Study Overview

Objective. To determine whether in-person visits for primary care patients resulted in improved weight loss maintenance relative to monthly mailings, with both groups receiving access to portion-controlled meals.

Design. Randomized clinical trial.

Setting and participants. This study took place within 2 university-affiliated primary care clinics in Colorado. For the first phase of the study, investigators enrolled 104 obese adult patients (18–79 years; BMI 30–49.9 kg/m²) who had been diagnosed with at least one of the following: type 2 diabetes, sleep apnea, hypertension, or hyperlipidemia. Patients who had independently lost weight prior to trial entry (> 5% in 6 months), were on weight-gain–promoting medications such as steroids, or had previously undergone bariatric surgery were excluded. The trial started with a 6-month run-in phase where active weight loss was promoted using a high-intensity behavioral intervention based on the Diabetes Prevention Program as well as access to subsidized portion-controlled foods (Nutrisystem). At the end of the 6-month run-in, the remaining participants (n = 84, 79.3%) were then randomized, stratified by gender and whether or not they achieved 5% weight loss, into the 2 main study arms.

Intervention. The experimental study arm (n = 41, “intensified maintenance”) relied on monthly in-person visits and monthly phone calls to prevent weight regain (thus, these participants had twice monthly contact during maintenance). Both visit types in this arm were conducted by a graduate-level research assistant and included some structured educational content as well as problem-solving around diet and lifestyle issues. In contrast, the control arm (n = 43, “standard maintenance”) relied just on monthly mailings (or emails) of educational and support materials to promote weight loss maintenance. Participants in both groups had the opportunity to purchase subsidized portion-controlled foods/meals from Nutrisystem in order to facilitate continued adherence to the caloric restriction required for weight loss maintenance.

Main outcome measures. The primary outcome for this trial was change in weight, measured in kgs, during the 12-month maintenance period. Other biometric outcomes included changes in blood pressure, serum glucose, lipid levels, and the inflammatory marker hs-CRP. Patient-reported outcomes included changes in medication use. The investigators used intention-to-treat analysis, with mixed linear models adjusted for age and gender. No imputation techniques for missing data are reported, although complete follow-up data was obtained on 94% of patients.

Results. Participants in the standard and intensified weight maintenance arms of the trial were similar with respect to measured baseline characteristics. The average age of participants was 56 years, and three-quarters (75%) were female. The majority in both groups were white (77% in standard arm; 88% in intense), and over half had either a college or advanced degree (58.1% in standard arm, 51.2% in intense). Approximately one- third had diabetes (32.6% in standard arm, 34.1% in intense) and over half had hypertension (67.4% in standard arm, 63.4% in intense). Of the 84 participants who were randomized in the weight maintenance phase of the study, 79 completed the 12-month follow up (94%; no difference in attrition between groups).

After 12 months of maintenance, participants in the intensified maintenance arm regained just 1.6 (± 1.3) kg of lost weight, while those in the standard arm regained 5.0 (± 0.8) kg, a statistically significant difference (P = 0.01). The investigators also examined the subgroup of participants who, after the 6-month run-in, had lost at least 5% of their initial body weight. For these individuals, almost three-quarters in the intensified maintenance arm (71.9%) maintained that > 5% loss by 18 months, compared to 51.7% in the standard group. This difference between groups was not statistically significant. There was a significant difference between groups for change in hs-CRP over the 12-month maintenance period, with the intensive group’s hs-CRP ending up an average of 1.46 mg/L lower than that of the standard group (P = 0.03). Although there was a similar trend favoring the intensive intervention for other biometric measures (change in waist circumference, glucose, blood pressure, and lipids were all more favorable in this arm), the between-group differences for these measures did not reach statistical significance. No significant differences between groups were observed with respect to changes in medication use over the 12-month maintenance intervention.

Conclusion. After 5 months of active weight loss, twice-monthly contact (using one in-person and one phone visit) plus portion-controlled foods during a 12-month weight maintenance phase resulted in significantly less weight regain than monthly mail or email-based counseling plus portion-controlled foods.

Commentary

Behavioral weight loss interventions, which typically require high-intensity in-person counseling over several months to a year, may be difficult to accomplish in the average primary care practice [1]. On the other hand, it may be the case that primary care practices are well-suited to assist patients who have already lost weight, as they enter weight-loss maintenance. While numerous studies have shown that patients who adhere to calorie-restricted diets (almost regardless of diet composition) are able to achieve clinically significant weight loss, less is known about effective methods of preventing weight regain. Several large trials have suggested that, as is the case with behavioral weight loss interventions, maintenance interventions are also more successful if they include regular contact, at least some of which is face-to-face [2,3]. These visits, along with other practices such as self-weighing and food diaries, may help patients maintain the energy balance necessary to stay at their new, lower body weight. There remains a gap, however, in terms of knowing whether the maintenance interventions from large randomized trials can be translated into the sometimes messy real world of clinical practice, where clinicians and patients are typically overburdened and busy.

The current study by Tsai et al does address some aspects of this important question. By recruiting “real-world” chronically ill patients from a primary care practice to participate in the trial, the results of this study may be more likely to generalize to the patient populations seen by practicing clinicians than the typically healthier, younger, community-recruited volunteers in large trials. Additionally, although the interventions in this study were not delivered by the primary care practice per se, they were low enough in intensity that they could theoretically be translated into most clinical practice settings, assuming reimbursement is not an issue. Monthly in-person visits certainly could be done by a physician (as under current CMS reimbursement guidelines), but would not have to be (the visits in this study were done by a graduate student with no formal training in behavioral interventions), and telephone visits could easily be done by clinical support staff. Even with this low level of visit intensity, patients had significantly less weight regain than those who were receiving monthly email or postal mail support (which, realistically, would still require some work on the part of primary care practices). Furthermore, there were suggestions of numerous parallel cardiometabolic benefits that might have been statistically significant with a larger sample size. This study benefited from several strengths in addition to its highly practical point of view. It was a randomized trial with a strong control group and long follow-up duration (18 months total). It used a run-in period for weight loss so that all who entered maintenance were doing so based on exposure to the same weight loss intervention. Happily, though, the investigators did not require successful weight loss (> 5%) for entry into the maintenance phase, which likely further contributed to the generalizability of their results. Another area where the run-in likely helped was with retention of subjects—94% of those randomized for maintenance contributed complete data at the end of the 12-month study period.

As acknowledged by the authors, this study also has some important limitations. As with most weight loss/diet interventions, the participants in this study were mostly female, and mostly non-Hispanic white, and thus a substantially less diverse population than is represented by patients with obesity in the US. Furthermore, although some aspects of the patient population did promote generalizability (recruitment from primary care, chronic illness burden), these patients were fairly highly educated, which may have impacted their adherence and results.

The use of subsidized portion-controlled meals in this study, while evidence-based, may have clouded the results somewhat. Perhaps the effect of both interventions would have been less pronounced had patients not been provided with subsidies to access these foods. In their discussion, the investigators acknowledge that the study lacked a comparison group with no access to portion-controlled foods and that, in a post-hoc analysis, greater use of these foods corresponded with better weight loss and weight loss maintenance among all participants.

Finally, although it was beyond the scope of this study, this trial does not provide any information about how weight loss medications in either the weight loss or maintenance phases might impact these types of interventions. Now that the FDA has approved a number of such medications for long-term use, it would be very helpful to have more information about how medications might be integrated into these types of strategies, for interested patients, as physicians could clearly play an integral role in the pharmacologic management of weight, alongside effective behavioral interventions.

Applications for Clinical Practice

Low-to-moderate intensity in-person and telephone-based visits during weight maintenance may help to protect against weight regain, and could realistically be an option for many primary care practices and their patients. However, aside from Medicare patients, for whom monthly primary care–based weight maintenance visits are now covered, physicians would need to understand how to code and bill such visits appropriately in order to avoid having patients face unexpected charges.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To determine whether in-person visits for primary care patients resulted in improved weight loss maintenance relative to monthly mailings, with both groups receiving access to portion-controlled meals.

Design. Randomized clinical trial.

Setting and participants. This study took place within 2 university-affiliated primary care clinics in Colorado. For the first phase of the study, investigators enrolled 104 obese adult patients (18–79 years; BMI 30–49.9 kg/m²) who had been diagnosed with at least one of the following: type 2 diabetes, sleep apnea, hypertension, or hyperlipidemia. Patients who had independently lost weight prior to trial entry (> 5% in 6 months), were on weight-gain–promoting medications such as steroids, or had previously undergone bariatric surgery were excluded. The trial started with a 6-month run-in phase where active weight loss was promoted using a high-intensity behavioral intervention based on the Diabetes Prevention Program as well as access to subsidized portion-controlled foods (Nutrisystem). At the end of the 6-month run-in, the remaining participants (n = 84, 79.3%) were then randomized, stratified by gender and whether or not they achieved 5% weight loss, into the 2 main study arms.

Intervention. The experimental study arm (n = 41, “intensified maintenance”) relied on monthly in-person visits and monthly phone calls to prevent weight regain (thus, these participants had twice monthly contact during maintenance). Both visit types in this arm were conducted by a graduate-level research assistant and included some structured educational content as well as problem-solving around diet and lifestyle issues. In contrast, the control arm (n = 43, “standard maintenance”) relied just on monthly mailings (or emails) of educational and support materials to promote weight loss maintenance. Participants in both groups had the opportunity to purchase subsidized portion-controlled foods/meals from Nutrisystem in order to facilitate continued adherence to the caloric restriction required for weight loss maintenance.

Main outcome measures. The primary outcome for this trial was change in weight, measured in kgs, during the 12-month maintenance period. Other biometric outcomes included changes in blood pressure, serum glucose, lipid levels, and the inflammatory marker hs-CRP. Patient-reported outcomes included changes in medication use. The investigators used intention-to-treat analysis, with mixed linear models adjusted for age and gender. No imputation techniques for missing data are reported, although complete follow-up data was obtained on 94% of patients.

Results. Participants in the standard and intensified weight maintenance arms of the trial were similar with respect to measured baseline characteristics. The average age of participants was 56 years, and three-quarters (75%) were female. The majority in both groups were white (77% in standard arm; 88% in intense), and over half had either a college or advanced degree (58.1% in standard arm, 51.2% in intense). Approximately one- third had diabetes (32.6% in standard arm, 34.1% in intense) and over half had hypertension (67.4% in standard arm, 63.4% in intense). Of the 84 participants who were randomized in the weight maintenance phase of the study, 79 completed the 12-month follow up (94%; no difference in attrition between groups).

After 12 months of maintenance, participants in the intensified maintenance arm regained just 1.6 (± 1.3) kg of lost weight, while those in the standard arm regained 5.0 (± 0.8) kg, a statistically significant difference (P = 0.01). The investigators also examined the subgroup of participants who, after the 6-month run-in, had lost at least 5% of their initial body weight. For these individuals, almost three-quarters in the intensified maintenance arm (71.9%) maintained that > 5% loss by 18 months, compared to 51.7% in the standard group. This difference between groups was not statistically significant. There was a significant difference between groups for change in hs-CRP over the 12-month maintenance period, with the intensive group’s hs-CRP ending up an average of 1.46 mg/L lower than that of the standard group (P = 0.03). Although there was a similar trend favoring the intensive intervention for other biometric measures (change in waist circumference, glucose, blood pressure, and lipids were all more favorable in this arm), the between-group differences for these measures did not reach statistical significance. No significant differences between groups were observed with respect to changes in medication use over the 12-month maintenance intervention.

Conclusion. After 5 months of active weight loss, twice-monthly contact (using one in-person and one phone visit) plus portion-controlled foods during a 12-month weight maintenance phase resulted in significantly less weight regain than monthly mail or email-based counseling plus portion-controlled foods.

Commentary

Behavioral weight loss interventions, which typically require high-intensity in-person counseling over several months to a year, may be difficult to accomplish in the average primary care practice [1]. On the other hand, it may be the case that primary care practices are well-suited to assist patients who have already lost weight, as they enter weight-loss maintenance. While numerous studies have shown that patients who adhere to calorie-restricted diets (almost regardless of diet composition) are able to achieve clinically significant weight loss, less is known about effective methods of preventing weight regain. Several large trials have suggested that, as is the case with behavioral weight loss interventions, maintenance interventions are also more successful if they include regular contact, at least some of which is face-to-face [2,3]. These visits, along with other practices such as self-weighing and food diaries, may help patients maintain the energy balance necessary to stay at their new, lower body weight. There remains a gap, however, in terms of knowing whether the maintenance interventions from large randomized trials can be translated into the sometimes messy real world of clinical practice, where clinicians and patients are typically overburdened and busy.

