found that the use of lay navigation is associated with reduced costs and resource use for the health care system. Prior studies have examined the use of care navigation in complex chronic disease management, such as HIV infection and cancer [1,2] and have often found positive impacts on patient satisfaction, adherence to treatments, and reducing care disparities in vulnerable populations [3]. Care navigation has been performed using clinical staff, such as nursing, but with lay persons as well [4]. Lay persons offer the benefit of reduced costs, and if they are able to perform the care navigation tasks well with training, clinical staff use may not be necessary.

This study uses alternative methods to randomization to generate a balanced non-navigated control group for comparison to determine the impact of care navigation. The limitation is that the propensity score method used may balance potential confounders that are specified but unmeasured confounders were not accounted for in the analysis [5]. Another limitation is that the comparison group may not be concurrent, because non-navigated patients prior to the initiation of the navigation program were included in the control group. As care delivery often changes over time, non-concurrent comparison may introduce bias in the study. Nonetheless, the effect that is found on costs and resource utilization appear to be a strong one and is consistent with prior studies on the effects of care navigation.

Although this study spanned several clinical settings across a large geographic area, it is unclear if the program will offer similar benefits at other institutions. Additional studies that examine the impact of lay navigation on other patient outcomes such as satisfaction will be useful, as will studying the model at other institutions and in other settings to examine whether the program’s effects can be generalized.

Applications for Clinical Practice

In general, evidence suggests that patient navigation is an effective intervention for use in health care. Clinicians should consider assigning team members to help their patients with cancer navigate the health care system.

—William W. Hung, MD, MPH

Study Overview

Objective. To determine the effect of navigation for older cancer patients by lay persons on health care use and Medicare costs.

Design. Observational cohort study using propensity score–matched controls.

Setting and participants. The study was conducted at the University of Alabama at Birmingham Health System Cancer Community Network, which consists of 2 academic and 10 community cancer centers across Alabama, Georgia, Florida, Mississippi and Tennessee. Participants were Medicare beneficiaries who received care at these facilities from 1 Jan 2012 to 31 Dec 2015. The patient population includes Medicare beneficiaries age 65 years or older with primary Medicare Part A and B insurance and a cancer diagnosis from 2012 to 2015, and excludes those with Medicare health maintenance organization coverage. Only patients with 1 quarter of observation prior to receiving patient navigation and those with 2 quarters of observation after initiation of navigation services were included in the sample. Propensity score matching method was used to establish a matched group of patients without patient navigation. Covariates included in the propensity score matching include age at diagnosis, race, sex, cancer acuity, phase of care, comorbidity score, cost of care, treatment with chemotherapy and emergency department (ED) and intensive care unit use at baseline.

Patients were identified to receive patient navigation through review of patient census in the ED and hospital, clinical referral, and self-referral. High-risk patients were prioritized to receive navigation; this included patients with metastatic disease, cancers that have high morbidity, chronic diseases that have high morbidity, or a history of recent acute care utilization.

Navigation program. The patient navigation program was started in 2013 as an innovation project funded by the Center for Medicare and Medicaid Services. Implementation began in March 2013 and all sites started to enroll patients for patient navigation by October 2013. Patient navigation was conducted by lay navigators who were hired from within the community. Navigators were required to have a bachelor’s degree but were not licensed clinicians such as a nurse or social worker. Patient navigators aimed to proactively identify patient needs, connect patient with resources, coordinate patient care, and empower patients to take an active role in their own care. Navigators performed distress screenings that assessed patients’ practical, information, financial, familial, emotional, spiritual and physical concerns. Assistance was given to patients at patients’ request and algorithms were used to guide frequency of contact.

Main outcome measures. The main outcome measure was Medicare costs per beneficiary per quarter; these costs include all amounts paid by Medicare for all care received but exclude Medicare Part D prescription drug costs. Other outcomes included source of costs and resource utilization defined by number of ED visits, hospitalizations, and intensive care unit admissions per quarter. The return on investment was also examined with the investment defined by salaries for the patient navigators, including fringe benefits; each navigator had a mean caseload of 152 patients per quarter. The return on investment was calculated as reduced Medicare costs of navigated patients compared with non-navigated patients multiplied by the number of patients served.

Main results. A total of 6214 matched pairs of navigated and non-navigated patients were included in the analysis. The mean age of the patients was 75 (SD ± 7) and 12% were African American. Medicare costs declined faster among those with navigation compared to the control group by $781 more per quarter per navigated patient. Inpatient and outpatient costs had the largest decline at $294 and $275 respectively. Resource use decreased in the navigated group more so than the non-navigated group, with a 6% more decrease per quarter in ED visits, 8% more decrease in hospitalization, and 11% more decrease in intensive care unit admissions. The return on investment was estimated at 1:10 with a $475,024 reduction in Medicare cost per navigator annually.

Conclusion. Navigation by lay persons among older Medicare beneficiaries with cancer is associated with a decrease in Medicare costs and resource utilization. There is substantial return on investment when considering the salaries of navigator staff against the Medicare savings associated with care navigation. Lay navigation appears to have benefits of reducing health care costs and resource use.

Commentary

The U.S. health care system is often difficult to navigate for older persons, particularly those with complex health care needs. Older adults with chronic disease, including cancer, may utilize care in multiple settings and with multiple providers and teams, making it challenging to organize and obtain needed care. In this study, the authors examined the impact of a patient navigation program on older patients with cancer and found that the use of lay navigation is associated with reduced costs and resource use for the health care system. Prior studies have examined the use of care navigation in complex chronic disease management, such as HIV infection and cancer [1,2] and have often found positive impacts on patient satisfaction, adherence to treatments, and reducing care disparities in vulnerable populations [3]. Care navigation has been performed using clinical staff, such as nursing, but with lay persons as well [4]. Lay persons offer the benefit of reduced costs, and if they are able to perform the care navigation tasks well with training, clinical staff use may not be necessary.

This study uses alternative methods to randomization to generate a balanced non-navigated control group for comparison to determine the impact of care navigation. The limitation is that the propensity score method used may balance potential confounders that are specified but unmeasured confounders were not accounted for in the analysis [5]. Another limitation is that the comparison group may not be concurrent, because non-navigated patients prior to the initiation of the navigation program were included in the control group. As care delivery often changes over time, non-concurrent comparison may introduce bias in the study. Nonetheless, the effect that is found on costs and resource utilization appear to be a strong one and is consistent with prior studies on the effects of care navigation.

Although this study spanned several clinical settings across a large geographic area, it is unclear if the program will offer similar benefits at other institutions. Additional studies that examine the impact of lay navigation on other patient outcomes such as satisfaction will be useful, as will studying the model at other institutions and in other settings to examine whether the program’s effects can be generalized.

Applications for Clinical Practice

In general, evidence suggests that patient navigation is an effective intervention for use in health care. Clinicians should consider assigning team members to help their patients with cancer navigate the health care system.

—William W. Hung, MD, MPH

Study Overview

Objective. To examine the screening practices of family practitioners (FPs) and pediatricians for type 2 diabetes (T2D) in adolescents.

Design. Cross-sectional study.

Setting and participants. The researchers randomly sampled 700 pediatricians and 700 FPs who participated in direct patient care using the American Medical Association Physician Masterfile using a mail survey. Exclusion criteria included providers who were residents, hospital staff, retirees, or employed by federally owned medical facilities, certified with a subspecialty, or over age 70.

Main outcome measures. Providers were given a hypothetical case of an obese, female, teenaged patient with concurrent associated risk factors for T2D (family history of T2D, minority race, signs of insulin resistance) and asked what initial screening tests they would order. Respondents were then informed of the updated American Diabetes Association (ADA) guidelines that added hemoglobin A1c as a screening test to diagnose diabetes. The survey then asked if knowing this change in recommendation has changed or will change their screening practices in adolescents.

Main results. 1400 surveys were mailed. After 2 were excluded due to mailing issues, 52% of providers provided responses. Of these, 129 providers reported that they did not care for adolescents (age 10–17), resulting in 604 providers in the final sample, 398 pediatricians and 335 FPs.

The vast majority (92%) said they would screen the hypothetical case for diabetes, with most initially ordering a fasting test (fasting plasma glucose or 2-hour glucose tolerance test) (63%) or A1c test (58%). Of the 58% who planned to order HbA1c, only 35% ordered it in combination with a fasting test. HbA1c was significantly more likely to be ordered by pediatricians than by FPs (P = 0.001). After being presented with the new guidelines, 84% said then would now order HbA1c, a 27% increase.

Conclusion. In response to information about the new guidelines, providers were more likely to order A1c as part of initial testing. Due to the lower test performance in children and increased cost of the test, the use of HbA1c without fasting tests may result in missed diagnosis of T2D in adolescents as well as increased health care costs.

Commentary

Rates of childhood obesity continue to rise throughout the United States. Obese children are at risk for numerous comorbidities such as hypertension, hyperlipidemia, and T2D [1,2]. It is important for providers to use effective screening tools for risk assessment of prediabetes/T2DM in children.

The standard tests for diagnosing diabetes are the fasting plasma glucose test and the 2-hour plasma glucose test. While accurate, these tests are not convenient. In 2010, the ADA added an easier method of testing for T2D: an HbA1c, with results greater than or equal to 6.5% indicating diabetes [3]. However, this recommendation is controversial, given studies suggesting that HbA1c is not as reliable in children as it is in adults [4–6]. The ADA itself acknowledges that there are limited data in the pediatric population.

In this study, most providers were unaware of the 4-year-old revised guidelines offering the A1c option but are planning to apply the guidelines going forward. According to the study, this would result in a 27% increase in providers utilizing HbA1c.

Should increased uptake of A1c as an initial screening test be a concern? Using it in combination with other tests may be useful for assessing which adolescents will need further testing [3–6]. Additionally, by starting with a test that can be performed in the office with no regard to fasting time, it is possible that more cases of T2D will be found by primary care providers treating adolescents.

A weakness of the study is the potential for response bias related to mailed surveys. An additional weakness is that the researchers utilized only 1 hypothetical situation. Providing additional hypothetical situations may have allowed for further understanding of screening practices. The investigators also did not include nurse practitioners or physician assistants in their sample, a growing percentage of whom may care for adolescent populations at risk for T2D or be primary referral sources.

Applications for Clinical Practice

Providers can use HbA1c to screen for diabetes in nonfasting adolescents at risk for diabetes. While the test may not be as accurate in pediatric patients, utilizing HbA1C as directed by the ADA may aid in diagnosing patients that may otherwise miss follow-up appointments to complete a fasting test.

                                                                                                                                                                                           —Jennifer L. Nahum, MSN, CPNP-AC, PPCNP-BC, and Allison Squires, PhD, RN

Study Overview

Objective. To examine the screening practices of family practitioners (FPs) and pediatricians for type 2 diabetes (T2D) in adolescents.

Design. Cross-sectional study.

Setting and participants. The researchers randomly sampled 700 pediatricians and 700 FPs who participated in direct patient care using the American Medical Association Physician Masterfile using a mail survey. Exclusion criteria included providers who were residents, hospital staff, retirees, or employed by federally owned medical facilities, certified with a subspecialty, or over age 70.

Main outcome measures. Providers were given a hypothetical case of an obese, female, teenaged patient with concurrent associated risk factors for T2D (family history of T2D, minority race, signs of insulin resistance) and asked what initial screening tests they would order. Respondents were then informed of the updated American Diabetes Association (ADA) guidelines that added hemoglobin A1c as a screening test to diagnose diabetes. The survey then asked if knowing this change in recommendation has changed or will change their screening practices in adolescents.

Main results. 1400 surveys were mailed. After 2 were excluded due to mailing issues, 52% of providers provided responses. Of these, 129 providers reported that they did not care for adolescents (age 10–17), resulting in 604 providers in the final sample, 398 pediatricians and 335 FPs.

The vast majority (92%) said they would screen the hypothetical case for diabetes, with most initially ordering a fasting test (fasting plasma glucose or 2-hour glucose tolerance test) (63%) or A1c test (58%). Of the 58% who planned to order HbA1c, only 35% ordered it in combination with a fasting test. HbA1c was significantly more likely to be ordered by pediatricians than by FPs (P = 0.001). After being presented with the new guidelines, 84% said then would now order HbA1c, a 27% increase.

Conclusion. In response to information about the new guidelines, providers were more likely to order A1c as part of initial testing. Due to the lower test performance in children and increased cost of the test, the use of HbA1c without fasting tests may result in missed diagnosis of T2D in adolescents as well as increased health care costs.