The current study by Tsai et al does address some aspects of this important question. By recruiting “real-world” chronically ill patients from a primary care practice to participate in the trial, the results of this study may be more likely to generalize to the patient populations seen by practicing clinicians than the typically healthier, younger, community-recruited volunteers in large trials. Additionally, although the interventions in this study were not delivered by the primary care practice per se, they were low enough in intensity that they could theoretically be translated into most clinical practice settings, assuming reimbursement is not an issue. Monthly in-person visits certainly could be done by a physician (as under current CMS reimbursement guidelines), but would not have to be (the visits in this study were done by a graduate student with no formal training in behavioral interventions), and telephone visits could easily be done by clinical support staff. Even with this low level of visit intensity, patients had significantly less weight regain than those who were receiving monthly email or postal mail support (which, realistically, would still require some work on the part of primary care practices). Furthermore, there were suggestions of numerous parallel cardiometabolic benefits that might have been statistically significant with a larger sample size. This study benefited from several strengths in addition to its highly practical point of view. It was a randomized trial with a strong control group and long follow-up duration (18 months total). It used a run-in period for weight loss so that all who entered maintenance were doing so based on exposure to the same weight loss intervention. Happily, though, the investigators did not require successful weight loss (> 5%) for entry into the maintenance phase, which likely further contributed to the generalizability of their results. Another area where the run-in likely helped was with retention of subjects—94% of those randomized for maintenance contributed complete data at the end of the 12-month study period.

As acknowledged by the authors, this study also has some important limitations. As with most weight loss/diet interventions, the participants in this study were mostly female, and mostly non-Hispanic white, and thus a substantially less diverse population than is represented by patients with obesity in the US. Furthermore, although some aspects of the patient population did promote generalizability (recruitment from primary care, chronic illness burden), these patients were fairly highly educated, which may have impacted their adherence and results.

The use of subsidized portion-controlled meals in this study, while evidence-based, may have clouded the results somewhat. Perhaps the effect of both interventions would have been less pronounced had patients not been provided with subsidies to access these foods. In their discussion, the investigators acknowledge that the study lacked a comparison group with no access to portion-controlled foods and that, in a post-hoc analysis, greater use of these foods corresponded with better weight loss and weight loss maintenance among all participants.

Finally, although it was beyond the scope of this study, this trial does not provide any information about how weight loss medications in either the weight loss or maintenance phases might impact these types of interventions. Now that the FDA has approved a number of such medications for long-term use, it would be very helpful to have more information about how medications might be integrated into these types of strategies, for interested patients, as physicians could clearly play an integral role in the pharmacologic management of weight, alongside effective behavioral interventions.

Applications for Clinical Practice

Low-to-moderate intensity in-person and telephone-based visits during weight maintenance may help to protect against weight regain, and could realistically be an option for many primary care practices and their patients. However, aside from Medicare patients, for whom monthly primary care–based weight maintenance visits are now covered, physicians would need to understand how to code and bill such visits appropriately in order to avoid having patients face unexpected charges.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To determine whether in-person visits for primary care patients resulted in improved weight loss maintenance relative to monthly mailings, with both groups receiving access to portion-controlled meals.

Design. Randomized clinical trial.

Setting and participants. This study took place within 2 university-affiliated primary care clinics in Colorado. For the first phase of the study, investigators enrolled 104 obese adult patients (18–79 years; BMI 30–49.9 kg/m²) who had been diagnosed with at least one of the following: type 2 diabetes, sleep apnea, hypertension, or hyperlipidemia. Patients who had independently lost weight prior to trial entry (> 5% in 6 months), were on weight-gain–promoting medications such as steroids, or had previously undergone bariatric surgery were excluded. The trial started with a 6-month run-in phase where active weight loss was promoted using a high-intensity behavioral intervention based on the Diabetes Prevention Program as well as access to subsidized portion-controlled foods (Nutrisystem). At the end of the 6-month run-in, the remaining participants (n = 84, 79.3%) were then randomized, stratified by gender and whether or not they achieved 5% weight loss, into the 2 main study arms.

Intervention. The experimental study arm (n = 41, “intensified maintenance”) relied on monthly in-person visits and monthly phone calls to prevent weight regain (thus, these participants had twice monthly contact during maintenance). Both visit types in this arm were conducted by a graduate-level research assistant and included some structured educational content as well as problem-solving around diet and lifestyle issues. In contrast, the control arm (n = 43, “standard maintenance”) relied just on monthly mailings (or emails) of educational and support materials to promote weight loss maintenance. Participants in both groups had the opportunity to purchase subsidized portion-controlled foods/meals from Nutrisystem in order to facilitate continued adherence to the caloric restriction required for weight loss maintenance.

Main outcome measures. The primary outcome for this trial was change in weight, measured in kgs, during the 12-month maintenance period. Other biometric outcomes included changes in blood pressure, serum glucose, lipid levels, and the inflammatory marker hs-CRP. Patient-reported outcomes included changes in medication use. The investigators used intention-to-treat analysis, with mixed linear models adjusted for age and gender. No imputation techniques for missing data are reported, although complete follow-up data was obtained on 94% of patients.

Results. Participants in the standard and intensified weight maintenance arms of the trial were similar with respect to measured baseline characteristics. The average age of participants was 56 years, and three-quarters (75%) were female. The majority in both groups were white (77% in standard arm; 88% in intense), and over half had either a college or advanced degree (58.1% in standard arm, 51.2% in intense). Approximately one- third had diabetes (32.6% in standard arm, 34.1% in intense) and over half had hypertension (67.4% in standard arm, 63.4% in intense). Of the 84 participants who were randomized in the weight maintenance phase of the study, 79 completed the 12-month follow up (94%; no difference in attrition between groups).

After 12 months of maintenance, participants in the intensified maintenance arm regained just 1.6 (± 1.3) kg of lost weight, while those in the standard arm regained 5.0 (± 0.8) kg, a statistically significant difference (P = 0.01). The investigators also examined the subgroup of participants who, after the 6-month run-in, had lost at least 5% of their initial body weight. For these individuals, almost three-quarters in the intensified maintenance arm (71.9%) maintained that > 5% loss by 18 months, compared to 51.7% in the standard group. This difference between groups was not statistically significant. There was a significant difference between groups for change in hs-CRP over the 12-month maintenance period, with the intensive group’s hs-CRP ending up an average of 1.46 mg/L lower than that of the standard group (P = 0.03). Although there was a similar trend favoring the intensive intervention for other biometric measures (change in waist circumference, glucose, blood pressure, and lipids were all more favorable in this arm), the between-group differences for these measures did not reach statistical significance. No significant differences between groups were observed with respect to changes in medication use over the 12-month maintenance intervention.

Conclusion. After 5 months of active weight loss, twice-monthly contact (using one in-person and one phone visit) plus portion-controlled foods during a 12-month weight maintenance phase resulted in significantly less weight regain than monthly mail or email-based counseling plus portion-controlled foods.

Commentary

Behavioral weight loss interventions, which typically require high-intensity in-person counseling over several months to a year, may be difficult to accomplish in the average primary care practice [1]. On the other hand, it may be the case that primary care practices are well-suited to assist patients who have already lost weight, as they enter weight-loss maintenance. While numerous studies have shown that patients who adhere to calorie-restricted diets (almost regardless of diet composition) are able to achieve clinically significant weight loss, less is known about effective methods of preventing weight regain. Several large trials have suggested that, as is the case with behavioral weight loss interventions, maintenance interventions are also more successful if they include regular contact, at least some of which is face-to-face [2,3]. These visits, along with other practices such as self-weighing and food diaries, may help patients maintain the energy balance necessary to stay at their new, lower body weight. There remains a gap, however, in terms of knowing whether the maintenance interventions from large randomized trials can be translated into the sometimes messy real world of clinical practice, where clinicians and patients are typically overburdened and busy.

The current study by Tsai et al does address some aspects of this important question. By recruiting “real-world” chronically ill patients from a primary care practice to participate in the trial, the results of this study may be more likely to generalize to the patient populations seen by practicing clinicians than the typically healthier, younger, community-recruited volunteers in large trials. Additionally, although the interventions in this study were not delivered by the primary care practice per se, they were low enough in intensity that they could theoretically be translated into most clinical practice settings, assuming reimbursement is not an issue. Monthly in-person visits certainly could be done by a physician (as under current CMS reimbursement guidelines), but would not have to be (the visits in this study were done by a graduate student with no formal training in behavioral interventions), and telephone visits could easily be done by clinical support staff. Even with this low level of visit intensity, patients had significantly less weight regain than those who were receiving monthly email or postal mail support (which, realistically, would still require some work on the part of primary care practices). Furthermore, there were suggestions of numerous parallel cardiometabolic benefits that might have been statistically significant with a larger sample size. This study benefited from several strengths in addition to its highly practical point of view. It was a randomized trial with a strong control group and long follow-up duration (18 months total). It used a run-in period for weight loss so that all who entered maintenance were doing so based on exposure to the same weight loss intervention. Happily, though, the investigators did not require successful weight loss (> 5%) for entry into the maintenance phase, which likely further contributed to the generalizability of their results. Another area where the run-in likely helped was with retention of subjects—94% of those randomized for maintenance contributed complete data at the end of the 12-month study period.

As acknowledged by the authors, this study also has some important limitations. As with most weight loss/diet interventions, the participants in this study were mostly female, and mostly non-Hispanic white, and thus a substantially less diverse population than is represented by patients with obesity in the US. Furthermore, although some aspects of the patient population did promote generalizability (recruitment from primary care, chronic illness burden), these patients were fairly highly educated, which may have impacted their adherence and results.

The use of subsidized portion-controlled meals in this study, while evidence-based, may have clouded the results somewhat. Perhaps the effect of both interventions would have been less pronounced had patients not been provided with subsidies to access these foods. In their discussion, the investigators acknowledge that the study lacked a comparison group with no access to portion-controlled foods and that, in a post-hoc analysis, greater use of these foods corresponded with better weight loss and weight loss maintenance among all participants.

Finally, although it was beyond the scope of this study, this trial does not provide any information about how weight loss medications in either the weight loss or maintenance phases might impact these types of interventions. Now that the FDA has approved a number of such medications for long-term use, it would be very helpful to have more information about how medications might be integrated into these types of strategies, for interested patients, as physicians could clearly play an integral role in the pharmacologic management of weight, alongside effective behavioral interventions.

Applications for Clinical Practice

Low-to-moderate intensity in-person and telephone-based visits during weight maintenance may help to protect against weight regain, and could realistically be an option for many primary care practices and their patients. However, aside from Medicare patients, for whom monthly primary care–based weight maintenance visits are now covered, physicians would need to understand how to code and bill such visits appropriately in order to avoid having patients face unexpected charges.

—Kristina Lewis, MD, MPH

From the University of California Irvine Health/Chao Family Comprehensive Cancer Center Orange, CA (Ms. Boyle) and the University of California San Francisco Medical Center, San Francisco, CA (Dr. Anderson).

Abstract

• Objective: To describe components of a unique interactive workshop focusing on the enhancement of critical care nurses’ communication skills within the realm of prognosis and goals of care discussions with family members and physicians.
• Methods: A series of one-day workshops were offered to critical care nurses practicing in the 5 University of California hospital settings. After workshop attendance, nurse participants were followed by workshop facilitators in their units to ensure new communication skills were being integrated into practice and to problem solve if barriers were met.
• Results: Improvement in nurses’ self-confidence in engaging in these discussions was seen. This confidence was sustained months following workshop participation.
• Conclusion: The combination of critical care nurse workshop participation that involved skill enhancement through role-playing, in combination with clinical follow-up with attendees, resulted in positive affirmation of nurse communication skills specific to prognosis and goals of care discussions with family members and physicians.