Commentary

Rates of childhood obesity continue to rise throughout the United States. Obese children are at risk for numerous comorbidities such as hypertension, hyperlipidemia, and T2D [1,2]. It is important for providers to use effective screening tools for risk assessment of prediabetes/T2DM in children.

The standard tests for diagnosing diabetes are the fasting plasma glucose test and the 2-hour plasma glucose test. While accurate, these tests are not convenient. In 2010, the ADA added an easier method of testing for T2D: an HbA1c, with results greater than or equal to 6.5% indicating diabetes [3]. However, this recommendation is controversial, given studies suggesting that HbA1c is not as reliable in children as it is in adults [4–6]. The ADA itself acknowledges that there are limited data in the pediatric population.

In this study, most providers were unaware of the 4-year-old revised guidelines offering the A1c option but are planning to apply the guidelines going forward. According to the study, this would result in a 27% increase in providers utilizing HbA1c.

Should increased uptake of A1c as an initial screening test be a concern? Using it in combination with other tests may be useful for assessing which adolescents will need further testing [3–6]. Additionally, by starting with a test that can be performed in the office with no regard to fasting time, it is possible that more cases of T2D will be found by primary care providers treating adolescents.

A weakness of the study is the potential for response bias related to mailed surveys. An additional weakness is that the researchers utilized only 1 hypothetical situation. Providing additional hypothetical situations may have allowed for further understanding of screening practices. The investigators also did not include nurse practitioners or physician assistants in their sample, a growing percentage of whom may care for adolescent populations at risk for T2D or be primary referral sources.

Applications for Clinical Practice

Providers can use HbA1c to screen for diabetes in nonfasting adolescents at risk for diabetes. While the test may not be as accurate in pediatric patients, utilizing HbA1C as directed by the ADA may aid in diagnosing patients that may otherwise miss follow-up appointments to complete a fasting test.

                                                                                                                                                                                           —Jennifer L. Nahum, MSN, CPNP-AC, PPCNP-BC, and Allison Squires, PhD, RN

Study Overview

Objective. To examine the screening practices of family practitioners (FPs) and pediatricians for type 2 diabetes (T2D) in adolescents.

Design. Cross-sectional study.

Setting and participants. The researchers randomly sampled 700 pediatricians and 700 FPs who participated in direct patient care using the American Medical Association Physician Masterfile using a mail survey. Exclusion criteria included providers who were residents, hospital staff, retirees, or employed by federally owned medical facilities, certified with a subspecialty, or over age 70.

Main outcome measures. Providers were given a hypothetical case of an obese, female, teenaged patient with concurrent associated risk factors for T2D (family history of T2D, minority race, signs of insulin resistance) and asked what initial screening tests they would order. Respondents were then informed of the updated American Diabetes Association (ADA) guidelines that added hemoglobin A1c as a screening test to diagnose diabetes. The survey then asked if knowing this change in recommendation has changed or will change their screening practices in adolescents.

Main results. 1400 surveys were mailed. After 2 were excluded due to mailing issues, 52% of providers provided responses. Of these, 129 providers reported that they did not care for adolescents (age 10–17), resulting in 604 providers in the final sample, 398 pediatricians and 335 FPs.

The vast majority (92%) said they would screen the hypothetical case for diabetes, with most initially ordering a fasting test (fasting plasma glucose or 2-hour glucose tolerance test) (63%) or A1c test (58%). Of the 58% who planned to order HbA1c, only 35% ordered it in combination with a fasting test. HbA1c was significantly more likely to be ordered by pediatricians than by FPs (P = 0.001). After being presented with the new guidelines, 84% said then would now order HbA1c, a 27% increase.

Conclusion. In response to information about the new guidelines, providers were more likely to order A1c as part of initial testing. Due to the lower test performance in children and increased cost of the test, the use of HbA1c without fasting tests may result in missed diagnosis of T2D in adolescents as well as increased health care costs.

Commentary

Rates of childhood obesity continue to rise throughout the United States. Obese children are at risk for numerous comorbidities such as hypertension, hyperlipidemia, and T2D [1,2]. It is important for providers to use effective screening tools for risk assessment of prediabetes/T2DM in children.

The standard tests for diagnosing diabetes are the fasting plasma glucose test and the 2-hour plasma glucose test. While accurate, these tests are not convenient. In 2010, the ADA added an easier method of testing for T2D: an HbA1c, with results greater than or equal to 6.5% indicating diabetes [3]. However, this recommendation is controversial, given studies suggesting that HbA1c is not as reliable in children as it is in adults [4–6]. The ADA itself acknowledges that there are limited data in the pediatric population.

In this study, most providers were unaware of the 4-year-old revised guidelines offering the A1c option but are planning to apply the guidelines going forward. According to the study, this would result in a 27% increase in providers utilizing HbA1c.

Should increased uptake of A1c as an initial screening test be a concern? Using it in combination with other tests may be useful for assessing which adolescents will need further testing [3–6]. Additionally, by starting with a test that can be performed in the office with no regard to fasting time, it is possible that more cases of T2D will be found by primary care providers treating adolescents.

A weakness of the study is the potential for response bias related to mailed surveys. An additional weakness is that the researchers utilized only 1 hypothetical situation. Providing additional hypothetical situations may have allowed for further understanding of screening practices. The investigators also did not include nurse practitioners or physician assistants in their sample, a growing percentage of whom may care for adolescent populations at risk for T2D or be primary referral sources.

Applications for Clinical Practice

Providers can use HbA1c to screen for diabetes in nonfasting adolescents at risk for diabetes. While the test may not be as accurate in pediatric patients, utilizing HbA1C as directed by the ADA may aid in diagnosing patients that may otherwise miss follow-up appointments to complete a fasting test.

                                                                                                                                                                                           —Jennifer L. Nahum, MSN, CPNP-AC, PPCNP-BC, and Allison Squires, PhD, RN

Study Overview

Objective. To evaluate efficacy of adding bevacizumab to first-line chemotherapy for treatment of extensive-disease small-cell lung cancer (ED-SCLC).

Design. Phase III prospective multicenter randomized clinical trial.

Setting and participants. The study was conducted at 29 Italian centers and was supported by the Agenzia Italiana del Farmaco. Study entry was limited to patients with histologically or cytologically documented ED-SCLC who were previously untreated with systemic therapy, were 18 years of age or older, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2. Adequate bone marrow, renal, and liver functions were required. Patients with asymptomatic, treated brain metastases were eligible for trial participation. Exclusions included the following: mixed histologic diagnosis of SCLC and non–SCLC; history of grade 2 hemoptysis; evidence of lung tumor cavitation; significant traumatic injury within the 4 weeks before first dose of study treatment; other active malignancies (previous or current); and any underlying medical condition that might be aggravated by treatment.

Intervention. Patients received a combination of intravenous cisplatin (25 mg/m² on days 1 to 3), etoposide (100 mg/m² on days 1 to 3), and bevacizumab (7.5 mg/kg intravenously on day 1) administered every 3 weeks (experimental arm); or the same cisplatin and etoposide chemotherapy regimen alone given every 3 weeks (control arm). Carboplatin (area under the curve 5 on day 1) could be substituted for cisplatin in case of cisplatin contraindications or cisplatin-associated toxicity. Tumor response, on the basis of investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1), was evaluated every 3 cycles during chemotherapy treatment. After 6 cycles of chemotherapy, tumor assessment was performed every 9 weeks in both arms. In the absence of progression, patients in the treatment arm continued bevacizumab alone until disease progression or for a maximum of 18 courses. Survival follow-up information was collected every 6 months after treatment termination or last dose of study drug, until death or loss to follow-up.

Main outcome measure. The primary end point was overall survival (OS). Response rate, toxicity, and progression-free survival (PFS) were secondary end points.

Main results. 205 patients were randomized between November 2009 and October 2015. 204 patients were considered in the intent-to-treat analysis (103 in the control arm and 101 in the treatment arm). Most patients were male with ECOG PS of 0 to 1. Median age was 64 years. The median number of chemotherapy courses administered was 6 in both arms. Cisplatin was used in majority of the patients. Average relative dose intensities for all drugs were well balanced between 2 groups. A lower percentage of patients in the treatment arm (14.7%) than in the control arm (22.3%) discontinued treatment because of radiologic disease progression, which was the main reason for treatment discontinuation.

At a median follow-up of 34.9 months, the median PFS was 5.7 in the control arm and 6.7 months in the treatment arm (hazard ratio [HR], 0.72; 95% CI, 0.54 to 0.97; P = 0.30). Median OS times were 8.9 months and 9.8 months, and 1-year survival rates were 25% and 37% (HR, 0.78; 95% CI, 0.58 to 1.06; P = 0.113) in the control arm and treatment arm, respectively. A significant effect of the maintenance treatment on OS (HR, 0.60; 95% CI, 0.40 to 0.91, P = 0.011) was observed. A subgroup analysis revealed a statistically significant interaction for OS between treatment and sex; the addition of bevacizumab led to a significant survival benefit in men (HR, 0.55) and to a possible detrimental effect in women (HR, 1.55; interaction test, P = 0.003).

Addition of bevacizumab did not result in increase in hematologic toxicity such as anemia, neutropenia, or thrombocytopenia. Concerning the nonhematologic toxicity, only hypertension was more frequent in the bevacizumab arm (6.3%) compared to chemotherapy alone arm (1%). The rates of proteinuria and thrombosis were similar in both arms.

Conclusion. The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in PFS, which, however, did not translate into a statistically significant increase in OS.

Commentary

SCLC currently accounts for approximately 12% to 15% of all lung cancers [1]. It is characterized by a rapid growth rate, metastasis at the time of diagnosis, sensitivity to first-line platinum-based chemotherapy, and invariable recurrence and progressive resistance to subsequent lines of therapy. A number of clinical trials over the past 2 decades have failed to produce outcomes superior to platinum-based doublet chemotherapy, leaving a significant unmet need [2]. Vascular endothelial growth factor (VEGF) is the most important proangiogenic factor, and it is implicated in tumor growth [3]. Bevacizumab, a humanized monoclonal antibody directed against VEGF, is now indicated in the treatment of several tumor types including non–SCLC and breast, colorectal, kidney, and ovarian cancer. Positive signal with bevacizumab was seen in phase II studies, providing rationale for this phase III trial [4,5] .

The study by Tiseo and colleagues reported the outcomes of a randomized study that added bevacizumab to standard combination therapy with platinum and etoposide for the treatment of ED-SCLC. A small statistically significant improvement was seen in PFS (6.7 months vs. 5.7 months, favoring the bevacizumab group). However, the study failed to meet the primary end point of improved OS.

So where do antiangiogenesis agents go from here? Alternative angiogenesis inhibitors with broader mechanism of action are being explored in clinical trials. One such trial (ClinicalTrials.gov identifier: NCT02945852) is evaluating the role of the tyrosine kinase inhibitor apatinib in combination with chemotherapy in ED-SCLC. Apatinib selectively inhibits the vascular growth factor receptor-2 (VEGFR2). In addition, this agent also inhibits c-kit and c-SRC tyrosine kinase. It would be interesting to see if antiangiogenic agents with broader mechanisms would be more effective in SCLC. Immunotherapy with checkpoint inhibitors such as nivolumab and pembrolizumab have revolutionized the lung cancer treatment paradigm. It would be interesting to see if bevacizumab could be safely added to these immunotherapy agents. The ongoing CheckMate 370 (ClinicalTrials.gov identifier: NCT02574078) is addressing this question, evaluating the safety of combining nivolumab with bevacizumab in non-SCLC.

Applications for Clinical Practice

The current study does not support the addition of bevacizumab as a standard therapeutic option in the first-line treatment of ED-SCLC. However, given that there was a trend towards improved OS, alternative strategies of incorporating antiangiogenesis agents should be considered in future clinical trials.

—Deval Rajyaguru, MD

Study Overview

Objective. To evaluate efficacy of adding bevacizumab to first-line chemotherapy for treatment of extensive-disease small-cell lung cancer (ED-SCLC).

Design. Phase III prospective multicenter randomized clinical trial.

Setting and participants. The study was conducted at 29 Italian centers and was supported by the Agenzia Italiana del Farmaco. Study entry was limited to patients with histologically or cytologically documented ED-SCLC who were previously untreated with systemic therapy, were 18 years of age or older, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2. Adequate bone marrow, renal, and liver functions were required. Patients with asymptomatic, treated brain metastases were eligible for trial participation. Exclusions included the following: mixed histologic diagnosis of SCLC and non–SCLC; history of grade 2 hemoptysis; evidence of lung tumor cavitation; significant traumatic injury within the 4 weeks before first dose of study treatment; other active malignancies (previous or current); and any underlying medical condition that might be aggravated by treatment.

Intervention. Patients received a combination of intravenous cisplatin (25 mg/m² on days 1 to 3), etoposide (100 mg/m² on days 1 to 3), and bevacizumab (7.5 mg/kg intravenously on day 1) administered every 3 weeks (experimental arm); or the same cisplatin and etoposide chemotherapy regimen alone given every 3 weeks (control arm). Carboplatin (area under the curve 5 on day 1) could be substituted for cisplatin in case of cisplatin contraindications or cisplatin-associated toxicity. Tumor response, on the basis of investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1), was evaluated every 3 cycles during chemotherapy treatment. After 6 cycles of chemotherapy, tumor assessment was performed every 9 weeks in both arms. In the absence of progression, patients in the treatment arm continued bevacizumab alone until disease progression or for a maximum of 18 courses. Survival follow-up information was collected every 6 months after treatment termination or last dose of study drug, until death or loss to follow-up.

Main outcome measure. The primary end point was overall survival (OS). Response rate, toxicity, and progression-free survival (PFS) were secondary end points.

Main results. 205 patients were randomized between November 2009 and October 2015. 204 patients were considered in the intent-to-treat analysis (103 in the control arm and 101 in the treatment arm). Most patients were male with ECOG PS of 0 to 1. Median age was 64 years. The median number of chemotherapy courses administered was 6 in both arms. Cisplatin was used in majority of the patients. Average relative dose intensities for all drugs were well balanced between 2 groups. A lower percentage of patients in the treatment arm (14.7%) than in the control arm (22.3%) discontinued treatment because of radiologic disease progression, which was the main reason for treatment discontinuation.

At a median follow-up of 34.9 months, the median PFS was 5.7 in the control arm and 6.7 months in the treatment arm (hazard ratio [HR], 0.72; 95% CI, 0.54 to 0.97; P = 0.30). Median OS times were 8.9 months and 9.8 months, and 1-year survival rates were 25% and 37% (HR, 0.78; 95% CI, 0.58 to 1.06; P = 0.113) in the control arm and treatment arm, respectively. A significant effect of the maintenance treatment on OS (HR, 0.60; 95% CI, 0.40 to 0.91, P = 0.011) was observed. A subgroup analysis revealed a statistically significant interaction for OS between treatment and sex; the addition of bevacizumab led to a significant survival benefit in men (HR, 0.55) and to a possible detrimental effect in women (HR, 1.55; interaction test, P = 0.003).

Addition of bevacizumab did not result in increase in hematologic toxicity such as anemia, neutropenia, or thrombocytopenia. Concerning the nonhematologic toxicity, only hypertension was more frequent in the bevacizumab arm (6.3%) compared to chemotherapy alone arm (1%). The rates of proteinuria and thrombosis were similar in both arms.

Conclusion. The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in PFS, which, however, did not translate into a statistically significant increase in OS.

Commentary

SCLC currently accounts for approximately 12% to 15% of all lung cancers [1]. It is characterized by a rapid growth rate, metastasis at the time of diagnosis, sensitivity to first-line platinum-based chemotherapy, and invariable recurrence and progressive resistance to subsequent lines of therapy. A number of clinical trials over the past 2 decades have failed to produce outcomes superior to platinum-based doublet chemotherapy, leaving a significant unmet need [2]. Vascular endothelial growth factor (VEGF) is the most important proangiogenic factor, and it is implicated in tumor growth [3]. Bevacizumab, a humanized monoclonal antibody directed against VEGF, is now indicated in the treatment of several tumor types including non–SCLC and breast, colorectal, kidney, and ovarian cancer. Positive signal with bevacizumab was seen in phase II studies, providing rationale for this phase III trial [4,5] .

The study by Tiseo and colleagues reported the outcomes of a randomized study that added bevacizumab to standard combination therapy with platinum and etoposide for the treatment of ED-SCLC. A small statistically significant improvement was seen in PFS (6.7 months vs. 5.7 months, favoring the bevacizumab group). However, the study failed to meet the primary end point of improved OS.

So where do antiangiogenesis agents go from here? Alternative angiogenesis inhibitors with broader mechanism of action are being explored in clinical trials. One such trial (ClinicalTrials.gov identifier: NCT02945852) is evaluating the role of the tyrosine kinase inhibitor apatinib in combination with chemotherapy in ED-SCLC. Apatinib selectively inhibits the vascular growth factor receptor-2 (VEGFR2). In addition, this agent also inhibits c-kit and c-SRC tyrosine kinase. It would be interesting to see if antiangiogenic agents with broader mechanisms would be more effective in SCLC. Immunotherapy with checkpoint inhibitors such as nivolumab and pembrolizumab have revolutionized the lung cancer treatment paradigm. It would be interesting to see if bevacizumab could be safely added to these immunotherapy agents. The ongoing CheckMate 370 (ClinicalTrials.gov identifier: NCT02574078) is addressing this question, evaluating the safety of combining nivolumab with bevacizumab in non-SCLC.

Applications for Clinical Practice

The current study does not support the addition of bevacizumab as a standard therapeutic option in the first-line treatment of ED-SCLC. However, given that there was a trend towards improved OS, alternative strategies of incorporating antiangiogenesis agents should be considered in future clinical trials.

—Deval Rajyaguru, MD

Study Overview

Objective. To evaluate efficacy of adding bevacizumab to first-line chemotherapy for treatment of extensive-disease small-cell lung cancer (ED-SCLC).

Design. Phase III prospective multicenter randomized clinical trial.

Setting and participants. The study was conducted at 29 Italian centers and was supported by the Agenzia Italiana del Farmaco. Study entry was limited to patients with histologically or cytologically documented ED-SCLC who were previously untreated with systemic therapy, were 18 years of age or older, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2. Adequate bone marrow, renal, and liver functions were required. Patients with asymptomatic, treated brain metastases were eligible for trial participation. Exclusions included the following: mixed histologic diagnosis of SCLC and non–SCLC; history of grade 2 hemoptysis; evidence of lung tumor cavitation; significant traumatic injury within the 4 weeks before first dose of study treatment; other active malignancies (previous or current); and any underlying medical condition that might be aggravated by treatment.

Intervention. Patients received a combination of intravenous cisplatin (25 mg/m² on days 1 to 3), etoposide (100 mg/m² on days 1 to 3), and bevacizumab (7.5 mg/kg intravenously on day 1) administered every 3 weeks (experimental arm); or the same cisplatin and etoposide chemotherapy regimen alone given every 3 weeks (control arm). Carboplatin (area under the curve 5 on day 1) could be substituted for cisplatin in case of cisplatin contraindications or cisplatin-associated toxicity. Tumor response, on the basis of investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1), was evaluated every 3 cycles during chemotherapy treatment. After 6 cycles of chemotherapy, tumor assessment was performed every 9 weeks in both arms. In the absence of progression, patients in the treatment arm continued bevacizumab alone until disease progression or for a maximum of 18 courses. Survival follow-up information was collected every 6 months after treatment termination or last dose of study drug, until death or loss to follow-up.

Main outcome measure. The primary end point was overall survival (OS). Response rate, toxicity, and progression-free survival (PFS) were secondary end points.

Main results. 205 patients were randomized between November 2009 and October 2015. 204 patients were considered in the intent-to-treat analysis (103 in the control arm and 101 in the treatment arm). Most patients were male with ECOG PS of 0 to 1. Median age was 64 years. The median number of chemotherapy courses administered was 6 in both arms. Cisplatin was used in majority of the patients. Average relative dose intensities for all drugs were well balanced between 2 groups. A lower percentage of patients in the treatment arm (14.7%) than in the control arm (22.3%) discontinued treatment because of radiologic disease progression, which was the main reason for treatment discontinuation.

At a median follow-up of 34.9 months, the median PFS was 5.7 in the control arm and 6.7 months in the treatment arm (hazard ratio [HR], 0.72; 95% CI, 0.54 to 0.97; P = 0.30). Median OS times were 8.9 months and 9.8 months, and 1-year survival rates were 25% and 37% (HR, 0.78; 95% CI, 0.58 to 1.06; P = 0.113) in the control arm and treatment arm, respectively. A significant effect of the maintenance treatment on OS (HR, 0.60; 95% CI, 0.40 to 0.91, P = 0.011) was observed. A subgroup analysis revealed a statistically significant interaction for OS between treatment and sex; the addition of bevacizumab led to a significant survival benefit in men (HR, 0.55) and to a possible detrimental effect in women (HR, 1.55; interaction test, P = 0.003).

Addition of bevacizumab did not result in increase in hematologic toxicity such as anemia, neutropenia, or thrombocytopenia. Concerning the nonhematologic toxicity, only hypertension was more frequent in the bevacizumab arm (6.3%) compared to chemotherapy alone arm (1%). The rates of proteinuria and thrombosis were similar in both arms.

Conclusion. The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in PFS, which, however, did not translate into a statistically significant increase in OS.

Commentary

SCLC currently accounts for approximately 12% to 15% of all lung cancers [1]. It is characterized by a rapid growth rate, metastasis at the time of diagnosis, sensitivity to first-line platinum-based chemotherapy, and invariable recurrence and progressive resistance to subsequent lines of therapy. A number of clinical trials over the past 2 decades have failed to produce outcomes superior to platinum-based doublet chemotherapy, leaving a significant unmet need [2]. Vascular endothelial growth factor (VEGF) is the most important proangiogenic factor, and it is implicated in tumor growth [3]. Bevacizumab, a humanized monoclonal antibody directed against VEGF, is now indicated in the treatment of several tumor types including non–SCLC and breast, colorectal, kidney, and ovarian cancer. Positive signal with bevacizumab was seen in phase II studies, providing rationale for this phase III trial [4,5] .

The study by Tiseo and colleagues reported the outcomes of a randomized study that added bevacizumab to standard combination therapy with platinum and etoposide for the treatment of ED-SCLC. A small statistically significant improvement was seen in PFS (6.7 months vs. 5.7 months, favoring the bevacizumab group). However, the study failed to meet the primary end point of improved OS.

So where do antiangiogenesis agents go from here? Alternative angiogenesis inhibitors with broader mechanism of action are being explored in clinical trials. One such trial (ClinicalTrials.gov identifier: NCT02945852) is evaluating the role of the tyrosine kinase inhibitor apatinib in combination with chemotherapy in ED-SCLC. Apatinib selectively inhibits the vascular growth factor receptor-2 (VEGFR2). In addition, this agent also inhibits c-kit and c-SRC tyrosine kinase. It would be interesting to see if antiangiogenic agents with broader mechanisms would be more effective in SCLC. Immunotherapy with checkpoint inhibitors such as nivolumab and pembrolizumab have revolutionized the lung cancer treatment paradigm. It would be interesting to see if bevacizumab could be safely added to these immunotherapy agents. The ongoing CheckMate 370 (ClinicalTrials.gov identifier: NCT02574078) is addressing this question, evaluating the safety of combining nivolumab with bevacizumab in non-SCLC.

Applications for Clinical Practice

The current study does not support the addition of bevacizumab as a standard therapeutic option in the first-line treatment of ED-SCLC. However, given that there was a trend towards improved OS, alternative strategies of incorporating antiangiogenesis agents should be considered in future clinical trials.

—Deval Rajyaguru, MD

Study Overview

Objective. To investigate the association between habitually high levels of physical activity and the compliance of the large and small arteries in men and women throughout the life span.

Design. Cross-sectional study.

Setting and participants. 83 healthy men (n = 44) and women (n = 39) aged between 18 and 78 years were recruited to participate in the study. Potential participants were recruited via flyers designed to elicit responses from either very highly active (participate in regular, vigorous exercise more than 5 times per week) or less active/sedentary individuals (participate in light to moderate exercise less than 3 times per week or none at all). Both groups subjectively reported maintaining the specified activity level for at least the past 5 years. The highly active subjects performed regular vigorous swimming as their primary mode of exercise training as most were members of a varsity or masters swim team. All subjects were free of overt chronic diseases, nonsmokers, and none were taking vasoactive medications as assessed by a medical history questionnaire. All subjects provided written informed consent to participate. The study was reviewed and approved by the institutional review board at Indiana University.