There is increasing evidence that in the absence of quality communication between professional caregivers and those they care for, negative outcomes may prevail, such as reduced patient/family satisfaction, lower health status awareness, and a decreased sense of being cared about and cared for [1–5]. Communication skill competency is a critical corollary of nursing practice. In the intensive care unit (ICU) setting, patients and families have cited skilled communication as a core element of high-quality care [3,6]. Proficiency in this realm enhances nurses’ understanding of the patient and family’s encounter with health care and provides a vehicle to gather information, inform, teach, and offer emotional support. Additionally, it identifies values, goals, health care preferences, worries and concerns, and facilitates the nurses’ coordination of care [7]. Despite this skill’s importance, however, it is generally not taught in basic education and until recently has been overlooked as a key competency [8,9].

Skilled communication in palliative and end-of-life care is pivotal for discussing prognosis and care planning. In the acute care setting this is particularly relevant as the majority of Americans die in hospitals versus their preferred site of home [10]. Additionally, 1 in 5 Americans die during or shortly after receiving care in an ICU [11]. Hence, while the ICU is a setting in which intensive effort to save lives is employed, it is also a setting where death frequently occurs. The complexity and highly emotive nature of critical care often results in family needs for information and support not being met [12]. A number of reasons for this occurrence have been proposed. In this paper, we will delineate barriers to critical care nurses’ involvement in prognosis and goals of care discussions, identify why nurse involvement in this communication is needed, describe a unique workshop exemplar with a sample role play that characterizes the workshop, and offer recommendations for colleagues interested in replicating similar education offerings.

Barriers to Communication

In the ICU, the sheer number of professionals families interact with may cause confusion. In particular, numerous medical consultants commonly offer opposing opinions. Additionally, each specialist may provide information that focuses on their area of expertise such that the “big picture” is not relayed to the patient and family. Emotional discomfort on the part of the health professional around discussions of poor prognosis, goals of care, and code status may prompt limiting discussion time with patients and families and even the avoidance of interpersonal exchanges [13–15]. Health professionals have also reported concern that end-of-life discussions will increase patient distress [16]. Among health care professionals, the subject of mortality may prompt personal anxiety, trigger unresolved grief, or fear that they will “become emotional” in front of the patient/family [7]. Lack of knowledge about cultural and religious norms has been cited as a barrier, as has time constraints [17,18]. Most frequently, inadequate or absent communication skill training is noted as a significant barrier [19,20]. Many ICU nurses also report feeling marginalized due their exclusion from goals of care and decision-making discussions with patients and families they know well [21,22].

Nurses As Key Palliative Care Communicators

Education efforts that foster communication proficiency during serious illness have traditionally focused on training physicians. Recently, nursing has become a focus of communication skill enhancement in recognition of nurses’ intense and protracted interactions with patients and families in the acute care setting. Nurses are the ‘constant’ in the patient and family’s journey through the fragmented health care system [21,23]. They often have the best knowledge of, and strongest relationship with, the family and often have had extensive discussions with them about their loved one’s status [24]. Nurses are aware of the patients’ symptom experiences and are privy to valuable information about the concerns and priorities of patients and families [12]. Additionally, having the most continuous presence, nurses have seen and heard interactions with clinicians from numerous disciplines. Nurses are the most visible, constant resource for patient and family education, information and support, and thus they perceive one of their most important roles to be that of advocate for the patient and family [20,21].

Communication Training Programs for Critical Care Nurses

Education is critical to enhance communication skills within palliative care [7,15,17,20,21,24]. The preferred teaching style within this realm is role play, where skills can be practiced and the affective component of engaging in sensitive discussions can be addressed [25–27]. Role play also demonstrates firsthand the importance of nonverbal communication (eg, body language, proximity, use of gestures, tone of voice) [7,20] and facilitates nurses’ gaining a sense of comfort with wordless communication [18].

Communication skills training programs have been designed to provide bedside critical care nurses with the tools they need to be active participants in discussions of prognosis, goals of care, and palliative care with families and physicians [27,28]. These programs have demonstrated improvement in nurses’ confidence to engage in key palliative care-related discussions. Essential elements of these programs include (1) delineation of the role of the bedside nurse in palliative care communication; (2) presentation and learner-centered practice of communication skills using role play; and (3) a reflection session focused on self-care and sustainability.

Across the 5 academic University of California medical centers (San Francisco, Davis, Los Angeles, Irvine, and San Diego), a communication training program based on this work has been implemented [29]. The one-day workshop, entitled IMPACT-ICU (Integrating Multidisciplinary Palliative Care into the ICU), has taught a total of 527 critical care nurses across the 5 centers. In addition to classroom training, the IMPACT-ICU program also includes proactive specialty palliative nursing support for bedside nurses by facilitating the availability of palliative care advanced practice nurses and nurse educators resources. This support helps nurses to apply the skills learned in the workshop in their practice. During rounds at the bedside, the nurse resources coach the bedside staff on the “how” and “when” of addressing palliative care needs. Education and support on a range of topics are offered, including clarifying goals and interventions provided by palliative care teams, the specifics of how to provide family emotional support and delivery of understandable information, the assessment and management of symptoms distress, and the nurses’ role in organizing and participating in family meetings. Case-specific consultations are also offered that address how to interface with resistant medical staff. The importance of nurse documentation of these varied exchanges is also emphasized.

IMPACT-ICU Workshop

A maximum of 15 nurses participate in each 8-hour workshop. The session begins with introductions and small group discussions about what the participants perceive to be the greatest barriers to goals of care discussions and fostering patient/family decision-making in the ICU. Participants are also asked to reflect on what they want to learn as a result of their workshop attendance.

A short didactic session then reviews the definition of palliative care and its core components, addresses the nurses’ role in communication within palliative care, a social worker’s perspective of what it is like to be a family member in the ICU, and the outline of the day. This includes delineation of expectations for involvement within the role plays and the various roles to be enacted. An emphasis is placed on the workshop being a safe place to explore and trial skills with the support of colleagues, and that practice is the optimum way to integrate communication expertise into the nurses’ skill set.

The “4 Cs” serves as the instructional basis for nurse communication skill enhancement [27]. This model outlines 4 key nursing roles in optimizing communication within palliative care:

Convening: Making sure multidisciplinary patient/family/clinician communication occurs.

Checking: Identifying the patient and family needs for information; ensuring that patients and families clearly receive desired information; ensuring that clinicians understand patient and family perspectives.

Caring: Naming emotions and responding to feeling.

Continuing: Following up after discussions to clarify and reinforce information and provide support.

Sample Role Play

Facilitator: So our first role play is focused on eliciting patient and family perspectives and needs. I need a learner and someone to play the role of the family member.

Learner: I’ll give it a try.

Facilitator: Lisa, you’re going to do great. Who wants to play the family member?

Workshop Participant: I’ll do it.

Facilitator: So Mary (who has agreed to play the role of the wife), why don’t you read us the scenario. (She reads it out loud to the group).

Facilitator: Lisa, as the nurse, I want you to look at your guide and tell me what your goal is for this conversation with Mrs. Ames and then which skill you want to practice.

Learner: I think I want to try eliciting the patient and family’s needs for information and I’ll try “Tell Me More” statements.

Facilitator: Alright. So remember Lisa, if you feel the conversation isn’t going well, you can call a “time out.” I can do this as well if I feel you need to start over. I’ll also call a time out when I feel you have met your goal. Sound OK? Mary, do you have any questions playing the part of Mrs. Ames?

Wife Role: Well, how hard should I make this for her? Should I be one of those “difficult” family members?

Facilitator: Our goal here is not to “stump” you or make it particularly difficult. We want you to try out these skills and get a sense of your “comfort zone.” So let’s start with some basic communication skills, OK?

Wife Role: Alright.

Facilitator: Why don’t we set the stage, such that Lisa, you are Mr. Ames’ nurse assessing him at the start of your shift, when Mrs. Ames enters. This is the first time you have taken care of him. The night nurse has told you that he has been requiring increasing ventilator support and his renal function is declining. Per Mrs. Ames’ request, the night nurse called her to let her know how he was doing and Mrs. Ames told her she would be in shortly.

Wife Role: (nervously enters the room and grasps her husband’s hand and looks at the nurse). How’s he doing? Is he better? The night nurse called me and I was so worried I rushed over here.

Learner: (Turns to Mrs. Ames and extends her hand). Are you Mrs. Ames? I’m Lisa and I am going to be taking care of Mr. Ames today. Let me just finish my assessment and how about we talk then? Will that be OK? It will be just a few minutes.

Wife Role: Alright, I’ll be in the waiting area but please come get me as soon as you can.

Learner: I will. (Nurse then shortly comes into the waiting area and asks Mrs. Ames to come back into the ICU where she invites her to sit just outside Mr. Ames’ room). Mrs. Ames, how are you doing? This must be so stressful for you, having your husband in the ICU.

Wife Role: It’s awful. He’s never been in the hospital before this and look at him, all hooked up to machines. I’m so worried. He seems to be getting worse instead of better.

Learner: What’s your understanding of what is going on?

Wife Role: I really don’t know. One doctor comes in and says one thing and then another comes in and tells me the opposite. I’m so confused I don’t know what to think.

Learner: Would having a better idea of his condition from the doctors who are treating him help you have a better understanding?

Wife Role: Oh, yes, but they always seem in such a hurry.

Learner: What exactly would you like to know?

Wife: Well, I want to know when he can get off that breathing machine because we have been planning to go to our son’s house for Thanksgiving.

Facilitator: Time out. Lisa, did you meet your conversation goal?

Learner: Um, I’m not sure, I guess so.

Facilitator: (Turns to Observers). What do you think, did she meet her goal?

Observer: Yes, she determined Mrs. Ames’ need for more information and she asked her what she wanted to know exactly.

Facilitator: What else did we see Lisa do to enhance communication with Mrs. Ames?

Observer: Well, when Mrs. Ames rushed into the room and asked her for information, Lisa didn’t just jump in and spout out values for the ventilator and his output. She took the time to introduce herself and de-escalate Mrs. Ames’ anxiety and she followed up on her promise to come get her in the waiting room as soon as she could.

Facilitator: Why do you think was important?

Observer: It helps establish trust.

Facilitator: Did Lisa use the skill she wanted to try out?

Observer: Yes.

Facilitator: How do you know? What did you hear her say?

Observer: She said, “What’s your understanding of what is going on with Mr. Ames?”

Facilitator: Absolutely. Great job, Lisa. And who wants to take a guess at how long Lisa’s exchange with Mrs. Ames took?

Observer: Less than two minutes?

Facilitator: That’s right. So just as you consider how long it takes, and how proficient you are, in starting an IV or inserting a Foley catheter, when you have a goal in mind and have practiced the skills to do it well, any skill can be mastered.

Feedback

Participants in the workshops uniformly report an enhanced sense of self-confidence in their palliative care communication skills as a result of their participation [29]. Key to the success of the workshop is the ongoing contact by the workshop facilitators with participants. Rounding is routinely planned such that each participant is visited weekly by a workshop facilitator in their clinical area to determine if the bedside nurse has practiced the new skills and if so, how the interaction transpired. Positive feedback is given for attempts to engage in new behaviors and participants are reminded that with any new skill, repetitive trials are necessary to foster success.

Lessons Learned and Next Steps

One of our major lessons learned was recognizing that it was difficult for many critical care nurses to practice the new communication skills. Nurses are trained to fix problems and perform medico-technical tasks; “listening” has not always been recognized as real work [18]. We needed to reinforce that skills like eliciting another’s perspective or making reflection statements are equally important to those associated with behavioral/technical proficiency.

While our program has been successful, we recognize that the next step in fostering ideal palliative care communication is to provide education within an interdisciplinary context. We recommend that colleagues interested in replicating this or a similar education intervention, survey nurse participants prior to and following workshop participation to measure attitudes, self confidence and perceived barriers over time [30]. We hope to translate our positive experience into a program that engages multiple professionals in the enhancement of optimum palliative care communication proficiency.

Corresponding author: Deborah A. Boyle MSN, RN, AOCNS, Department of Nursing Quality, Research and Education, University of California, Irvine Health, 101 The City Drive, Bldg 22A, Room 3104, Orange, CA 92868.

From the University of California Irvine Health/Chao Family Comprehensive Cancer Center Orange, CA (Ms. Boyle) and the University of California San Francisco Medical Center, San Francisco, CA (Dr. Anderson).