Physical activity was self-assessed in all subject groups with a log detailing their activity over the previous 7 days. To ensure the older highly active population performed vigorous physical activity ≥ 5 days per week, the subjective activity log was verified by a 7-day previously validated, commercially available heart rate monitor and accelerometer (Actiheart, CamNtech, Cambridge, UK).

Main outcome measure. Compliance of the small and large arteries (inverse of stiffness) measured using a commercial pulse wave analyzer (Model CR-2000, Hypertension Diagnositics, Eagen, MN), which according to the manufacturer measures proximal capacitive compliance (C1, or estimate of large artery compliance) and distal oscillatory compliance (C2, or small artery compliance) [1].

Results. The study found a positive association between routine vigorous physical activity and arterial compliance. Specifically, the results suggest that vigorous physical activity is associated with greater compliance of the small and large arteries in both younger and older adults (P < 0.05). In addition, both the highly active and less active younger groups as well as the highly active older group demonstrated greater large arterial compliance compared to the less active older group (P < 0.008). No significant differences were found between men and women.

Conclusion. Researchers concluded that participation in habitual vigorous physical activity is associated with benefits to the compliance of the small and large arteries. Habitual vigorous physical activity over time may attenuate age-associated cardiovascular impairments.

Commentary

Arterial compliance declines with age, and increased arterial stiffness is associated with an increased risk of cardiovascular events [2]. Evidence suggests that physical activity may delay or prevent age-related increases in arterial stiffness [3]. Previous research regarding age-related arterial stiffness and exercise has focused primarily on the large arteries. For example, Tanaka found that regular aerobic-endurance exercise attenuates age-related reductions in central arterial compliance and restores levels in previously sedentary healthy middle-aged and older men [3]. More recently, a study by Duprez [4] found that small artery elasticity was superior to large artery elasticity with regard to predicting future CHD, stroke, and heart failure.

In this study, researchers cross-sectionally investigated the relationship of intense and continuous physical activity in young and older adults. The form of vigorous activity in this study was competitive swimming, as participants were recruited from a collegiate varsity and masters swim team. The study found a statistically strong association between routine vigorous physical activity and arterial compliance. These findings agree with several studies showing the benefits of vigorous exercise, but go beyond these by presenting findings on small artery compliance.

Methodologically, this study has some limitations. With the small sample, the study may not have been adequately powered. Further, physical activity assessment was by self-report in the main. Even though researchers had the participants keep a log, self-report measures may be inaccurate. Another limitation was the indirect method of measuring compliance, in which the radial waveform is calibrated to brachial blood pressure values. However, the researchers followed a valid model using the same BP level–based procedures reported in previous studies [1].

Applications for Clinical Practice

CVD is a major cause of disability and mortality in the United States. Health care professionals have a significant role to play in reducing cardiovascular risk factors in their patients, including encouraging aerobic exercise. The American Heart Association recommends at least 30 minutes of moderate-intensity aerobic activity at least 5 days per week or at least 25 minutes of vigorous aerobic activity at least 3 days per week, or a combination of moderate- and vigorous-intensity aerobic activity [4]. Patients can also be reminded that even modest levels of physical activity are associated with health benefits.

—Paloma Cesar de Sales, BS, RN, MS

Study Overview

Objective. To investigate the association between habitually high levels of physical activity and the compliance of the large and small arteries in men and women throughout the life span.

Design. Cross-sectional study.

Setting and participants. 83 healthy men (n = 44) and women (n = 39) aged between 18 and 78 years were recruited to participate in the study. Potential participants were recruited via flyers designed to elicit responses from either very highly active (participate in regular, vigorous exercise more than 5 times per week) or less active/sedentary individuals (participate in light to moderate exercise less than 3 times per week or none at all). Both groups subjectively reported maintaining the specified activity level for at least the past 5 years. The highly active subjects performed regular vigorous swimming as their primary mode of exercise training as most were members of a varsity or masters swim team. All subjects were free of overt chronic diseases, nonsmokers, and none were taking vasoactive medications as assessed by a medical history questionnaire. All subjects provided written informed consent to participate. The study was reviewed and approved by the institutional review board at Indiana University.

Physical activity was self-assessed in all subject groups with a log detailing their activity over the previous 7 days. To ensure the older highly active population performed vigorous physical activity ≥ 5 days per week, the subjective activity log was verified by a 7-day previously validated, commercially available heart rate monitor and accelerometer (Actiheart, CamNtech, Cambridge, UK).

Main outcome measure. Compliance of the small and large arteries (inverse of stiffness) measured using a commercial pulse wave analyzer (Model CR-2000, Hypertension Diagnositics, Eagen, MN), which according to the manufacturer measures proximal capacitive compliance (C1, or estimate of large artery compliance) and distal oscillatory compliance (C2, or small artery compliance) [1].

Results. The study found a positive association between routine vigorous physical activity and arterial compliance. Specifically, the results suggest that vigorous physical activity is associated with greater compliance of the small and large arteries in both younger and older adults (P < 0.05). In addition, both the highly active and less active younger groups as well as the highly active older group demonstrated greater large arterial compliance compared to the less active older group (P < 0.008). No significant differences were found between men and women.

Conclusion. Researchers concluded that participation in habitual vigorous physical activity is associated with benefits to the compliance of the small and large arteries. Habitual vigorous physical activity over time may attenuate age-associated cardiovascular impairments.

Commentary

Arterial compliance declines with age, and increased arterial stiffness is associated with an increased risk of cardiovascular events [2]. Evidence suggests that physical activity may delay or prevent age-related increases in arterial stiffness [3]. Previous research regarding age-related arterial stiffness and exercise has focused primarily on the large arteries. For example, Tanaka found that regular aerobic-endurance exercise attenuates age-related reductions in central arterial compliance and restores levels in previously sedentary healthy middle-aged and older men [3]. More recently, a study by Duprez [4] found that small artery elasticity was superior to large artery elasticity with regard to predicting future CHD, stroke, and heart failure.

In this study, researchers cross-sectionally investigated the relationship of intense and continuous physical activity in young and older adults. The form of vigorous activity in this study was competitive swimming, as participants were recruited from a collegiate varsity and masters swim team. The study found a statistically strong association between routine vigorous physical activity and arterial compliance. These findings agree with several studies showing the benefits of vigorous exercise, but go beyond these by presenting findings on small artery compliance.

Methodologically, this study has some limitations. With the small sample, the study may not have been adequately powered. Further, physical activity assessment was by self-report in the main. Even though researchers had the participants keep a log, self-report measures may be inaccurate. Another limitation was the indirect method of measuring compliance, in which the radial waveform is calibrated to brachial blood pressure values. However, the researchers followed a valid model using the same BP level–based procedures reported in previous studies [1].

Applications for Clinical Practice

CVD is a major cause of disability and mortality in the United States. Health care professionals have a significant role to play in reducing cardiovascular risk factors in their patients, including encouraging aerobic exercise. The American Heart Association recommends at least 30 minutes of moderate-intensity aerobic activity at least 5 days per week or at least 25 minutes of vigorous aerobic activity at least 3 days per week, or a combination of moderate- and vigorous-intensity aerobic activity [4]. Patients can also be reminded that even modest levels of physical activity are associated with health benefits.

—Paloma Cesar de Sales, BS, RN, MS

Study Overview

Objective. To investigate the association between habitually high levels of physical activity and the compliance of the large and small arteries in men and women throughout the life span.

Design. Cross-sectional study.

Setting and participants. 83 healthy men (n = 44) and women (n = 39) aged between 18 and 78 years were recruited to participate in the study. Potential participants were recruited via flyers designed to elicit responses from either very highly active (participate in regular, vigorous exercise more than 5 times per week) or less active/sedentary individuals (participate in light to moderate exercise less than 3 times per week or none at all). Both groups subjectively reported maintaining the specified activity level for at least the past 5 years. The highly active subjects performed regular vigorous swimming as their primary mode of exercise training as most were members of a varsity or masters swim team. All subjects were free of overt chronic diseases, nonsmokers, and none were taking vasoactive medications as assessed by a medical history questionnaire. All subjects provided written informed consent to participate. The study was reviewed and approved by the institutional review board at Indiana University.

Physical activity was self-assessed in all subject groups with a log detailing their activity over the previous 7 days. To ensure the older highly active population performed vigorous physical activity ≥ 5 days per week, the subjective activity log was verified by a 7-day previously validated, commercially available heart rate monitor and accelerometer (Actiheart, CamNtech, Cambridge, UK).

Main outcome measure. Compliance of the small and large arteries (inverse of stiffness) measured using a commercial pulse wave analyzer (Model CR-2000, Hypertension Diagnositics, Eagen, MN), which according to the manufacturer measures proximal capacitive compliance (C1, or estimate of large artery compliance) and distal oscillatory compliance (C2, or small artery compliance) [1].

Results. The study found a positive association between routine vigorous physical activity and arterial compliance. Specifically, the results suggest that vigorous physical activity is associated with greater compliance of the small and large arteries in both younger and older adults (P < 0.05). In addition, both the highly active and less active younger groups as well as the highly active older group demonstrated greater large arterial compliance compared to the less active older group (P < 0.008). No significant differences were found between men and women.

Conclusion. Researchers concluded that participation in habitual vigorous physical activity is associated with benefits to the compliance of the small and large arteries. Habitual vigorous physical activity over time may attenuate age-associated cardiovascular impairments.

Commentary

Arterial compliance declines with age, and increased arterial stiffness is associated with an increased risk of cardiovascular events [2]. Evidence suggests that physical activity may delay or prevent age-related increases in arterial stiffness [3]. Previous research regarding age-related arterial stiffness and exercise has focused primarily on the large arteries. For example, Tanaka found that regular aerobic-endurance exercise attenuates age-related reductions in central arterial compliance and restores levels in previously sedentary healthy middle-aged and older men [3]. More recently, a study by Duprez [4] found that small artery elasticity was superior to large artery elasticity with regard to predicting future CHD, stroke, and heart failure.

In this study, researchers cross-sectionally investigated the relationship of intense and continuous physical activity in young and older adults. The form of vigorous activity in this study was competitive swimming, as participants were recruited from a collegiate varsity and masters swim team. The study found a statistically strong association between routine vigorous physical activity and arterial compliance. These findings agree with several studies showing the benefits of vigorous exercise, but go beyond these by presenting findings on small artery compliance.

Methodologically, this study has some limitations. With the small sample, the study may not have been adequately powered. Further, physical activity assessment was by self-report in the main. Even though researchers had the participants keep a log, self-report measures may be inaccurate. Another limitation was the indirect method of measuring compliance, in which the radial waveform is calibrated to brachial blood pressure values. However, the researchers followed a valid model using the same BP level–based procedures reported in previous studies [1].

Applications for Clinical Practice

CVD is a major cause of disability and mortality in the United States. Health care professionals have a significant role to play in reducing cardiovascular risk factors in their patients, including encouraging aerobic exercise. The American Heart Association recommends at least 30 minutes of moderate-intensity aerobic activity at least 5 days per week or at least 25 minutes of vigorous aerobic activity at least 3 days per week, or a combination of moderate- and vigorous-intensity aerobic activity [4]. Patients can also be reminded that even modest levels of physical activity are associated with health benefits.

—Paloma Cesar de Sales, BS, RN, MS

Study Overview

Objective. To determine the effect of an intensive out-patient program for high-need patients in a Veterans Affairs patient-centered medical home.

Design. Randomized controlled trial.

Setting and participants. The study was conducted at a single VA health care facility. Participants were 583 patients whose health care costs were in the top 5% for the facility during a 9-month eligibility period or whose risk for 1-year hospitalization risk as determined by the Care Assessment Need risk prediction algorithm [1] was in the top 5% for the facility. Patients were excluded if they were enrolled in mental health intensive case management program, home-based primary program or palliative care program, or if they were in an inpatient setting for more than half of the eligibility period. 150 patients were randomly assigned to the intensive outpatient group and the rest were assigned to receive standard VA-based primary care, which uses the patient-centered medical home model [2].

Intervention. The intensive outpatient care group received care from a multidisciplinary team comprising a nurse practitioner, physician, social worker, and recreational therapist. The enhanced care included comprehensive patient assessment, identification and tracking of patients’ health-related goals and priorities, assessment of physical function, cognitive function, social support, medical adherence and level of patient activation, and care management for medical and social needs. Frequent contacts using telephone lines and in-person visits as needed, weekly team discussions of high-acuity patients, and coordination of care with VA and non-VA clinicians also occurred. Additionally, the program offered interventions to support patients’ and caregivers’ quality of life, such as recreation therapy.

Main outcome measures. The main outcome measures were health care costs and utilization. Total health care costs included inpatient, outpatient, and fee-basis care provided outside the VA. Utilization measures included hospitalization frequency, hospital length of stay, and number of outpatient and emergency room visits. The study team examined cost and utilization patterns during the 16 months prior to initiation of the program (baseline period) and the 17 months after initiation of the program (follow-up period). The study also evaluated patient care experience in the intensive care group via survey at baseline and at 6 months after enrollment. The survey included items from the Patient Satisfaction questionnaire, the Patient Activation Measures tool, and questions about satisfaction with the intensive care program and the likelihood to recommend the program to others.

Main results. Of the 150 patients assigned to the intervention, 140 patients were included in the analysis after excluding those who were ineligible or died before the intervention began; there were 405 in the usual care group. Among the 140 patients, 96 engaged in the program and 60 completed the follow-up survey. The average patient age was 66 years and over 90% were male, with the majority living in an urban area. The average number of chronic conditions was approximately 10, and about two-thirds had a mental health diagnosis. In the follow-up period, patients in the intensive outpatient care group had a higher number of outpatient primary care visits (average of 21.8 visits [SD 17.4]) compared with the usual care group (average of 7.4 visits [SD 7.5]). The number of acute medical or surgical hospitalizations in the follow-up period was similar between the 2 groups, as was the number of emergency room visits. There were also no significant differences on other inpatient or outpatient health care utilization measures. The intensive outpatient care program was not associated with reduced costs of care when compared with usual care. For measurements on patient experience, the majority of patients who completed the survey (92%) indicated that they would recommend the program to others and 70% indicated that they were extremely satisfied with the program’s medical care.

Conclusions. Intensive outpatient care for high-need patients in this VA setting was not associated with a decrease in acute health care utilization or reduced costs. Patients in the intensive outpatient care program indicated that they were satisfied with the program and would recommend the program to others.

Commentary

Management of high-risk, high-cost patients continues to be a challenge for the health care system. High-users account for a disproportionate amount of health care costs. It would seem reasonable that attending to these patients’ complex needs by providing lower-cost supplemental primary care services early would reduce the need for more expensive care (eg, hospitalization) down-stream.

In this study, researchers examined the impact of an intensive outpatient care program targeting high-need veterans on health care utilization and costs. Although patients liked the program, the results demonstrated no reduction in either acute care utilization, including inpatient hospitalization or emergency room visits, or costs. The findings are consistent with a number of prior studies that have demonstrated limited impact of care coordination programs on cost and utilization [3] albeit demonstrating impact on other clinically relevant outcomes, including patient experience.

The study authors proposed a few factors that may have contributed to this finding. One was that a longer follow-up period may be needed to demonstrate improved outcomes. Another was that there may be a mismatch between the patients’ needs and the services offered by the program. In addition, the intensive out-patient services may have uncovered unmet needs that led to appropriate care, which could increase costs. The role of these factors might be examined using process measures, or with ongoing collection of administrative data, perhaps in a future study.

In interpreting this study, it is important to point out certain differences between this study and the typical randomized clinical trial. In this study, patients were not enrolled in a clinical trial at the time of the intensive outpatient care program—it was considered a quality improvement initiative at the time when the program was started. Thus, the study subjects may be different from the subjects likely to be included in a randomized clinical trial, where subjects must agree to participate in research in order to be part of the study. The patients in this study therefore likely resemble the patient population in a clinical setting rather than in a research study setting.

The other difference is that in addition to examining the impact of the intervention, the study tests the targeting strategy of the intervention—in this case, targeting patients with high need using algorithms already embedded in the VA. This strategy contrasts with a number of outpatient collaborative care interventions [4,5] that target specific medical conditions. While targeting high-utilizers makes sense from an economic point of view, such a group may be more diverse and have more diverse needs than a study population with a condition-specific profile, eg, patients with chronic disease and depression [4]. Two thirds of the study population had a mental health diagnosis, but the team did not include specific mental health personnel or care protocols for mental health management.

Because of its design as a quality improvement project, the study suffers from a number of shortcomings that may threaten its internal validity, namely, the low follow-up rate, the lack of a comparison group for some outcomes, and perhaps, less assurance that participants were treated equally except for the study intervention.

Applications for Clinical Practice

The study adds to the current literature on interventions for improving care and reducing costs for patients with high health care needs. As health care costs continue to escalate, implementing strategies to improve efficiency continues to be a priority. The intensive outpatient care program may not be the solution for curbing costs for the study population at this time; perhaps follow-up studies that assess its impact on other relevant clinical outcomes with longer follow-up may tell a different story.

—William W. Hung, MD, MPH

Study Overview

Objective. To determine the effect of an intensive out-patient program for high-need patients in a Veterans Affairs patient-centered medical home.

Design. Randomized controlled trial.

Setting and participants. The study was conducted at a single VA health care facility. Participants were 583 patients whose health care costs were in the top 5% for the facility during a 9-month eligibility period or whose risk for 1-year hospitalization risk as determined by the Care Assessment Need risk prediction algorithm [1] was in the top 5% for the facility. Patients were excluded if they were enrolled in mental health intensive case management program, home-based primary program or palliative care program, or if they were in an inpatient setting for more than half of the eligibility period. 150 patients were randomly assigned to the intensive outpatient group and the rest were assigned to receive standard VA-based primary care, which uses the patient-centered medical home model [2].

Intervention. The intensive outpatient care group received care from a multidisciplinary team comprising a nurse practitioner, physician, social worker, and recreational therapist. The enhanced care included comprehensive patient assessment, identification and tracking of patients’ health-related goals and priorities, assessment of physical function, cognitive function, social support, medical adherence and level of patient activation, and care management for medical and social needs. Frequent contacts using telephone lines and in-person visits as needed, weekly team discussions of high-acuity patients, and coordination of care with VA and non-VA clinicians also occurred. Additionally, the program offered interventions to support patients’ and caregivers’ quality of life, such as recreation therapy.

Main outcome measures. The main outcome measures were health care costs and utilization. Total health care costs included inpatient, outpatient, and fee-basis care provided outside the VA. Utilization measures included hospitalization frequency, hospital length of stay, and number of outpatient and emergency room visits. The study team examined cost and utilization patterns during the 16 months prior to initiation of the program (baseline period) and the 17 months after initiation of the program (follow-up period). The study also evaluated patient care experience in the intensive care group via survey at baseline and at 6 months after enrollment. The survey included items from the Patient Satisfaction questionnaire, the Patient Activation Measures tool, and questions about satisfaction with the intensive care program and the likelihood to recommend the program to others.

Main results. Of the 150 patients assigned to the intervention, 140 patients were included in the analysis after excluding those who were ineligible or died before the intervention began; there were 405 in the usual care group. Among the 140 patients, 96 engaged in the program and 60 completed the follow-up survey. The average patient age was 66 years and over 90% were male, with the majority living in an urban area. The average number of chronic conditions was approximately 10, and about two-thirds had a mental health diagnosis. In the follow-up period, patients in the intensive outpatient care group had a higher number of outpatient primary care visits (average of 21.8 visits [SD 17.4]) compared with the usual care group (average of 7.4 visits [SD 7.5]). The number of acute medical or surgical hospitalizations in the follow-up period was similar between the 2 groups, as was the number of emergency room visits. There were also no significant differences on other inpatient or outpatient health care utilization measures. The intensive outpatient care program was not associated with reduced costs of care when compared with usual care. For measurements on patient experience, the majority of patients who completed the survey (92%) indicated that they would recommend the program to others and 70% indicated that they were extremely satisfied with the program’s medical care.

Conclusions. Intensive outpatient care for high-need patients in this VA setting was not associated with a decrease in acute health care utilization or reduced costs. Patients in the intensive outpatient care program indicated that they were satisfied with the program and would recommend the program to others.

Commentary

Management of high-risk, high-cost patients continues to be a challenge for the health care system. High-users account for a disproportionate amount of health care costs. It would seem reasonable that attending to these patients’ complex needs by providing lower-cost supplemental primary care services early would reduce the need for more expensive care (eg, hospitalization) down-stream.

In this study, researchers examined the impact of an intensive outpatient care program targeting high-need veterans on health care utilization and costs. Although patients liked the program, the results demonstrated no reduction in either acute care utilization, including inpatient hospitalization or emergency room visits, or costs. The findings are consistent with a number of prior studies that have demonstrated limited impact of care coordination programs on cost and utilization [3] albeit demonstrating impact on other clinically relevant outcomes, including patient experience.

The study authors proposed a few factors that may have contributed to this finding. One was that a longer follow-up period may be needed to demonstrate improved outcomes. Another was that there may be a mismatch between the patients’ needs and the services offered by the program. In addition, the intensive out-patient services may have uncovered unmet needs that led to appropriate care, which could increase costs. The role of these factors might be examined using process measures, or with ongoing collection of administrative data, perhaps in a future study.

In interpreting this study, it is important to point out certain differences between this study and the typical randomized clinical trial. In this study, patients were not enrolled in a clinical trial at the time of the intensive outpatient care program—it was considered a quality improvement initiative at the time when the program was started. Thus, the study subjects may be different from the subjects likely to be included in a randomized clinical trial, where subjects must agree to participate in research in order to be part of the study. The patients in this study therefore likely resemble the patient population in a clinical setting rather than in a research study setting.

The other difference is that in addition to examining the impact of the intervention, the study tests the targeting strategy of the intervention—in this case, targeting patients with high need using algorithms already embedded in the VA. This strategy contrasts with a number of outpatient collaborative care interventions [4,5] that target specific medical conditions. While targeting high-utilizers makes sense from an economic point of view, such a group may be more diverse and have more diverse needs than a study population with a condition-specific profile, eg, patients with chronic disease and depression [4]. Two thirds of the study population had a mental health diagnosis, but the team did not include specific mental health personnel or care protocols for mental health management.

Because of its design as a quality improvement project, the study suffers from a number of shortcomings that may threaten its internal validity, namely, the low follow-up rate, the lack of a comparison group for some outcomes, and perhaps, less assurance that participants were treated equally except for the study intervention.

Applications for Clinical Practice

The study adds to the current literature on interventions for improving care and reducing costs for patients with high health care needs. As health care costs continue to escalate, implementing strategies to improve efficiency continues to be a priority. The intensive outpatient care program may not be the solution for curbing costs for the study population at this time; perhaps follow-up studies that assess its impact on other relevant clinical outcomes with longer follow-up may tell a different story.

—William W. Hung, MD, MPH

Study Overview

Objective. To determine the effect of an intensive out-patient program for high-need patients in a Veterans Affairs patient-centered medical home.

Design. Randomized controlled trial.

Setting and participants. The study was conducted at a single VA health care facility. Participants were 583 patients whose health care costs were in the top 5% for the facility during a 9-month eligibility period or whose risk for 1-year hospitalization risk as determined by the Care Assessment Need risk prediction algorithm [1] was in the top 5% for the facility. Patients were excluded if they were enrolled in mental health intensive case management program, home-based primary program or palliative care program, or if they were in an inpatient setting for more than half of the eligibility period. 150 patients were randomly assigned to the intensive outpatient group and the rest were assigned to receive standard VA-based primary care, which uses the patient-centered medical home model [2].

Intervention. The intensive outpatient care group received care from a multidisciplinary team comprising a nurse practitioner, physician, social worker, and recreational therapist. The enhanced care included comprehensive patient assessment, identification and tracking of patients’ health-related goals and priorities, assessment of physical function, cognitive function, social support, medical adherence and level of patient activation, and care management for medical and social needs. Frequent contacts using telephone lines and in-person visits as needed, weekly team discussions of high-acuity patients, and coordination of care with VA and non-VA clinicians also occurred. Additionally, the program offered interventions to support patients’ and caregivers’ quality of life, such as recreation therapy.

Main outcome measures. The main outcome measures were health care costs and utilization. Total health care costs included inpatient, outpatient, and fee-basis care provided outside the VA. Utilization measures included hospitalization frequency, hospital length of stay, and number of outpatient and emergency room visits. The study team examined cost and utilization patterns during the 16 months prior to initiation of the program (baseline period) and the 17 months after initiation of the program (follow-up period). The study also evaluated patient care experience in the intensive care group via survey at baseline and at 6 months after enrollment. The survey included items from the Patient Satisfaction questionnaire, the Patient Activation Measures tool, and questions about satisfaction with the intensive care program and the likelihood to recommend the program to others.