Abstract

• Objective: To describe components of a unique interactive workshop focusing on the enhancement of critical care nurses’ communication skills within the realm of prognosis and goals of care discussions with family members and physicians.
• Methods: A series of one-day workshops were offered to critical care nurses practicing in the 5 University of California hospital settings. After workshop attendance, nurse participants were followed by workshop facilitators in their units to ensure new communication skills were being integrated into practice and to problem solve if barriers were met.
• Results: Improvement in nurses’ self-confidence in engaging in these discussions was seen. This confidence was sustained months following workshop participation.
• Conclusion: The combination of critical care nurse workshop participation that involved skill enhancement through role-playing, in combination with clinical follow-up with attendees, resulted in positive affirmation of nurse communication skills specific to prognosis and goals of care discussions with family members and physicians.

There is increasing evidence that in the absence of quality communication between professional caregivers and those they care for, negative outcomes may prevail, such as reduced patient/family satisfaction, lower health status awareness, and a decreased sense of being cared about and cared for [1–5]. Communication skill competency is a critical corollary of nursing practice. In the intensive care unit (ICU) setting, patients and families have cited skilled communication as a core element of high-quality care [3,6]. Proficiency in this realm enhances nurses’ understanding of the patient and family’s encounter with health care and provides a vehicle to gather information, inform, teach, and offer emotional support. Additionally, it identifies values, goals, health care preferences, worries and concerns, and facilitates the nurses’ coordination of care [7]. Despite this skill’s importance, however, it is generally not taught in basic education and until recently has been overlooked as a key competency [8,9].

Skilled communication in palliative and end-of-life care is pivotal for discussing prognosis and care planning. In the acute care setting this is particularly relevant as the majority of Americans die in hospitals versus their preferred site of home [10]. Additionally, 1 in 5 Americans die during or shortly after receiving care in an ICU [11]. Hence, while the ICU is a setting in which intensive effort to save lives is employed, it is also a setting where death frequently occurs. The complexity and highly emotive nature of critical care often results in family needs for information and support not being met [12]. A number of reasons for this occurrence have been proposed. In this paper, we will delineate barriers to critical care nurses’ involvement in prognosis and goals of care discussions, identify why nurse involvement in this communication is needed, describe a unique workshop exemplar with a sample role play that characterizes the workshop, and offer recommendations for colleagues interested in replicating similar education offerings.

Barriers to Communication

In the ICU, the sheer number of professionals families interact with may cause confusion. In particular, numerous medical consultants commonly offer opposing opinions. Additionally, each specialist may provide information that focuses on their area of expertise such that the “big picture” is not relayed to the patient and family. Emotional discomfort on the part of the health professional around discussions of poor prognosis, goals of care, and code status may prompt limiting discussion time with patients and families and even the avoidance of interpersonal exchanges [13–15]. Health professionals have also reported concern that end-of-life discussions will increase patient distress [16]. Among health care professionals, the subject of mortality may prompt personal anxiety, trigger unresolved grief, or fear that they will “become emotional” in front of the patient/family [7]. Lack of knowledge about cultural and religious norms has been cited as a barrier, as has time constraints [17,18]. Most frequently, inadequate or absent communication skill training is noted as a significant barrier [19,20]. Many ICU nurses also report feeling marginalized due their exclusion from goals of care and decision-making discussions with patients and families they know well [21,22].

Nurses As Key Palliative Care Communicators

Education efforts that foster communication proficiency during serious illness have traditionally focused on training physicians. Recently, nursing has become a focus of communication skill enhancement in recognition of nurses’ intense and protracted interactions with patients and families in the acute care setting. Nurses are the ‘constant’ in the patient and family’s journey through the fragmented health care system [21,23]. They often have the best knowledge of, and strongest relationship with, the family and often have had extensive discussions with them about their loved one’s status [24]. Nurses are aware of the patients’ symptom experiences and are privy to valuable information about the concerns and priorities of patients and families [12]. Additionally, having the most continuous presence, nurses have seen and heard interactions with clinicians from numerous disciplines. Nurses are the most visible, constant resource for patient and family education, information and support, and thus they perceive one of their most important roles to be that of advocate for the patient and family [20,21].

Communication Training Programs for Critical Care Nurses

Education is critical to enhance communication skills within palliative care [7,15,17,20,21,24]. The preferred teaching style within this realm is role play, where skills can be practiced and the affective component of engaging in sensitive discussions can be addressed [25–27]. Role play also demonstrates firsthand the importance of nonverbal communication (eg, body language, proximity, use of gestures, tone of voice) [7,20] and facilitates nurses’ gaining a sense of comfort with wordless communication [18].

Communication skills training programs have been designed to provide bedside critical care nurses with the tools they need to be active participants in discussions of prognosis, goals of care, and palliative care with families and physicians [27,28]. These programs have demonstrated improvement in nurses’ confidence to engage in key palliative care-related discussions. Essential elements of these programs include (1) delineation of the role of the bedside nurse in palliative care communication; (2) presentation and learner-centered practice of communication skills using role play; and (3) a reflection session focused on self-care and sustainability.

Across the 5 academic University of California medical centers (San Francisco, Davis, Los Angeles, Irvine, and San Diego), a communication training program based on this work has been implemented [29]. The one-day workshop, entitled IMPACT-ICU (Integrating Multidisciplinary Palliative Care into the ICU), has taught a total of 527 critical care nurses across the 5 centers. In addition to classroom training, the IMPACT-ICU program also includes proactive specialty palliative nursing support for bedside nurses by facilitating the availability of palliative care advanced practice nurses and nurse educators resources. This support helps nurses to apply the skills learned in the workshop in their practice. During rounds at the bedside, the nurse resources coach the bedside staff on the “how” and “when” of addressing palliative care needs. Education and support on a range of topics are offered, including clarifying goals and interventions provided by palliative care teams, the specifics of how to provide family emotional support and delivery of understandable information, the assessment and management of symptoms distress, and the nurses’ role in organizing and participating in family meetings. Case-specific consultations are also offered that address how to interface with resistant medical staff. The importance of nurse documentation of these varied exchanges is also emphasized.

IMPACT-ICU Workshop

A maximum of 15 nurses participate in each 8-hour workshop. The session begins with introductions and small group discussions about what the participants perceive to be the greatest barriers to goals of care discussions and fostering patient/family decision-making in the ICU. Participants are also asked to reflect on what they want to learn as a result of their workshop attendance.

A short didactic session then reviews the definition of palliative care and its core components, addresses the nurses’ role in communication within palliative care, a social worker’s perspective of what it is like to be a family member in the ICU, and the outline of the day. This includes delineation of expectations for involvement within the role plays and the various roles to be enacted. An emphasis is placed on the workshop being a safe place to explore and trial skills with the support of colleagues, and that practice is the optimum way to integrate communication expertise into the nurses’ skill set.

The “4 Cs” serves as the instructional basis for nurse communication skill enhancement [27]. This model outlines 4 key nursing roles in optimizing communication within palliative care:

Convening: Making sure multidisciplinary patient/family/clinician communication occurs.

Checking: Identifying the patient and family needs for information; ensuring that patients and families clearly receive desired information; ensuring that clinicians understand patient and family perspectives.

Caring: Naming emotions and responding to feeling.

Continuing: Following up after discussions to clarify and reinforce information and provide support.

Sample Role Play

Facilitator: So our first role play is focused on eliciting patient and family perspectives and needs. I need a learner and someone to play the role of the family member.

Learner: I’ll give it a try.

Facilitator: Lisa, you’re going to do great. Who wants to play the family member?

Workshop Participant: I’ll do it.

Facilitator: So Mary (who has agreed to play the role of the wife), why don’t you read us the scenario. (She reads it out loud to the group).

Facilitator: Lisa, as the nurse, I want you to look at your guide and tell me what your goal is for this conversation with Mrs. Ames and then which skill you want to practice.

Learner: I think I want to try eliciting the patient and family’s needs for information and I’ll try “Tell Me More” statements.

Facilitator: Alright. So remember Lisa, if you feel the conversation isn’t going well, you can call a “time out.” I can do this as well if I feel you need to start over. I’ll also call a time out when I feel you have met your goal. Sound OK? Mary, do you have any questions playing the part of Mrs. Ames?

Wife Role: Well, how hard should I make this for her? Should I be one of those “difficult” family members?

Facilitator: Our goal here is not to “stump” you or make it particularly difficult. We want you to try out these skills and get a sense of your “comfort zone.” So let’s start with some basic communication skills, OK?

Wife Role: Alright.

Facilitator: Why don’t we set the stage, such that Lisa, you are Mr. Ames’ nurse assessing him at the start of your shift, when Mrs. Ames enters. This is the first time you have taken care of him. The night nurse has told you that he has been requiring increasing ventilator support and his renal function is declining. Per Mrs. Ames’ request, the night nurse called her to let her know how he was doing and Mrs. Ames told her she would be in shortly.

Wife Role: (nervously enters the room and grasps her husband’s hand and looks at the nurse). How’s he doing? Is he better? The night nurse called me and I was so worried I rushed over here.

Learner: (Turns to Mrs. Ames and extends her hand). Are you Mrs. Ames? I’m Lisa and I am going to be taking care of Mr. Ames today. Let me just finish my assessment and how about we talk then? Will that be OK? It will be just a few minutes.

Wife Role: Alright, I’ll be in the waiting area but please come get me as soon as you can.

Learner: I will. (Nurse then shortly comes into the waiting area and asks Mrs. Ames to come back into the ICU where she invites her to sit just outside Mr. Ames’ room). Mrs. Ames, how are you doing? This must be so stressful for you, having your husband in the ICU.

Wife Role: It’s awful. He’s never been in the hospital before this and look at him, all hooked up to machines. I’m so worried. He seems to be getting worse instead of better.

Learner: What’s your understanding of what is going on?

Wife Role: I really don’t know. One doctor comes in and says one thing and then another comes in and tells me the opposite. I’m so confused I don’t know what to think.

Learner: Would having a better idea of his condition from the doctors who are treating him help you have a better understanding?

Wife Role: Oh, yes, but they always seem in such a hurry.

Learner: What exactly would you like to know?

Wife: Well, I want to know when he can get off that breathing machine because we have been planning to go to our son’s house for Thanksgiving.

Facilitator: Time out. Lisa, did you meet your conversation goal?

Learner: Um, I’m not sure, I guess so.

Facilitator: (Turns to Observers). What do you think, did she meet her goal?

Observer: Yes, she determined Mrs. Ames’ need for more information and she asked her what she wanted to know exactly.

Facilitator: What else did we see Lisa do to enhance communication with Mrs. Ames?

Observer: Well, when Mrs. Ames rushed into the room and asked her for information, Lisa didn’t just jump in and spout out values for the ventilator and his output. She took the time to introduce herself and de-escalate Mrs. Ames’ anxiety and she followed up on her promise to come get her in the waiting room as soon as she could.

Facilitator: Why do you think was important?

Observer: It helps establish trust.

Facilitator: Did Lisa use the skill she wanted to try out?

Observer: Yes.

Facilitator: How do you know? What did you hear her say?

Observer: She said, “What’s your understanding of what is going on with Mr. Ames?”

Facilitator: Absolutely. Great job, Lisa. And who wants to take a guess at how long Lisa’s exchange with Mrs. Ames took?

Observer: Less than two minutes?

Facilitator: That’s right. So just as you consider how long it takes, and how proficient you are, in starting an IV or inserting a Foley catheter, when you have a goal in mind and have practiced the skills to do it well, any skill can be mastered.

Feedback

Participants in the workshops uniformly report an enhanced sense of self-confidence in their palliative care communication skills as a result of their participation [29]. Key to the success of the workshop is the ongoing contact by the workshop facilitators with participants. Rounding is routinely planned such that each participant is visited weekly by a workshop facilitator in their clinical area to determine if the bedside nurse has practiced the new skills and if so, how the interaction transpired. Positive feedback is given for attempts to engage in new behaviors and participants are reminded that with any new skill, repetitive trials are necessary to foster success.

Lessons Learned and Next Steps

One of our major lessons learned was recognizing that it was difficult for many critical care nurses to practice the new communication skills. Nurses are trained to fix problems and perform medico-technical tasks; “listening” has not always been recognized as real work [18]. We needed to reinforce that skills like eliciting another’s perspective or making reflection statements are equally important to those associated with behavioral/technical proficiency.

While our program has been successful, we recognize that the next step in fostering ideal palliative care communication is to provide education within an interdisciplinary context. We recommend that colleagues interested in replicating this or a similar education intervention, survey nurse participants prior to and following workshop participation to measure attitudes, self confidence and perceived barriers over time [30]. We hope to translate our positive experience into a program that engages multiple professionals in the enhancement of optimum palliative care communication proficiency.

Corresponding author: Deborah A. Boyle MSN, RN, AOCNS, Department of Nursing Quality, Research and Education, University of California, Irvine Health, 101 The City Drive, Bldg 22A, Room 3104, Orange, CA 92868.

From the University of California Irvine Health/Chao Family Comprehensive Cancer Center Orange, CA (Ms. Boyle) and the University of California San Francisco Medical Center, San Francisco, CA (Dr. Anderson).

Abstract

• Objective: To describe components of a unique interactive workshop focusing on the enhancement of critical care nurses’ communication skills within the realm of prognosis and goals of care discussions with family members and physicians.
• Methods: A series of one-day workshops were offered to critical care nurses practicing in the 5 University of California hospital settings. After workshop attendance, nurse participants were followed by workshop facilitators in their units to ensure new communication skills were being integrated into practice and to problem solve if barriers were met.
• Results: Improvement in nurses’ self-confidence in engaging in these discussions was seen. This confidence was sustained months following workshop participation.
• Conclusion: The combination of critical care nurse workshop participation that involved skill enhancement through role-playing, in combination with clinical follow-up with attendees, resulted in positive affirmation of nurse communication skills specific to prognosis and goals of care discussions with family members and physicians.

There is increasing evidence that in the absence of quality communication between professional caregivers and those they care for, negative outcomes may prevail, such as reduced patient/family satisfaction, lower health status awareness, and a decreased sense of being cared about and cared for [1–5]. Communication skill competency is a critical corollary of nursing practice. In the intensive care unit (ICU) setting, patients and families have cited skilled communication as a core element of high-quality care [3,6]. Proficiency in this realm enhances nurses’ understanding of the patient and family’s encounter with health care and provides a vehicle to gather information, inform, teach, and offer emotional support. Additionally, it identifies values, goals, health care preferences, worries and concerns, and facilitates the nurses’ coordination of care [7]. Despite this skill’s importance, however, it is generally not taught in basic education and until recently has been overlooked as a key competency [8,9].

Skilled communication in palliative and end-of-life care is pivotal for discussing prognosis and care planning. In the acute care setting this is particularly relevant as the majority of Americans die in hospitals versus their preferred site of home [10]. Additionally, 1 in 5 Americans die during or shortly after receiving care in an ICU [11]. Hence, while the ICU is a setting in which intensive effort to save lives is employed, it is also a setting where death frequently occurs. The complexity and highly emotive nature of critical care often results in family needs for information and support not being met [12]. A number of reasons for this occurrence have been proposed. In this paper, we will delineate barriers to critical care nurses’ involvement in prognosis and goals of care discussions, identify why nurse involvement in this communication is needed, describe a unique workshop exemplar with a sample role play that characterizes the workshop, and offer recommendations for colleagues interested in replicating similar education offerings.

Barriers to Communication

In the ICU, the sheer number of professionals families interact with may cause confusion. In particular, numerous medical consultants commonly offer opposing opinions. Additionally, each specialist may provide information that focuses on their area of expertise such that the “big picture” is not relayed to the patient and family. Emotional discomfort on the part of the health professional around discussions of poor prognosis, goals of care, and code status may prompt limiting discussion time with patients and families and even the avoidance of interpersonal exchanges [13–15]. Health professionals have also reported concern that end-of-life discussions will increase patient distress [16]. Among health care professionals, the subject of mortality may prompt personal anxiety, trigger unresolved grief, or fear that they will “become emotional” in front of the patient/family [7]. Lack of knowledge about cultural and religious norms has been cited as a barrier, as has time constraints [17,18]. Most frequently, inadequate or absent communication skill training is noted as a significant barrier [19,20]. Many ICU nurses also report feeling marginalized due their exclusion from goals of care and decision-making discussions with patients and families they know well [21,22].

Nurses As Key Palliative Care Communicators

Education efforts that foster communication proficiency during serious illness have traditionally focused on training physicians. Recently, nursing has become a focus of communication skill enhancement in recognition of nurses’ intense and protracted interactions with patients and families in the acute care setting. Nurses are the ‘constant’ in the patient and family’s journey through the fragmented health care system [21,23]. They often have the best knowledge of, and strongest relationship with, the family and often have had extensive discussions with them about their loved one’s status [24]. Nurses are aware of the patients’ symptom experiences and are privy to valuable information about the concerns and priorities of patients and families [12]. Additionally, having the most continuous presence, nurses have seen and heard interactions with clinicians from numerous disciplines. Nurses are the most visible, constant resource for patient and family education, information and support, and thus they perceive one of their most important roles to be that of advocate for the patient and family [20,21].

Communication Training Programs for Critical Care Nurses

Education is critical to enhance communication skills within palliative care [7,15,17,20,21,24]. The preferred teaching style within this realm is role play, where skills can be practiced and the affective component of engaging in sensitive discussions can be addressed [25–27]. Role play also demonstrates firsthand the importance of nonverbal communication (eg, body language, proximity, use of gestures, tone of voice) [7,20] and facilitates nurses’ gaining a sense of comfort with wordless communication [18].

Communication skills training programs have been designed to provide bedside critical care nurses with the tools they need to be active participants in discussions of prognosis, goals of care, and palliative care with families and physicians [27,28]. These programs have demonstrated improvement in nurses’ confidence to engage in key palliative care-related discussions. Essential elements of these programs include (1) delineation of the role of the bedside nurse in palliative care communication; (2) presentation and learner-centered practice of communication skills using role play; and (3) a reflection session focused on self-care and sustainability.

Across the 5 academic University of California medical centers (San Francisco, Davis, Los Angeles, Irvine, and San Diego), a communication training program based on this work has been implemented [29]. The one-day workshop, entitled IMPACT-ICU (Integrating Multidisciplinary Palliative Care into the ICU), has taught a total of 527 critical care nurses across the 5 centers. In addition to classroom training, the IMPACT-ICU program also includes proactive specialty palliative nursing support for bedside nurses by facilitating the availability of palliative care advanced practice nurses and nurse educators resources. This support helps nurses to apply the skills learned in the workshop in their practice. During rounds at the bedside, the nurse resources coach the bedside staff on the “how” and “when” of addressing palliative care needs. Education and support on a range of topics are offered, including clarifying goals and interventions provided by palliative care teams, the specifics of how to provide family emotional support and delivery of understandable information, the assessment and management of symptoms distress, and the nurses’ role in organizing and participating in family meetings. Case-specific consultations are also offered that address how to interface with resistant medical staff. The importance of nurse documentation of these varied exchanges is also emphasized.

IMPACT-ICU Workshop

A maximum of 15 nurses participate in each 8-hour workshop. The session begins with introductions and small group discussions about what the participants perceive to be the greatest barriers to goals of care discussions and fostering patient/family decision-making in the ICU. Participants are also asked to reflect on what they want to learn as a result of their workshop attendance.

A short didactic session then reviews the definition of palliative care and its core components, addresses the nurses’ role in communication within palliative care, a social worker’s perspective of what it is like to be a family member in the ICU, and the outline of the day. This includes delineation of expectations for involvement within the role plays and the various roles to be enacted. An emphasis is placed on the workshop being a safe place to explore and trial skills with the support of colleagues, and that practice is the optimum way to integrate communication expertise into the nurses’ skill set.

The “4 Cs” serves as the instructional basis for nurse communication skill enhancement [27]. This model outlines 4 key nursing roles in optimizing communication within palliative care:

Convening: Making sure multidisciplinary patient/family/clinician communication occurs.

Checking: Identifying the patient and family needs for information; ensuring that patients and families clearly receive desired information; ensuring that clinicians understand patient and family perspectives.

Caring: Naming emotions and responding to feeling.

Continuing: Following up after discussions to clarify and reinforce information and provide support.

Sample Role Play

Facilitator: So our first role play is focused on eliciting patient and family perspectives and needs. I need a learner and someone to play the role of the family member.

Learner: I’ll give it a try.

Facilitator: Lisa, you’re going to do great. Who wants to play the family member?

Workshop Participant: I’ll do it.

Facilitator: So Mary (who has agreed to play the role of the wife), why don’t you read us the scenario. (She reads it out loud to the group).

Facilitator: Lisa, as the nurse, I want you to look at your guide and tell me what your goal is for this conversation with Mrs. Ames and then which skill you want to practice.

Learner: I think I want to try eliciting the patient and family’s needs for information and I’ll try “Tell Me More” statements.

Facilitator: Alright. So remember Lisa, if you feel the conversation isn’t going well, you can call a “time out.” I can do this as well if I feel you need to start over. I’ll also call a time out when I feel you have met your goal. Sound OK? Mary, do you have any questions playing the part of Mrs. Ames?

Wife Role: Well, how hard should I make this for her? Should I be one of those “difficult” family members?

Facilitator: Our goal here is not to “stump” you or make it particularly difficult. We want you to try out these skills and get a sense of your “comfort zone.” So let’s start with some basic communication skills, OK?

Wife Role: Alright.

Facilitator: Why don’t we set the stage, such that Lisa, you are Mr. Ames’ nurse assessing him at the start of your shift, when Mrs. Ames enters. This is the first time you have taken care of him. The night nurse has told you that he has been requiring increasing ventilator support and his renal function is declining. Per Mrs. Ames’ request, the night nurse called her to let her know how he was doing and Mrs. Ames told her she would be in shortly.

Wife Role: (nervously enters the room and grasps her husband’s hand and looks at the nurse). How’s he doing? Is he better? The night nurse called me and I was so worried I rushed over here.

Learner: (Turns to Mrs. Ames and extends her hand). Are you Mrs. Ames? I’m Lisa and I am going to be taking care of Mr. Ames today. Let me just finish my assessment and how about we talk then? Will that be OK? It will be just a few minutes.

Wife Role: Alright, I’ll be in the waiting area but please come get me as soon as you can.

Learner: I will. (Nurse then shortly comes into the waiting area and asks Mrs. Ames to come back into the ICU where she invites her to sit just outside Mr. Ames’ room). Mrs. Ames, how are you doing? This must be so stressful for you, having your husband in the ICU.

Wife Role: It’s awful. He’s never been in the hospital before this and look at him, all hooked up to machines. I’m so worried. He seems to be getting worse instead of better.

Learner: What’s your understanding of what is going on?

Wife Role: I really don’t know. One doctor comes in and says one thing and then another comes in and tells me the opposite. I’m so confused I don’t know what to think.

Learner: Would having a better idea of his condition from the doctors who are treating him help you have a better understanding?

Wife Role: Oh, yes, but they always seem in such a hurry.

Learner: What exactly would you like to know?

Wife: Well, I want to know when he can get off that breathing machine because we have been planning to go to our son’s house for Thanksgiving.

Facilitator: Time out. Lisa, did you meet your conversation goal?

Learner: Um, I’m not sure, I guess so.

Facilitator: (Turns to Observers). What do you think, did she meet her goal?

Observer: Yes, she determined Mrs. Ames’ need for more information and she asked her what she wanted to know exactly.

Facilitator: What else did we see Lisa do to enhance communication with Mrs. Ames?

Observer: Well, when Mrs. Ames rushed into the room and asked her for information, Lisa didn’t just jump in and spout out values for the ventilator and his output. She took the time to introduce herself and de-escalate Mrs. Ames’ anxiety and she followed up on her promise to come get her in the waiting room as soon as she could.

Facilitator: Why do you think was important?

Observer: It helps establish trust.

Facilitator: Did Lisa use the skill she wanted to try out?

Observer: Yes.

Facilitator: How do you know? What did you hear her say?

Observer: She said, “What’s your understanding of what is going on with Mr. Ames?”

Facilitator: Absolutely. Great job, Lisa. And who wants to take a guess at how long Lisa’s exchange with Mrs. Ames took?

Observer: Less than two minutes?

Facilitator: That’s right. So just as you consider how long it takes, and how proficient you are, in starting an IV or inserting a Foley catheter, when you have a goal in mind and have practiced the skills to do it well, any skill can be mastered.