Main results. Of the 150 patients assigned to the intervention, 140 patients were included in the analysis after excluding those who were ineligible or died before the intervention began; there were 405 in the usual care group. Among the 140 patients, 96 engaged in the program and 60 completed the follow-up survey. The average patient age was 66 years and over 90% were male, with the majority living in an urban area. The average number of chronic conditions was approximately 10, and about two-thirds had a mental health diagnosis. In the follow-up period, patients in the intensive outpatient care group had a higher number of outpatient primary care visits (average of 21.8 visits [SD 17.4]) compared with the usual care group (average of 7.4 visits [SD 7.5]). The number of acute medical or surgical hospitalizations in the follow-up period was similar between the 2 groups, as was the number of emergency room visits. There were also no significant differences on other inpatient or outpatient health care utilization measures. The intensive outpatient care program was not associated with reduced costs of care when compared with usual care. For measurements on patient experience, the majority of patients who completed the survey (92%) indicated that they would recommend the program to others and 70% indicated that they were extremely satisfied with the program’s medical care.

Conclusions. Intensive outpatient care for high-need patients in this VA setting was not associated with a decrease in acute health care utilization or reduced costs. Patients in the intensive outpatient care program indicated that they were satisfied with the program and would recommend the program to others.

Commentary

Management of high-risk, high-cost patients continues to be a challenge for the health care system. High-users account for a disproportionate amount of health care costs. It would seem reasonable that attending to these patients’ complex needs by providing lower-cost supplemental primary care services early would reduce the need for more expensive care (eg, hospitalization) down-stream.

In this study, researchers examined the impact of an intensive outpatient care program targeting high-need veterans on health care utilization and costs. Although patients liked the program, the results demonstrated no reduction in either acute care utilization, including inpatient hospitalization or emergency room visits, or costs. The findings are consistent with a number of prior studies that have demonstrated limited impact of care coordination programs on cost and utilization [3] albeit demonstrating impact on other clinically relevant outcomes, including patient experience.

The study authors proposed a few factors that may have contributed to this finding. One was that a longer follow-up period may be needed to demonstrate improved outcomes. Another was that there may be a mismatch between the patients’ needs and the services offered by the program. In addition, the intensive out-patient services may have uncovered unmet needs that led to appropriate care, which could increase costs. The role of these factors might be examined using process measures, or with ongoing collection of administrative data, perhaps in a future study.

In interpreting this study, it is important to point out certain differences between this study and the typical randomized clinical trial. In this study, patients were not enrolled in a clinical trial at the time of the intensive outpatient care program—it was considered a quality improvement initiative at the time when the program was started. Thus, the study subjects may be different from the subjects likely to be included in a randomized clinical trial, where subjects must agree to participate in research in order to be part of the study. The patients in this study therefore likely resemble the patient population in a clinical setting rather than in a research study setting.

The other difference is that in addition to examining the impact of the intervention, the study tests the targeting strategy of the intervention—in this case, targeting patients with high need using algorithms already embedded in the VA. This strategy contrasts with a number of outpatient collaborative care interventions [4,5] that target specific medical conditions. While targeting high-utilizers makes sense from an economic point of view, such a group may be more diverse and have more diverse needs than a study population with a condition-specific profile, eg, patients with chronic disease and depression [4]. Two thirds of the study population had a mental health diagnosis, but the team did not include specific mental health personnel or care protocols for mental health management.

Because of its design as a quality improvement project, the study suffers from a number of shortcomings that may threaten its internal validity, namely, the low follow-up rate, the lack of a comparison group for some outcomes, and perhaps, less assurance that participants were treated equally except for the study intervention.

Applications for Clinical Practice

The study adds to the current literature on interventions for improving care and reducing costs for patients with high health care needs. As health care costs continue to escalate, implementing strategies to improve efficiency continues to be a priority. The intensive outpatient care program may not be the solution for curbing costs for the study population at this time; perhaps follow-up studies that assess its impact on other relevant clinical outcomes with longer follow-up may tell a different story.

—William W. Hung, MD, MPH

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate factors related to interactions with primary care physicians (PCPs) that may contribute to successful weight loss and maintenance among low-income, African-American women.

Design. Mixed methods, positive deviance framework.

Setting and participants. Participants were African-American women aged 18–64 years from an urban university-based family medicine practice who received Medicaid, resided in Philadelphia, and had a body mass index (BMI) of ≥ 30kg/m². From among these, “positive deviant” cases were identified as patients with EMR-confirmed weight loss of at least 10% of patient’s maximum weight between 2007–2012 and maintenance of this loss for at least 6 months. Controls were defined as patients who had not lost a significant amount of weight during this time period. Patients were excluded if they were an amputee or wheelchair-bound; had bariatric surgery, severe illness during weight loss, EMR-documented unintended weight loss, pregnancy at time of weight loss, a psychiatric disorder or were taking antipsychotic medication; had an intellectual disability; or could not give consent to participate.

Main outcomes measures. PCP- and patient-reported weight variables were collected through the EMR (documentation of dietary counseling by PCP, documentation of a weight-related problem, diagnosis of overweight, obesity, or morbid obesity on the problem list), surveys (additional predicters of positive deviant membership, including patient-reported weight-related diagnosis or discussion of weight with PCP or health professional), and interviews. Logistic regression was used to determine whether a priori-identified EMR and survey variables could predict positive deviant group membership, adjusting for demographic variables significantly associated with the outcome of interest or hypothesized to be confounders of the associations between predictors and outcomes (results were adjusted for age in the EMR analysis and for employment status and education level in the survey analysis). Once thematic saturation was reached, interviews were analyzed by a 4-member coding panel using a modified approach to grounded theory to identify themes.

Main results. For the EMR analysis, data from 161 positive deviant cases and 602 controls were analyzed. For the survey analysis, data from 35 positive deviant cases and 36 controls matched for age and maximum BMI were analyzed. For in-depth interviews, thematic saturation was reached after collecting data from 20 positive deviant participants. In the EMR analyses, documentation of dietary counseling and a weight-related diagnosis were significant predictors of positive deviant membership after adjusting for age (P < 0.001 and P = 0.011, respectively). However, documentation of obesity on the problem list was predictive of control group membership (P = 0.032). In the survey analysis, neither patient-reported weight-related diagnosis nor discussion of weight with a medical provider were predictors of positive deviant membership (P = 0.890 and P = 0.373, respectively). In the qualitative analysis of interviews with positive deviant participants, 5 themes emerged: (1) framing the problem of obesity in the context of other health problems provided motivation; (2) having a full discussion around weight management was important; (3) an ongoing conversation and relationship was valuable; (4) celebrating small successes was beneficial for ongoing motivation; and (5) advice was helpful but self-motivation was required in order to make a change.

Conclusions. PCP counseling may be an important factor in promoting weight loss in low-income, African-American women, a population at high risk for obesity. Patients may benefit from their PCPs drawing connections between obesity and weight-related medical conditions and enhancing intrinsic motivation for weight loss.

Commentary

The increasing prevalence and clinical consequences of having obesity are well-documented, with low-income minorities disproportionately burdened by this condition [1,2]. The United States Preventive Services Task Force (USPTF) recommends that all patients be screened for obesity and offered intensive lifestyle counseling [3], yet evidence-based guidelines for best approaches to incorporate this into practice are few and unclear, and even fewer are specific to high-risk patient populations [4–9].

This study adds to the literature by using a positive deviance approach to identify PCP-related factors that predict successful weight loss among low-income African-American women. This approach has rarely been used in the obesity literature. In a few childhood obesity studies, this approach was used to identify motivations used by child “positive outliers” to improve their BMI [10], characterize variations of feeding and activity practices by parents of healthy children normally at high risk for obesity [11], and explore successful health and BMI reduction strategies used among positive outlier families [12]. Positive deviance has also been used to characterize and change nutritional behavior and understand successful weight-control practices among adults [13–15]. One study has suggested that studying “positive deviant” physicians that regularly provide weight counseling may help to provide practice methods to increase these practices in the primary care settings [16].

Thus, the study approach in using a positive deviance framework is an important and unique strength. Addi-tionally, the authors used a mixed-methods approach, analyzing EMR, survey, and interview data to assess PCP- and patient-reported weight-related factors that predict successful weight loss. As the authors describe, their results confirm findings from previous studies looking at counseling preferences among ethnic minority women and PCP attitudes and practices related to weight management.

They acknowledge important limitations of their study design, primarily the generalizability of findings only to urban, low-income, African-American women, the small sample size in the survey analysis, and the use of EMR data to collect data on PCP counseling (as opposed to interviews, for example). It important to also acknowledge that this study was conducted at a family medicine practice, and physician behavior and practices likely do not generalize to other PCPs and specialists. Additionally, while their intention was to use a positive deviance framework, conducting interviews among a subset of their control cases may have provided useful information regarding negative or ineffective PCP interactions regarding weight loss and management.

Applications for Clinical Practice

As the authors emphasize, the outcomes of this study are especially relevant for PCPs and other health practitioners, as the identified themes can help guide weight counseling that incorporates patient preferences and promotes successful weight loss. Importantly, these findings underscore that the role of the physician is important in promoting weight loss, yet it does not require in-depth knowledge and training in evidence-based weight loss strategies. While dietary counseling is still helpful, patients with successful weight loss value the supportive relationship with their physician, their physician drawing connections between obesity and weight-related medical conditions, and their physician enhancing intrinsic motivations for weight loss.

Study Overview

Objective. To evaluate factors related to interactions with primary care physicians (PCPs) that may contribute to successful weight loss and maintenance among low-income, African-American women.

Design. Mixed methods, positive deviance framework.

Setting and participants. Participants were African-American women aged 18–64 years from an urban university-based family medicine practice who received Medicaid, resided in Philadelphia, and had a body mass index (BMI) of ≥ 30kg/m². From among these, “positive deviant” cases were identified as patients with EMR-confirmed weight loss of at least 10% of patient’s maximum weight between 2007–2012 and maintenance of this loss for at least 6 months. Controls were defined as patients who had not lost a significant amount of weight during this time period. Patients were excluded if they were an amputee or wheelchair-bound; had bariatric surgery, severe illness during weight loss, EMR-documented unintended weight loss, pregnancy at time of weight loss, a psychiatric disorder or were taking antipsychotic medication; had an intellectual disability; or could not give consent to participate.

Main outcomes measures. PCP- and patient-reported weight variables were collected through the EMR (documentation of dietary counseling by PCP, documentation of a weight-related problem, diagnosis of overweight, obesity, or morbid obesity on the problem list), surveys (additional predicters of positive deviant membership, including patient-reported weight-related diagnosis or discussion of weight with PCP or health professional), and interviews. Logistic regression was used to determine whether a priori-identified EMR and survey variables could predict positive deviant group membership, adjusting for demographic variables significantly associated with the outcome of interest or hypothesized to be confounders of the associations between predictors and outcomes (results were adjusted for age in the EMR analysis and for employment status and education level in the survey analysis). Once thematic saturation was reached, interviews were analyzed by a 4-member coding panel using a modified approach to grounded theory to identify themes.

Main results. For the EMR analysis, data from 161 positive deviant cases and 602 controls were analyzed. For the survey analysis, data from 35 positive deviant cases and 36 controls matched for age and maximum BMI were analyzed. For in-depth interviews, thematic saturation was reached after collecting data from 20 positive deviant participants. In the EMR analyses, documentation of dietary counseling and a weight-related diagnosis were significant predictors of positive deviant membership after adjusting for age (P < 0.001 and P = 0.011, respectively). However, documentation of obesity on the problem list was predictive of control group membership (P = 0.032). In the survey analysis, neither patient-reported weight-related diagnosis nor discussion of weight with a medical provider were predictors of positive deviant membership (P = 0.890 and P = 0.373, respectively). In the qualitative analysis of interviews with positive deviant participants, 5 themes emerged: (1) framing the problem of obesity in the context of other health problems provided motivation; (2) having a full discussion around weight management was important; (3) an ongoing conversation and relationship was valuable; (4) celebrating small successes was beneficial for ongoing motivation; and (5) advice was helpful but self-motivation was required in order to make a change.

Conclusions. PCP counseling may be an important factor in promoting weight loss in low-income, African-American women, a population at high risk for obesity. Patients may benefit from their PCPs drawing connections between obesity and weight-related medical conditions and enhancing intrinsic motivation for weight loss.