Feedback

Participants in the workshops uniformly report an enhanced sense of self-confidence in their palliative care communication skills as a result of their participation [29]. Key to the success of the workshop is the ongoing contact by the workshop facilitators with participants. Rounding is routinely planned such that each participant is visited weekly by a workshop facilitator in their clinical area to determine if the bedside nurse has practiced the new skills and if so, how the interaction transpired. Positive feedback is given for attempts to engage in new behaviors and participants are reminded that with any new skill, repetitive trials are necessary to foster success.

Lessons Learned and Next Steps

One of our major lessons learned was recognizing that it was difficult for many critical care nurses to practice the new communication skills. Nurses are trained to fix problems and perform medico-technical tasks; “listening” has not always been recognized as real work [18]. We needed to reinforce that skills like eliciting another’s perspective or making reflection statements are equally important to those associated with behavioral/technical proficiency.

While our program has been successful, we recognize that the next step in fostering ideal palliative care communication is to provide education within an interdisciplinary context. We recommend that colleagues interested in replicating this or a similar education intervention, survey nurse participants prior to and following workshop participation to measure attitudes, self confidence and perceived barriers over time [30]. We hope to translate our positive experience into a program that engages multiple professionals in the enhancement of optimum palliative care communication proficiency.

Corresponding author: Deborah A. Boyle MSN, RN, AOCNS, Department of Nursing Quality, Research and Education, University of California, Irvine Health, 101 The City Drive, Bldg 22A, Room 3104, Orange, CA 92868.

From the Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Abstract

• Objective: To review the diagnosis and management of pancreatic cystic lesions.
• Methods: Narrative review of the literature.
• Results: Pancreatic cystic lesions are clinically relevant as some are precursor lesions to pancreatic adenocarcinoma. Mucinous cystic neoplasms and intraductal papillary mucinous neoplasms are 2 commonly encountered pre-cancerous pancreatic cysts. Many cysts are identified incidentally due to frequent use of high-resolution CT and MRI imaging technology. Proposed diagnostic and management algorithms exist to guide clinical practice but are limited by a lack of evidence and discordance among various guidelines. New cyst fluid biomarkers are under development to diagnose cyst types and risk of cancer.
• Conclusion: Pancreatic cysts are increasingly encountered in clinical practice and represent a growing problem. Diagnostic and management algorithms are available to assist practice but are limited by the available evidence. A multidisciplinary approach is recommended.

In the United States there were an estimated 46,420 new cases of pancreatic cancer in 2014 [1]. Of all major cancers, pancreatic cancer had the lowest 5-year survival rate at 6% [1]. Of the 3 known precursor lesions to pancreas adenocarcinoma, 2 are pancreatic cysts [2]. Correctly identifying those with cancer, those with cancer potential (premalignant), and those that are benign (harboring no malignant potential) can be difficult.

Case 1

A 57-year-old male had a 1.5-cm pancreatic cyst located in the head that was found on computed tomography (CT) imaging for suspected renal colic. He had no history or complaints suspicious for pancreatic disease. A CT pancreas protocol scan was obtained, which demonstrated a simple appearing cyst with no mural nodules. The pancreatic and biliary ducts were normal. His laboratory evaluations including liver function testing and lipase were normal.

• What is the approach to incidentally discovered pancreatic cysts?

While many pancreatic cysts are first discovered by cross sectional imaging (CT or MRI), the diagnostic accuracy of defining cyst type and the presence of malignancy is imperfect. The area under the curve (AUC) for differentiating malignant from benign pancreatic cysts ranges from 0.64 to 0.82 for CT and 0.73 to 0.91 for MRI, and no difference between the 2 were observed [12,13]. Several guidelines are currently available to offer guidance on management [6,14,15,16,17]. Much of the current evidence includes retrospective case series with no randomized control trials. The guidelines, therefore, mostly represent consensus-based expert extrapolation of available data.

The American Gastroenterological Association (AGA) recently produced guidelines in 2015 [14]. In comparison to the international consensus guidelines, there are a few key differences, which have now become a point of vigorous debate and disagreement among pancreatologists and confusion among general gastroenterologists and surgeons in the community. Where the international consensus guidelines have stricter criteria to define the appropriateness of surgery, the AGA guidelines are more liberal. AGA defined cysts appropriate for surgery as having 2 out of 3 of the following features: (1) cyst size ≥ 3 cm, (2) presence of a solid component in the cyst, and (3) dilation of the main pancreatic duct. Those having 1 out of 3 criteria were defined as needing further investigation with EUS [14]. These criteria are more relaxed and will likely lead to more surgical resections.

Another difference involves surveillance recommendations. The international consensus guidelines do not define a period when surveillance can be safely stopped. The AGA guidelines define 5 years as the period where if there is no significant change in the cyst from surveillance MRIs performed every 1 to 2 years, then surveillance can be stopped [14]. As the natural history of these cysts remain substantially uncertain, with evidence that malignant transformation occurs after 5 years, this particular recommendation by the AGA remains highly controversial [18,19]. Other differences between these 2 guidelines are summarized in Table 2 [6,14].

Until the surveillance recommendations by the AGA are validated with further studies, we generally follow the 2012 international consensus guidelines. We generally prefer MRI for initial and surveillance evaluations of pancreatic cysts. Besides the lack of radiation exposure, some studies show MRI to have better inter-reader variability [20], better resolution to show cyst communication with the main pancreatic duct [21], and better characterization of peripheral pancreatic cysts [22]. At our center, when a solid mass is suspected, a CT pancreas protocol is preferred in lieu of an MRI by our surgical team.

Case 1 Continued

Despite the reassuring CEA and cytology results, a high concern for a malignant cystic lesion remained based on cyst size, main pancreatic duct dilation, and atrophy noted in the distal pancreas. The patient underwent surgical resection including subtotal pancreatectomy, splenectomy, subtotal gastrectomy, and superior mesenteric and portal vein resection with reconstruction. Pathology revealed the cyst to be a benign pseudocyst.

This case reflects some of the critical challenges in current management of pancreatic cysts. By history, this patient had no suspicion for pancreatitis, making a pseudocyst less likely in a differential diagnosis. When the patient presented 7 years later, again with no reported history of pancreatitis, there was clinical concern for a branch duct IPMN. Although the cyst fluid CEA and cytology were reassuring, the patient met surgical criteria by the 2006 international consensus criteria and the more recent AGA guidelines. Interestingly, the narrowed 2012 international consensus guidelines for surgical resection would have recommended observation. This case highlights the need for better diagnostic tests.

• What is the epidemiology of pancreatic fluid collections and how do they present?

Pancreatic fluid collections are not true cysts as they lack an epithelial cell lining. They often occur in the context of either acute or chronic pancreatitis, and are considered benign or nonmucinous cysts [7,8]. Duct disruption occurs causing pancreatic fluid accumulation, initially defined as an acute peri-pancreatic fluid collection, or an acute necrotic collection if necrosis is present. Over about 4 weeks a more defined cyst wall forms and the cyst is now classified as either a pseudocyst or walled-off pancreatic necrosis [23]. In one review, the median age at presentation was 49 with a male:female ratio of 2:1. Only 52% of fluid collections were discovered following an acute attack of pancreatitis [24]. The risk factors for pancreatic fluid collections are similar to the risk factors for pancreatitis, with the most common being alcohol use and gallstones [24]. Potential symptoms include abdominal pain, weight loss, gastrointestinal bleeding from pseudoaneurysms, obstructive symptoms, sepsis from super infection, and obstructive jaundice [8,24,25,26,27].

• How are pancreatic fluid collections diagnosed and managed?

Clinical suspicion for pancreatic fluid collections should increase if a cyst is diagnosed in the context of acute or chronic pancreatitis [28]. However, other types of cysts can cause ductal obstruction and pancreatitis, so further investigation may be needed, including review of prior imaging if available. The presence of internal debris, the presence of imaging findings of acute or chronic pancreatitis, and fluid extension beyond the pancreas and taking the shape of the retroperitoneum are often characteristics found in pancreatic fluid collections [29,28,30]. If needed, FNA with assay of amylase may be helpful. An amylase value of 5680 IU/L or greater was 84% sensitive and 64% specific (AUC 0.69) for pseudocysts in one study [31].

Management of pancreatic fluid collections is largely based on surgical series. Drainage procedures for pancreatic fluid collections are often undertaken for intractable symptoms or concerns of infection [8,24,25,26]. Asymptomatic pseudocysts can be safely followed. Specific techniques used for pancreatic fluid collection management vary by institutional expertise. Endoscopic drainage can be done by transpapillary stenting if main duct communication is present, or transgastric/transduodenal stenting if the cyst wall is mature and accessible by these approaches [32]. If necrosis is present this can be debrided endoscopically [33]. Laparoscopic surgical options are preferred to open approaches, and can be performed in 1 procedure where endoscopic approaches may require multiple procedures. The most common approach is to drain the cyst by creating a cyst-gastrostomy, or when not feasible a cyst-duodenostomy or cyst-jejunostomy [26,34]. Percutaneous drainage is less commonly performed and used for unstable patients as it can lead to cutaneous fistulas [34]. The best technique for intervention should be decided in the context of a multidisciplinary team. The option for conservative management should be considered as well because about 60% of those managed conservatively will have resolution in 1 year [35].

Case 2

• What is the role of endoscopic ultrasound with FNA in the diagnosis of pancreatic cysts?

While more invasive than CT or MRI, EUS provides detailed imaging to characterize relevant clinical features and allows fine needle aspiration of the cyst fluid and tissue of intra-cystic masses (Table 2) [6,14]. While MRI imaging resolution is continuing to improve [22,36,37], EUS is generally considered superior [38] for diagnosing high-risk lesions. A limitation of EUS, however, is significant inter-observer variability when compared with MRI [37,39,40].

EUS enables FNA of the cyst, which offers unique oppor-tunities for diagnosis. Cyst fluid cytology unfortunately has limited diagnostic yield, with a recent meta-analysis showing sensitivity 63%, specificity 88%, and AUC of 0.89 in differentiating mucinous from nonmucinous cysts [41]. The low sensitivity is likely because cyst fluid is paucicellular. Techniques that include targeting the cyst wall are under investigation and may improve the diagnostic yield of cytological analysis [42]. Tumor markers such as CEA have been widely used in the cyst fluid, with a value > 192 ng/mL having 63% sensitivity and 88% specificity (AUC of 0.79) for mucinous pancreatic cysts [43]. Other cyst fluid markers have been or are being developed including mutated KRAS DNA [44], mutated GNAS DNA [45,46], micro RNA [47,48], glucose [49], proteomic analysis [50], and multiple other molecules [51]. At this time, many of these markers are under investigation.

Case 2 Continued

An endoscopic ultrasound was performed and showed normal main pancreatic and common bile ducts. No intra-cystic mural nodules were observed. FNA was performed. Cytology showed “paucicellular fluid” and the cyst fluid CEA was 319 ng/mL. Having met the original consensus criteria for surgical resection [17] based on size, the presence of mural nodules, and due to suspicion for a mucinous cyst based on the CEA level, the patient underwent a Whipple procedure. The final pathology was a branch-duct IPMN with moderate dysplasia.

• What interventions exist for treating pancreatic cysts?

Surgery is the mainstay of treatment for pancreatic cysts. The most common surgical procedure for worrisome cysts in the head of the pancreas is a pancreatoduodenectomy (Whipple procedure). For cysts in the distal pancreas, a laparoscopic distal pancreatectomy can be performed [52,53]. Middle pancreatectomy, total pancreatectomy, and enucleation are less commonly performed and remain under investigation. The most common complications after surgery are surgical site and nonsurgical site infection, bleeding, pancreatic fistula, and delayed gastric emptying [52,53]. Overall complication rate for pancreatic cyst surgery is 27% to 39%, and perioperative mortality is 0.5% to 4% at high-volume centers [52,53].

An area of active investigation involves EUS-directed chemical cyst ablation. Prior studies using ethanol intra-cystic injection alone showed cyst resolution in 33% of patients [54]. A combination of ethanol and paclitaxel showed cyst resolution in 62% of patients [55]. Though these techniques offer a less invasive alternative to surgery, the complete eradication of dysplastic cystic epithelium remains uncertain and long-term efficacy is unclear. Thus, these techniques should only be considered in the context of a clinical trial or perhaps in patients who are not surgical candidates [56].

Case 3

• What is the epidemiology of IPMNs and how do they present?

IPMNs are mucin-producing lesions (mucinous cysts) of the exocrine pancreas involving either the main or branch ducts that have the potential to develop into pancreatic adenocarcinoma [57]. The mean age at presentation for both branch duct IPMNs (BD-IPMNs) and main duct IPMNs (MD-IPMNs) is around 65 years [58,59]. In the United States, the male to female prevalence ratio is equal, though there is some geographic variation among different countries [58]. Risk factors for IPMN formation include diabetes, chronic pancreatitis, and a family history of pancreatic adenocarcinoma [60]. Presentation is often asymptomatic but may present with pancreatitis, abdominal pain, weight loss, jaundice, and pancreatic exocrine insufficiency [61]. They tend to occur in the pancreatic head [29]. IPMNs involve either the main pancreatic duct or branch duct or both [62], but this is not always visible by imaging [21]. MRI with MRCP is considered superior to CT in characterizing these lesions, specifically in identifying a connection with the pancreatic ducts [21].

• How are IPMNs diagnosed and managed?

MD-IPMNs harbor a higher risk of malignancy than BD-IPMNs. In one series, 64% of MD-IPMN resected specimens contained cancer [63]. Because of the high cancer risk, all guidelines recommend surgical resection for appropriate patients [6,14,15,16,17]. BD-IPMNs have a lower risk of cancer at diagnosis, present in 19.5% of resected specimens in one study [63]. As a surgical series, this may overstate the true prevalence, which is supported by another study. A cohort of 103 suspected BD-IPMNs patients were observed and those with high-risk features were resected. The overall rate of cancer at 5 years was 2.6%, and only 1 of 103 patients developed non-resectable disease [64]. For these reasons, suspected BD-IPMNs can often be safely monitored if they do not harbor any high risk stigmata as defined by the international consensus criteria (Table 2)[6]. Otherwise, suspected BD-IPMNs are managed in a similar manner to other pancreatic cysts (Table 2) [6,14].

Prognosis after resection is more favorable for IPMNs than for pancreatic adenocarcinoma, possibly due to earlier stage of detection. The 5-year survival for BD-IPMN is 90% after resection, and 47% for MD-IPMN after resection [62]. Survival rates for IPMNs with invasive adenocarcinoma are lower with a combined overall survival 24% to 42% at 5 years. Survival rates are similar to the survival rate for non-cystic pancreatic adenocarcinoma when controlling for size, invasiveness, and lymph node metastasis [65,66].

Guidelines for surveillance after resection have even fewer applicable studies. The 5-year postoperative recurrence rate is 0 to 20% for IPMNs [6]. The revised international consensus guidelines recommends surveillance 6 months after resection with CT or MRI for all IPMNs, but with no recommendation given on how long to continue surveillance [6]. For patients with invasive disease, the same follow up is recommended as for standard invasive adenocarcinoma [6]. The AGA recommends yearly MRI only for only patients with high-grade dysplasia or invasive disease, with consideration for lifelong surveillance [14].

Case 4

• What is the epidemiology of MCNs and how do they present?

MCNs are mucin-producing lesions (mucinous cysts) of the exocrine pancreas histologically defined by the presence of ovarian stroma [67]. They have the potential to develop into pancreatic adenocarcinoma. Unlike IPMNs, MCNs occur almost exclusively in women, and patients are generally younger. In one series, 99.7% of MCNs occurred in females, with a mean age of 47 [67]. Presenting symptoms, as with other cysts, are often vague. These include abdominal pain, fatigue, weight loss, pancreatitis, and a palpable mass. Only 25% of patients are asymptomatic [68].

• How are MCNs diagnosed and managed?

Approximately 95% of MCNs are located in the body or tail of the pancreas [67]. These lesions do not communicate with the pancreatic ducts unlike IPMNs, though they may still cause ductal obstruction and dilation [29]. They are often one large unilocular cyst with a thick cyst wall, but in 20% of cases they can have multiple septations [29]. Peripheral eggshell calcification on CT is present in roughly 25% of cases, which is sometimes helpful in differentiating these lesions from serous cystic neoplasms, which often have central calcification [69].

When diagnosed, MCNs are surgically removed [6,14]. A recent surgical series found that the rate of high-grade dysplasia in resected specimens was 5.5%, and the risk of invasive disease was 4.4% [70]. This data suggests that a more conservative approach of observation rather than immediate resection may be reasonable for some patients [70]. The prognosis is very good after MCN resection, with a 5-year survival of 97% to 100% for all comers [68,70]. However, invasive MCNs have a lower 5-year survival rate ranging from 15% to 75% [70,71]. Per the AGA guidelines, patients with invasive disease or dysplasia should undergo yearly surveillance with MRI [14]. This recommendation is based on a potential field defect described with IPMNs. However, the international consensus guidelines only recommends surveillance if invasive disease is present [6,68,71,72].

Case 5

A 59-year-old male presents for evaluation of sudden onset abdominal pain and an 8-pound weight loss over the past few months. Seven years ago a pancreatic cyst was diagnosed and has since been observed by serial imaging. His lipase was 400 U/L (normal < 82) with normal liver function tests. A CT scan of the abdomen and pelvis showed peri-pancreatic stranding consistent with pancreatitis and a large complex cyst in the head of the pancreas.

• What is the epidemiology of SCNs and how do they present?

SCNs are benign non–mucin-producing cystic lesions that are characterized by a glycogen-rich epithelium on histology [73]. Of patients with SCNs, 74% are female, with a median age 58 [10]. When diagnosed, most patients are usually asymptomatic (61%), but 27% present with abdominal pain. Other symptoms include jaundice, pancreatitis, nausea, and presence of a palpable abdominal mass. SCNs are more common in patients with von Hippel-Lindau syndrome [74].

• How are SCNs diagnosed and managed?

These cysts have fairly even distribution when discovered in the pancreas [53]. About 74% of lesions have smaller micro-cystic components [75]. About 20% of lesions have a characteristic honeycomb appearance, which is highly suggestive of an SCN [76]. About 30% of patients have a characteristic central stellate scar on CT which is also highly suggestive of an SCN [76]. Unlike mucinous neoplasms, peripheral calcification is usually not seen [69].

Malignancy associated with these cysts is very rare, with the largest cohort study reporting a rate of 0.1% [10]. The diagnosis can commonly be made by its unique imaging appearance [10]. Diagnostic biomarkers that may identify such cysts with more certainty are under active investigation [77]. Resection is reasonable and often performed for SCNs when they cause debilitating symptoms including refractory abdominal pain or pancreatitis. When resected and confirmed by pathology, no surveillance is required [14,78].

Conclusion

Pancreatic cysts are common incidental findings in clinical practice today. Many cause anxiety due to their association with pancreas cancer, but most are indolent and safe to observe. Even those cysts with malignant potential grow slowly and immediate surgery is often unnecessary. Several guidelines have been developed, and while there are similarities between them, there are enough critical differences unfortunately to cause some confusion among practitioners today. Further robust research is needed to help address and reconcile these differences. In the meantime, a multidisciplinary approach is highly recommended at dedicated centers of excellence for pancreatic diseases.

Corresponding author: Walter G. Park, MD, MS, 300 Pasteur Drive, MC: 5187, Stanford, CA 94305, [email protected].

Funding/support: Dr. Park is funded by an American College of Gastroenterology Junior Faculty Development Award and is a subcontinent for the National Cancer Institute's Early Detection Research Network.

Financial disclosures: None.

Author contributions: conception and design, TZ, WGP; analysis and interpretation of data, WGP; drafting of article, TZ, WGP; critical revision of the article, TZ, WGP.

From the Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Abstract

• Objective: To review the diagnosis and management of pancreatic cystic lesions.
• Methods: Narrative review of the literature.
• Results: Pancreatic cystic lesions are clinically relevant as some are precursor lesions to pancreatic adenocarcinoma. Mucinous cystic neoplasms and intraductal papillary mucinous neoplasms are 2 commonly encountered pre-cancerous pancreatic cysts. Many cysts are identified incidentally due to frequent use of high-resolution CT and MRI imaging technology. Proposed diagnostic and management algorithms exist to guide clinical practice but are limited by a lack of evidence and discordance among various guidelines. New cyst fluid biomarkers are under development to diagnose cyst types and risk of cancer.
• Conclusion: Pancreatic cysts are increasingly encountered in clinical practice and represent a growing problem. Diagnostic and management algorithms are available to assist practice but are limited by the available evidence. A multidisciplinary approach is recommended.

In the United States there were an estimated 46,420 new cases of pancreatic cancer in 2014 [1]. Of all major cancers, pancreatic cancer had the lowest 5-year survival rate at 6% [1]. Of the 3 known precursor lesions to pancreas adenocarcinoma, 2 are pancreatic cysts [2]. Correctly identifying those with cancer, those with cancer potential (premalignant), and those that are benign (harboring no malignant potential) can be difficult.

Case 1

A 57-year-old male had a 1.5-cm pancreatic cyst located in the head that was found on computed tomography (CT) imaging for suspected renal colic. He had no history or complaints suspicious for pancreatic disease. A CT pancreas protocol scan was obtained, which demonstrated a simple appearing cyst with no mural nodules. The pancreatic and biliary ducts were normal. His laboratory evaluations including liver function testing and lipase were normal.

• What is the approach to incidentally discovered pancreatic cysts?

While many pancreatic cysts are first discovered by cross sectional imaging (CT or MRI), the diagnostic accuracy of defining cyst type and the presence of malignancy is imperfect. The area under the curve (AUC) for differentiating malignant from benign pancreatic cysts ranges from 0.64 to 0.82 for CT and 0.73 to 0.91 for MRI, and no difference between the 2 were observed [12,13]. Several guidelines are currently available to offer guidance on management [6,14,15,16,17]. Much of the current evidence includes retrospective case series with no randomized control trials. The guidelines, therefore, mostly represent consensus-based expert extrapolation of available data.

The American Gastroenterological Association (AGA) recently produced guidelines in 2015 [14]. In comparison to the international consensus guidelines, there are a few key differences, which have now become a point of vigorous debate and disagreement among pancreatologists and confusion among general gastroenterologists and surgeons in the community. Where the international consensus guidelines have stricter criteria to define the appropriateness of surgery, the AGA guidelines are more liberal. AGA defined cysts appropriate for surgery as having 2 out of 3 of the following features: (1) cyst size ≥ 3 cm, (2) presence of a solid component in the cyst, and (3) dilation of the main pancreatic duct. Those having 1 out of 3 criteria were defined as needing further investigation with EUS [14]. These criteria are more relaxed and will likely lead to more surgical resections.

Another difference involves surveillance recommendations. The international consensus guidelines do not define a period when surveillance can be safely stopped. The AGA guidelines define 5 years as the period where if there is no significant change in the cyst from surveillance MRIs performed every 1 to 2 years, then surveillance can be stopped [14]. As the natural history of these cysts remain substantially uncertain, with evidence that malignant transformation occurs after 5 years, this particular recommendation by the AGA remains highly controversial [18,19]. Other differences between these 2 guidelines are summarized in Table 2 [6,14].

Until the surveillance recommendations by the AGA are validated with further studies, we generally follow the 2012 international consensus guidelines. We generally prefer MRI for initial and surveillance evaluations of pancreatic cysts. Besides the lack of radiation exposure, some studies show MRI to have better inter-reader variability [20], better resolution to show cyst communication with the main pancreatic duct [21], and better characterization of peripheral pancreatic cysts [22]. At our center, when a solid mass is suspected, a CT pancreas protocol is preferred in lieu of an MRI by our surgical team.

Case 1 Continued

Despite the reassuring CEA and cytology results, a high concern for a malignant cystic lesion remained based on cyst size, main pancreatic duct dilation, and atrophy noted in the distal pancreas. The patient underwent surgical resection including subtotal pancreatectomy, splenectomy, subtotal gastrectomy, and superior mesenteric and portal vein resection with reconstruction. Pathology revealed the cyst to be a benign pseudocyst.

This case reflects some of the critical challenges in current management of pancreatic cysts. By history, this patient had no suspicion for pancreatitis, making a pseudocyst less likely in a differential diagnosis. When the patient presented 7 years later, again with no reported history of pancreatitis, there was clinical concern for a branch duct IPMN. Although the cyst fluid CEA and cytology were reassuring, the patient met surgical criteria by the 2006 international consensus criteria and the more recent AGA guidelines. Interestingly, the narrowed 2012 international consensus guidelines for surgical resection would have recommended observation. This case highlights the need for better diagnostic tests.