Commentary

The increasing prevalence and clinical consequences of having obesity are well-documented, with low-income minorities disproportionately burdened by this condition [1,2]. The United States Preventive Services Task Force (USPTF) recommends that all patients be screened for obesity and offered intensive lifestyle counseling [3], yet evidence-based guidelines for best approaches to incorporate this into practice are few and unclear, and even fewer are specific to high-risk patient populations [4–9].

This study adds to the literature by using a positive deviance approach to identify PCP-related factors that predict successful weight loss among low-income African-American women. This approach has rarely been used in the obesity literature. In a few childhood obesity studies, this approach was used to identify motivations used by child “positive outliers” to improve their BMI [10], characterize variations of feeding and activity practices by parents of healthy children normally at high risk for obesity [11], and explore successful health and BMI reduction strategies used among positive outlier families [12]. Positive deviance has also been used to characterize and change nutritional behavior and understand successful weight-control practices among adults [13–15]. One study has suggested that studying “positive deviant” physicians that regularly provide weight counseling may help to provide practice methods to increase these practices in the primary care settings [16].

Thus, the study approach in using a positive deviance framework is an important and unique strength. Addi-tionally, the authors used a mixed-methods approach, analyzing EMR, survey, and interview data to assess PCP- and patient-reported weight-related factors that predict successful weight loss. As the authors describe, their results confirm findings from previous studies looking at counseling preferences among ethnic minority women and PCP attitudes and practices related to weight management.

They acknowledge important limitations of their study design, primarily the generalizability of findings only to urban, low-income, African-American women, the small sample size in the survey analysis, and the use of EMR data to collect data on PCP counseling (as opposed to interviews, for example). It important to also acknowledge that this study was conducted at a family medicine practice, and physician behavior and practices likely do not generalize to other PCPs and specialists. Additionally, while their intention was to use a positive deviance framework, conducting interviews among a subset of their control cases may have provided useful information regarding negative or ineffective PCP interactions regarding weight loss and management.

Applications for Clinical Practice

As the authors emphasize, the outcomes of this study are especially relevant for PCPs and other health practitioners, as the identified themes can help guide weight counseling that incorporates patient preferences and promotes successful weight loss. Importantly, these findings underscore that the role of the physician is important in promoting weight loss, yet it does not require in-depth knowledge and training in evidence-based weight loss strategies. While dietary counseling is still helpful, patients with successful weight loss value the supportive relationship with their physician, their physician drawing connections between obesity and weight-related medical conditions, and their physician enhancing intrinsic motivations for weight loss.

Study Overview

Objective. To evaluate factors related to interactions with primary care physicians (PCPs) that may contribute to successful weight loss and maintenance among low-income, African-American women.

Design. Mixed methods, positive deviance framework.

Setting and participants. Participants were African-American women aged 18–64 years from an urban university-based family medicine practice who received Medicaid, resided in Philadelphia, and had a body mass index (BMI) of ≥ 30kg/m². From among these, “positive deviant” cases were identified as patients with EMR-confirmed weight loss of at least 10% of patient’s maximum weight between 2007–2012 and maintenance of this loss for at least 6 months. Controls were defined as patients who had not lost a significant amount of weight during this time period. Patients were excluded if they were an amputee or wheelchair-bound; had bariatric surgery, severe illness during weight loss, EMR-documented unintended weight loss, pregnancy at time of weight loss, a psychiatric disorder or were taking antipsychotic medication; had an intellectual disability; or could not give consent to participate.

Main outcomes measures. PCP- and patient-reported weight variables were collected through the EMR (documentation of dietary counseling by PCP, documentation of a weight-related problem, diagnosis of overweight, obesity, or morbid obesity on the problem list), surveys (additional predicters of positive deviant membership, including patient-reported weight-related diagnosis or discussion of weight with PCP or health professional), and interviews. Logistic regression was used to determine whether a priori-identified EMR and survey variables could predict positive deviant group membership, adjusting for demographic variables significantly associated with the outcome of interest or hypothesized to be confounders of the associations between predictors and outcomes (results were adjusted for age in the EMR analysis and for employment status and education level in the survey analysis). Once thematic saturation was reached, interviews were analyzed by a 4-member coding panel using a modified approach to grounded theory to identify themes.

Main results. For the EMR analysis, data from 161 positive deviant cases and 602 controls were analyzed. For the survey analysis, data from 35 positive deviant cases and 36 controls matched for age and maximum BMI were analyzed. For in-depth interviews, thematic saturation was reached after collecting data from 20 positive deviant participants. In the EMR analyses, documentation of dietary counseling and a weight-related diagnosis were significant predictors of positive deviant membership after adjusting for age (P < 0.001 and P = 0.011, respectively). However, documentation of obesity on the problem list was predictive of control group membership (P = 0.032). In the survey analysis, neither patient-reported weight-related diagnosis nor discussion of weight with a medical provider were predictors of positive deviant membership (P = 0.890 and P = 0.373, respectively). In the qualitative analysis of interviews with positive deviant participants, 5 themes emerged: (1) framing the problem of obesity in the context of other health problems provided motivation; (2) having a full discussion around weight management was important; (3) an ongoing conversation and relationship was valuable; (4) celebrating small successes was beneficial for ongoing motivation; and (5) advice was helpful but self-motivation was required in order to make a change.

Conclusions. PCP counseling may be an important factor in promoting weight loss in low-income, African-American women, a population at high risk for obesity. Patients may benefit from their PCPs drawing connections between obesity and weight-related medical conditions and enhancing intrinsic motivation for weight loss.

Commentary

The increasing prevalence and clinical consequences of having obesity are well-documented, with low-income minorities disproportionately burdened by this condition [1,2]. The United States Preventive Services Task Force (USPTF) recommends that all patients be screened for obesity and offered intensive lifestyle counseling [3], yet evidence-based guidelines for best approaches to incorporate this into practice are few and unclear, and even fewer are specific to high-risk patient populations [4–9].

This study adds to the literature by using a positive deviance approach to identify PCP-related factors that predict successful weight loss among low-income African-American women. This approach has rarely been used in the obesity literature. In a few childhood obesity studies, this approach was used to identify motivations used by child “positive outliers” to improve their BMI [10], characterize variations of feeding and activity practices by parents of healthy children normally at high risk for obesity [11], and explore successful health and BMI reduction strategies used among positive outlier families [12]. Positive deviance has also been used to characterize and change nutritional behavior and understand successful weight-control practices among adults [13–15]. One study has suggested that studying “positive deviant” physicians that regularly provide weight counseling may help to provide practice methods to increase these practices in the primary care settings [16].

Thus, the study approach in using a positive deviance framework is an important and unique strength. Addi-tionally, the authors used a mixed-methods approach, analyzing EMR, survey, and interview data to assess PCP- and patient-reported weight-related factors that predict successful weight loss. As the authors describe, their results confirm findings from previous studies looking at counseling preferences among ethnic minority women and PCP attitudes and practices related to weight management.

They acknowledge important limitations of their study design, primarily the generalizability of findings only to urban, low-income, African-American women, the small sample size in the survey analysis, and the use of EMR data to collect data on PCP counseling (as opposed to interviews, for example). It important to also acknowledge that this study was conducted at a family medicine practice, and physician behavior and practices likely do not generalize to other PCPs and specialists. Additionally, while their intention was to use a positive deviance framework, conducting interviews among a subset of their control cases may have provided useful information regarding negative or ineffective PCP interactions regarding weight loss and management.

Applications for Clinical Practice

As the authors emphasize, the outcomes of this study are especially relevant for PCPs and other health practitioners, as the identified themes can help guide weight counseling that incorporates patient preferences and promotes successful weight loss. Importantly, these findings underscore that the role of the physician is important in promoting weight loss, yet it does not require in-depth knowledge and training in evidence-based weight loss strategies. While dietary counseling is still helpful, patients with successful weight loss value the supportive relationship with their physician, their physician drawing connections between obesity and weight-related medical conditions, and their physician enhancing intrinsic motivations for weight loss.

Study Overview

Objective. To assess the risks associated with magnetic resonance imaging (MRI) in patients with a pacemaker or implantable cardioverter-defibrillator (ICD) that is “non–MRI-conditional.”

Design. Prospective cohort study using the multicenter MagnaSafe Registry.

Setting and participants. Patients were included in the registry if they were 18 years of age or older and had a non–MRI-conditional pacemaker or ICD generator, from any manufacturer, that was implanted after 2001, with leads from any manufacturer, and if the patient’s physician determined that nonthoracic MRI at 1.5 tesla was clinically indicated. Exclusion criteria included an abandoned or inactive lead that could not be interrogated, an MRI-conditional pacemaker, a device implanted in a nonthoracic location, or a device with a battery that was near the end of its battery life. In addition, pacing-dependent patients with an ICD were also excluded.

Main outcome measures. The primary outcomes of the study were death, generator or lead failure requiring immediate replacement, loss of capture (for pacing-dependent patients with pacemakers), new-onset arrhythmia, and partial or full generator electrical reset. The secondary outcomes were changes in device settings including: a battery voltage decrease of 0.04V or more, a pacing lead threshold increase of 0.5V or more, a P-wave amplitude decrease of 50% or more, an R-wave amplitude decrease of 25% or more and of 50% or more, a pacing lead impedance change of 50 ohms or more, and a high-voltage (shock) lead impedance change of 3 ohms or more.

Main results. Between April 2009 and April 2014, clinically indicated nonthoracic MRI was performed in a total of 1000 pacemaker cases (818 patients) and 500 ICD cases (428 patients) across 19 centers in the United States. The majority (75%) of the MRI examinations were performed on the brain or the spine. The mean time patients spent within the magnetic field was 44 minutes. Four patients reported symptoms of generator-site discomfort; one patient with an ICD was removed from the scanner when a sensation of heating was described at the site of the generator implanted and did not complete the examination.

Regarding primary outcomes, no deaths, lead failures, losses of capture, or ventricular arrhythmias occurred during MRI. One ICD device was left in the active mode for anti-tachycardia therapy (a protocol violation) and the generator could not be interrogated after MRI and required immediate replacement. Four patients had atrial fibrillation and 2 patients had atrial flutter during or immediately after the MRI. All 6 patients returned to sinus rhythm within 49 hours after MRI. No ventricular arrhythmias were noted. There were also 6 cases of partial generator electrical reset with no clinical significance.

Regarding secondary outcomes, a decrease of 50% or more in P-wave amplitude was detected in 0.9% of pacemaker leads and in 0.3% of ICD leads; a decrease of 25% or more in R-wave amplitude was detected in 3.9% of pacemaker leads and in 1.5% of ICD leads, and a decrease of 50% or more in R-wave amplitude was detected in no pacemaker leads and in 0.2% of ICD leads. An increase in pacing lead threshold of 0.5 V or more was detected in 0.7% of pacemaker leads and in 0.8% of ICD leads. A pacing lead impedance change of 50 ohms or more was noted in 3.3% of pacemakers and in 4.2% of ICDs.

Conclusion. Device or lead failure did not occur in any patient with a non–MRI-conditional pacemaker or ICD who underwent clinically indicated nonthoracic MRI at 1.5 tesla when patients were appropriately screened and had the cardiac device reprogrammed in accordance with the protocol. Substantial changes in device settings were infrequent and did not result in clinical adverse events.

Commentary

It is estimated that 2 million people in the United States and an additional 6 million worldwide have an implanted non–MRI-conditional cardiac pacemaker or ICD [1]. At least half of patients with such devices are predicted to have a clinical indication for MRI during their lifetime after device implantation [2]. The use of MRI poses concerns due to the potential for magnetic field–induced cardiac lead heating, which could result in myocardial thermal injury and detrimental changes in pacing properties [3,4].

In this study, Russo and colleagues assessed the risks for patients with a non-MRI-conditional pacemaker or ICD receiving an MRI scan using a pre-scanning protocol. If the patient was asymptomatic and had an intrinsic heart rate of at least 40 beats per minute, the device was programmed to a no-pacing mode (ODO or OVO). Symptomatic patients or those with an intrinsic heart rate of less than 40 beats per minute were determined to be pacing-dependent, and the device was reprogrammed to an asynchronous pacing mode (DOO or VOO). All bradycardia and tachycardia therapies were inactivated before the MRI. Based on this standardized protocol, no major adverse outcomes occurred. All pacemaker or ICD device were reprogrammed in accordance with the pre-specified protocol except one case where the ICD device was left in the active mode for anti-tachycardia therapy (a protocol violation) and the generator could not be interrogated after MRI and required immediate replacement. In addition to patient safety, the authors also measure the functionality of the devices pre-MRI and post-MRI. One of these measurements were battery voltage changes, a small decrease was noted for both pacemakers and ICDs as expected. The radiofrequency energy generated during MRI scanning creates a temporary decrease in battery voltage, which had resolved in all pacemaker cases although some ICD voltage decreases of 0.04 V or more had not resolved by the end of the 6 month post-MRI follow-up.

Several limitations exist. The study registry included devices and leads from different manufacturers, but did not report outcomes by manufacturer. While overall it appears to be safe to conduct an MRI study for patients who have non–MRI-conditional devices, this study did not provide enough information for patients younger than 18 years of age, patients who required repeat MRI studies, MRI examinations of the thorax, or higher MRI field strengths—the newer 3 tesla high-resolution MRI machines.

Applications for Clinical Practice

This multicenter prospective cohort study provides strong evidence that patients with a non–MRI-conditional pacemaker or defibrillator can receive nonthoracic MRI studies at 1.5 tesla when a straight pre-scanning device interrogation is performed per the standardized protocol.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess the risks associated with magnetic resonance imaging (MRI) in patients with a pacemaker or implantable cardioverter-defibrillator (ICD) that is “non–MRI-conditional.”

Design. Prospective cohort study using the multicenter MagnaSafe Registry.

Setting and participants. Patients were included in the registry if they were 18 years of age or older and had a non–MRI-conditional pacemaker or ICD generator, from any manufacturer, that was implanted after 2001, with leads from any manufacturer, and if the patient’s physician determined that nonthoracic MRI at 1.5 tesla was clinically indicated. Exclusion criteria included an abandoned or inactive lead that could not be interrogated, an MRI-conditional pacemaker, a device implanted in a nonthoracic location, or a device with a battery that was near the end of its battery life. In addition, pacing-dependent patients with an ICD were also excluded.

Main outcome measures. The primary outcomes of the study were death, generator or lead failure requiring immediate replacement, loss of capture (for pacing-dependent patients with pacemakers), new-onset arrhythmia, and partial or full generator electrical reset. The secondary outcomes were changes in device settings including: a battery voltage decrease of 0.04V or more, a pacing lead threshold increase of 0.5V or more, a P-wave amplitude decrease of 50% or more, an R-wave amplitude decrease of 25% or more and of 50% or more, a pacing lead impedance change of 50 ohms or more, and a high-voltage (shock) lead impedance change of 3 ohms or more.

Main results. Between April 2009 and April 2014, clinically indicated nonthoracic MRI was performed in a total of 1000 pacemaker cases (818 patients) and 500 ICD cases (428 patients) across 19 centers in the United States. The majority (75%) of the MRI examinations were performed on the brain or the spine. The mean time patients spent within the magnetic field was 44 minutes. Four patients reported symptoms of generator-site discomfort; one patient with an ICD was removed from the scanner when a sensation of heating was described at the site of the generator implanted and did not complete the examination.

Regarding primary outcomes, no deaths, lead failures, losses of capture, or ventricular arrhythmias occurred during MRI. One ICD device was left in the active mode for anti-tachycardia therapy (a protocol violation) and the generator could not be interrogated after MRI and required immediate replacement. Four patients had atrial fibrillation and 2 patients had atrial flutter during or immediately after the MRI. All 6 patients returned to sinus rhythm within 49 hours after MRI. No ventricular arrhythmias were noted. There were also 6 cases of partial generator electrical reset with no clinical significance.

Regarding secondary outcomes, a decrease of 50% or more in P-wave amplitude was detected in 0.9% of pacemaker leads and in 0.3% of ICD leads; a decrease of 25% or more in R-wave amplitude was detected in 3.9% of pacemaker leads and in 1.5% of ICD leads, and a decrease of 50% or more in R-wave amplitude was detected in no pacemaker leads and in 0.2% of ICD leads. An increase in pacing lead threshold of 0.5 V or more was detected in 0.7% of pacemaker leads and in 0.8% of ICD leads. A pacing lead impedance change of 50 ohms or more was noted in 3.3% of pacemakers and in 4.2% of ICDs.

Conclusion. Device or lead failure did not occur in any patient with a non–MRI-conditional pacemaker or ICD who underwent clinically indicated nonthoracic MRI at 1.5 tesla when patients were appropriately screened and had the cardiac device reprogrammed in accordance with the protocol. Substantial changes in device settings were infrequent and did not result in clinical adverse events.

Commentary

It is estimated that 2 million people in the United States and an additional 6 million worldwide have an implanted non–MRI-conditional cardiac pacemaker or ICD [1]. At least half of patients with such devices are predicted to have a clinical indication for MRI during their lifetime after device implantation [2]. The use of MRI poses concerns due to the potential for magnetic field–induced cardiac lead heating, which could result in myocardial thermal injury and detrimental changes in pacing properties [3,4].

In this study, Russo and colleagues assessed the risks for patients with a non-MRI-conditional pacemaker or ICD receiving an MRI scan using a pre-scanning protocol. If the patient was asymptomatic and had an intrinsic heart rate of at least 40 beats per minute, the device was programmed to a no-pacing mode (ODO or OVO). Symptomatic patients or those with an intrinsic heart rate of less than 40 beats per minute were determined to be pacing-dependent, and the device was reprogrammed to an asynchronous pacing mode (DOO or VOO). All bradycardia and tachycardia therapies were inactivated before the MRI. Based on this standardized protocol, no major adverse outcomes occurred. All pacemaker or ICD device were reprogrammed in accordance with the pre-specified protocol except one case where the ICD device was left in the active mode for anti-tachycardia therapy (a protocol violation) and the generator could not be interrogated after MRI and required immediate replacement. In addition to patient safety, the authors also measure the functionality of the devices pre-MRI and post-MRI. One of these measurements were battery voltage changes, a small decrease was noted for both pacemakers and ICDs as expected. The radiofrequency energy generated during MRI scanning creates a temporary decrease in battery voltage, which had resolved in all pacemaker cases although some ICD voltage decreases of 0.04 V or more had not resolved by the end of the 6 month post-MRI follow-up.

Several limitations exist. The study registry included devices and leads from different manufacturers, but did not report outcomes by manufacturer. While overall it appears to be safe to conduct an MRI study for patients who have non–MRI-conditional devices, this study did not provide enough information for patients younger than 18 years of age, patients who required repeat MRI studies, MRI examinations of the thorax, or higher MRI field strengths—the newer 3 tesla high-resolution MRI machines.

Applications for Clinical Practice

This multicenter prospective cohort study provides strong evidence that patients with a non–MRI-conditional pacemaker or defibrillator can receive nonthoracic MRI studies at 1.5 tesla when a straight pre-scanning device interrogation is performed per the standardized protocol.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess the risks associated with magnetic resonance imaging (MRI) in patients with a pacemaker or implantable cardioverter-defibrillator (ICD) that is “non–MRI-conditional.”

Design. Prospective cohort study using the multicenter MagnaSafe Registry.

Setting and participants. Patients were included in the registry if they were 18 years of age or older and had a non–MRI-conditional pacemaker or ICD generator, from any manufacturer, that was implanted after 2001, with leads from any manufacturer, and if the patient’s physician determined that nonthoracic MRI at 1.5 tesla was clinically indicated. Exclusion criteria included an abandoned or inactive lead that could not be interrogated, an MRI-conditional pacemaker, a device implanted in a nonthoracic location, or a device with a battery that was near the end of its battery life. In addition, pacing-dependent patients with an ICD were also excluded.

Main outcome measures. The primary outcomes of the study were death, generator or lead failure requiring immediate replacement, loss of capture (for pacing-dependent patients with pacemakers), new-onset arrhythmia, and partial or full generator electrical reset. The secondary outcomes were changes in device settings including: a battery voltage decrease of 0.04V or more, a pacing lead threshold increase of 0.5V or more, a P-wave amplitude decrease of 50% or more, an R-wave amplitude decrease of 25% or more and of 50% or more, a pacing lead impedance change of 50 ohms or more, and a high-voltage (shock) lead impedance change of 3 ohms or more.

Main results. Between April 2009 and April 2014, clinically indicated nonthoracic MRI was performed in a total of 1000 pacemaker cases (818 patients) and 500 ICD cases (428 patients) across 19 centers in the United States. The majority (75%) of the MRI examinations were performed on the brain or the spine. The mean time patients spent within the magnetic field was 44 minutes. Four patients reported symptoms of generator-site discomfort; one patient with an ICD was removed from the scanner when a sensation of heating was described at the site of the generator implanted and did not complete the examination.

Regarding primary outcomes, no deaths, lead failures, losses of capture, or ventricular arrhythmias occurred during MRI. One ICD device was left in the active mode for anti-tachycardia therapy (a protocol violation) and the generator could not be interrogated after MRI and required immediate replacement. Four patients had atrial fibrillation and 2 patients had atrial flutter during or immediately after the MRI. All 6 patients returned to sinus rhythm within 49 hours after MRI. No ventricular arrhythmias were noted. There were also 6 cases of partial generator electrical reset with no clinical significance.

Regarding secondary outcomes, a decrease of 50% or more in P-wave amplitude was detected in 0.9% of pacemaker leads and in 0.3% of ICD leads; a decrease of 25% or more in R-wave amplitude was detected in 3.9% of pacemaker leads and in 1.5% of ICD leads, and a decrease of 50% or more in R-wave amplitude was detected in no pacemaker leads and in 0.2% of ICD leads. An increase in pacing lead threshold of 0.5 V or more was detected in 0.7% of pacemaker leads and in 0.8% of ICD leads. A pacing lead impedance change of 50 ohms or more was noted in 3.3% of pacemakers and in 4.2% of ICDs.

Conclusion. Device or lead failure did not occur in any patient with a non–MRI-conditional pacemaker or ICD who underwent clinically indicated nonthoracic MRI at 1.5 tesla when patients were appropriately screened and had the cardiac device reprogrammed in accordance with the protocol. Substantial changes in device settings were infrequent and did not result in clinical adverse events.

Commentary

It is estimated that 2 million people in the United States and an additional 6 million worldwide have an implanted non–MRI-conditional cardiac pacemaker or ICD [1]. At least half of patients with such devices are predicted to have a clinical indication for MRI during their lifetime after device implantation [2]. The use of MRI poses concerns due to the potential for magnetic field–induced cardiac lead heating, which could result in myocardial thermal injury and detrimental changes in pacing properties [3,4].

In this study, Russo and colleagues assessed the risks for patients with a non-MRI-conditional pacemaker or ICD receiving an MRI scan using a pre-scanning protocol. If the patient was asymptomatic and had an intrinsic heart rate of at least 40 beats per minute, the device was programmed to a no-pacing mode (ODO or OVO). Symptomatic patients or those with an intrinsic heart rate of less than 40 beats per minute were determined to be pacing-dependent, and the device was reprogrammed to an asynchronous pacing mode (DOO or VOO). All bradycardia and tachycardia therapies were inactivated before the MRI. Based on this standardized protocol, no major adverse outcomes occurred. All pacemaker or ICD device were reprogrammed in accordance with the pre-specified protocol except one case where the ICD device was left in the active mode for anti-tachycardia therapy (a protocol violation) and the generator could not be interrogated after MRI and required immediate replacement. In addition to patient safety, the authors also measure the functionality of the devices pre-MRI and post-MRI. One of these measurements were battery voltage changes, a small decrease was noted for both pacemakers and ICDs as expected. The radiofrequency energy generated during MRI scanning creates a temporary decrease in battery voltage, which had resolved in all pacemaker cases although some ICD voltage decreases of 0.04 V or more had not resolved by the end of the 6 month post-MRI follow-up.

Several limitations exist. The study registry included devices and leads from different manufacturers, but did not report outcomes by manufacturer. While overall it appears to be safe to conduct an MRI study for patients who have non–MRI-conditional devices, this study did not provide enough information for patients younger than 18 years of age, patients who required repeat MRI studies, MRI examinations of the thorax, or higher MRI field strengths—the newer 3 tesla high-resolution MRI machines.

Applications for Clinical Practice

This multicenter prospective cohort study provides strong evidence that patients with a non–MRI-conditional pacemaker or defibrillator can receive nonthoracic MRI studies at 1.5 tesla when a straight pre-scanning device interrogation is performed per the standardized protocol.

—Ka Ming Gordon Ngai, MD, MPH