• What is the epidemiology of pancreatic fluid collections and how do they present?

Pancreatic fluid collections are not true cysts as they lack an epithelial cell lining. They often occur in the context of either acute or chronic pancreatitis, and are considered benign or nonmucinous cysts [7,8]. Duct disruption occurs causing pancreatic fluid accumulation, initially defined as an acute peri-pancreatic fluid collection, or an acute necrotic collection if necrosis is present. Over about 4 weeks a more defined cyst wall forms and the cyst is now classified as either a pseudocyst or walled-off pancreatic necrosis [23]. In one review, the median age at presentation was 49 with a male:female ratio of 2:1. Only 52% of fluid collections were discovered following an acute attack of pancreatitis [24]. The risk factors for pancreatic fluid collections are similar to the risk factors for pancreatitis, with the most common being alcohol use and gallstones [24]. Potential symptoms include abdominal pain, weight loss, gastrointestinal bleeding from pseudoaneurysms, obstructive symptoms, sepsis from super infection, and obstructive jaundice [8,24,25,26,27].

• How are pancreatic fluid collections diagnosed and managed?

Clinical suspicion for pancreatic fluid collections should increase if a cyst is diagnosed in the context of acute or chronic pancreatitis [28]. However, other types of cysts can cause ductal obstruction and pancreatitis, so further investigation may be needed, including review of prior imaging if available. The presence of internal debris, the presence of imaging findings of acute or chronic pancreatitis, and fluid extension beyond the pancreas and taking the shape of the retroperitoneum are often characteristics found in pancreatic fluid collections [29,28,30]. If needed, FNA with assay of amylase may be helpful. An amylase value of 5680 IU/L or greater was 84% sensitive and 64% specific (AUC 0.69) for pseudocysts in one study [31].

Management of pancreatic fluid collections is largely based on surgical series. Drainage procedures for pancreatic fluid collections are often undertaken for intractable symptoms or concerns of infection [8,24,25,26]. Asymptomatic pseudocysts can be safely followed. Specific techniques used for pancreatic fluid collection management vary by institutional expertise. Endoscopic drainage can be done by transpapillary stenting if main duct communication is present, or transgastric/transduodenal stenting if the cyst wall is mature and accessible by these approaches [32]. If necrosis is present this can be debrided endoscopically [33]. Laparoscopic surgical options are preferred to open approaches, and can be performed in 1 procedure where endoscopic approaches may require multiple procedures. The most common approach is to drain the cyst by creating a cyst-gastrostomy, or when not feasible a cyst-duodenostomy or cyst-jejunostomy [26,34]. Percutaneous drainage is less commonly performed and used for unstable patients as it can lead to cutaneous fistulas [34]. The best technique for intervention should be decided in the context of a multidisciplinary team. The option for conservative management should be considered as well because about 60% of those managed conservatively will have resolution in 1 year [35].

Case 2

• What is the role of endoscopic ultrasound with FNA in the diagnosis of pancreatic cysts?

While more invasive than CT or MRI, EUS provides detailed imaging to characterize relevant clinical features and allows fine needle aspiration of the cyst fluid and tissue of intra-cystic masses (Table 2) [6,14]. While MRI imaging resolution is continuing to improve [22,36,37], EUS is generally considered superior [38] for diagnosing high-risk lesions. A limitation of EUS, however, is significant inter-observer variability when compared with MRI [37,39,40].

EUS enables FNA of the cyst, which offers unique oppor-tunities for diagnosis. Cyst fluid cytology unfortunately has limited diagnostic yield, with a recent meta-analysis showing sensitivity 63%, specificity 88%, and AUC of 0.89 in differentiating mucinous from nonmucinous cysts [41]. The low sensitivity is likely because cyst fluid is paucicellular. Techniques that include targeting the cyst wall are under investigation and may improve the diagnostic yield of cytological analysis [42]. Tumor markers such as CEA have been widely used in the cyst fluid, with a value > 192 ng/mL having 63% sensitivity and 88% specificity (AUC of 0.79) for mucinous pancreatic cysts [43]. Other cyst fluid markers have been or are being developed including mutated KRAS DNA [44], mutated GNAS DNA [45,46], micro RNA [47,48], glucose [49], proteomic analysis [50], and multiple other molecules [51]. At this time, many of these markers are under investigation.

Case 2 Continued

An endoscopic ultrasound was performed and showed normal main pancreatic and common bile ducts. No intra-cystic mural nodules were observed. FNA was performed. Cytology showed “paucicellular fluid” and the cyst fluid CEA was 319 ng/mL. Having met the original consensus criteria for surgical resection [17] based on size, the presence of mural nodules, and due to suspicion for a mucinous cyst based on the CEA level, the patient underwent a Whipple procedure. The final pathology was a branch-duct IPMN with moderate dysplasia.

• What interventions exist for treating pancreatic cysts?

Surgery is the mainstay of treatment for pancreatic cysts. The most common surgical procedure for worrisome cysts in the head of the pancreas is a pancreatoduodenectomy (Whipple procedure). For cysts in the distal pancreas, a laparoscopic distal pancreatectomy can be performed [52,53]. Middle pancreatectomy, total pancreatectomy, and enucleation are less commonly performed and remain under investigation. The most common complications after surgery are surgical site and nonsurgical site infection, bleeding, pancreatic fistula, and delayed gastric emptying [52,53]. Overall complication rate for pancreatic cyst surgery is 27% to 39%, and perioperative mortality is 0.5% to 4% at high-volume centers [52,53].

An area of active investigation involves EUS-directed chemical cyst ablation. Prior studies using ethanol intra-cystic injection alone showed cyst resolution in 33% of patients [54]. A combination of ethanol and paclitaxel showed cyst resolution in 62% of patients [55]. Though these techniques offer a less invasive alternative to surgery, the complete eradication of dysplastic cystic epithelium remains uncertain and long-term efficacy is unclear. Thus, these techniques should only be considered in the context of a clinical trial or perhaps in patients who are not surgical candidates [56].

Case 3

• What is the epidemiology of IPMNs and how do they present?

IPMNs are mucin-producing lesions (mucinous cysts) of the exocrine pancreas involving either the main or branch ducts that have the potential to develop into pancreatic adenocarcinoma [57]. The mean age at presentation for both branch duct IPMNs (BD-IPMNs) and main duct IPMNs (MD-IPMNs) is around 65 years [58,59]. In the United States, the male to female prevalence ratio is equal, though there is some geographic variation among different countries [58]. Risk factors for IPMN formation include diabetes, chronic pancreatitis, and a family history of pancreatic adenocarcinoma [60]. Presentation is often asymptomatic but may present with pancreatitis, abdominal pain, weight loss, jaundice, and pancreatic exocrine insufficiency [61]. They tend to occur in the pancreatic head [29]. IPMNs involve either the main pancreatic duct or branch duct or both [62], but this is not always visible by imaging [21]. MRI with MRCP is considered superior to CT in characterizing these lesions, specifically in identifying a connection with the pancreatic ducts [21].

• How are IPMNs diagnosed and managed?

MD-IPMNs harbor a higher risk of malignancy than BD-IPMNs. In one series, 64% of MD-IPMN resected specimens contained cancer [63]. Because of the high cancer risk, all guidelines recommend surgical resection for appropriate patients [6,14,15,16,17]. BD-IPMNs have a lower risk of cancer at diagnosis, present in 19.5% of resected specimens in one study [63]. As a surgical series, this may overstate the true prevalence, which is supported by another study. A cohort of 103 suspected BD-IPMNs patients were observed and those with high-risk features were resected. The overall rate of cancer at 5 years was 2.6%, and only 1 of 103 patients developed non-resectable disease [64]. For these reasons, suspected BD-IPMNs can often be safely monitored if they do not harbor any high risk stigmata as defined by the international consensus criteria (Table 2)[6]. Otherwise, suspected BD-IPMNs are managed in a similar manner to other pancreatic cysts (Table 2) [6,14].

Prognosis after resection is more favorable for IPMNs than for pancreatic adenocarcinoma, possibly due to earlier stage of detection. The 5-year survival for BD-IPMN is 90% after resection, and 47% for MD-IPMN after resection [62]. Survival rates for IPMNs with invasive adenocarcinoma are lower with a combined overall survival 24% to 42% at 5 years. Survival rates are similar to the survival rate for non-cystic pancreatic adenocarcinoma when controlling for size, invasiveness, and lymph node metastasis [65,66].

Guidelines for surveillance after resection have even fewer applicable studies. The 5-year postoperative recurrence rate is 0 to 20% for IPMNs [6]. The revised international consensus guidelines recommends surveillance 6 months after resection with CT or MRI for all IPMNs, but with no recommendation given on how long to continue surveillance [6]. For patients with invasive disease, the same follow up is recommended as for standard invasive adenocarcinoma [6]. The AGA recommends yearly MRI only for only patients with high-grade dysplasia or invasive disease, with consideration for lifelong surveillance [14].

Case 4

• What is the epidemiology of MCNs and how do they present?

MCNs are mucin-producing lesions (mucinous cysts) of the exocrine pancreas histologically defined by the presence of ovarian stroma [67]. They have the potential to develop into pancreatic adenocarcinoma. Unlike IPMNs, MCNs occur almost exclusively in women, and patients are generally younger. In one series, 99.7% of MCNs occurred in females, with a mean age of 47 [67]. Presenting symptoms, as with other cysts, are often vague. These include abdominal pain, fatigue, weight loss, pancreatitis, and a palpable mass. Only 25% of patients are asymptomatic [68].

• How are MCNs diagnosed and managed?

Approximately 95% of MCNs are located in the body or tail of the pancreas [67]. These lesions do not communicate with the pancreatic ducts unlike IPMNs, though they may still cause ductal obstruction and dilation [29]. They are often one large unilocular cyst with a thick cyst wall, but in 20% of cases they can have multiple septations [29]. Peripheral eggshell calcification on CT is present in roughly 25% of cases, which is sometimes helpful in differentiating these lesions from serous cystic neoplasms, which often have central calcification [69].

When diagnosed, MCNs are surgically removed [6,14]. A recent surgical series found that the rate of high-grade dysplasia in resected specimens was 5.5%, and the risk of invasive disease was 4.4% [70]. This data suggests that a more conservative approach of observation rather than immediate resection may be reasonable for some patients [70]. The prognosis is very good after MCN resection, with a 5-year survival of 97% to 100% for all comers [68,70]. However, invasive MCNs have a lower 5-year survival rate ranging from 15% to 75% [70,71]. Per the AGA guidelines, patients with invasive disease or dysplasia should undergo yearly surveillance with MRI [14]. This recommendation is based on a potential field defect described with IPMNs. However, the international consensus guidelines only recommends surveillance if invasive disease is present [6,68,71,72].

Case 5

A 59-year-old male presents for evaluation of sudden onset abdominal pain and an 8-pound weight loss over the past few months. Seven years ago a pancreatic cyst was diagnosed and has since been observed by serial imaging. His lipase was 400 U/L (normal < 82) with normal liver function tests. A CT scan of the abdomen and pelvis showed peri-pancreatic stranding consistent with pancreatitis and a large complex cyst in the head of the pancreas.

• What is the epidemiology of SCNs and how do they present?

SCNs are benign non–mucin-producing cystic lesions that are characterized by a glycogen-rich epithelium on histology [73]. Of patients with SCNs, 74% are female, with a median age 58 [10]. When diagnosed, most patients are usually asymptomatic (61%), but 27% present with abdominal pain. Other symptoms include jaundice, pancreatitis, nausea, and presence of a palpable abdominal mass. SCNs are more common in patients with von Hippel-Lindau syndrome [74].

• How are SCNs diagnosed and managed?

These cysts have fairly even distribution when discovered in the pancreas [53]. About 74% of lesions have smaller micro-cystic components [75]. About 20% of lesions have a characteristic honeycomb appearance, which is highly suggestive of an SCN [76]. About 30% of patients have a characteristic central stellate scar on CT which is also highly suggestive of an SCN [76]. Unlike mucinous neoplasms, peripheral calcification is usually not seen [69].

Malignancy associated with these cysts is very rare, with the largest cohort study reporting a rate of 0.1% [10]. The diagnosis can commonly be made by its unique imaging appearance [10]. Diagnostic biomarkers that may identify such cysts with more certainty are under active investigation [77]. Resection is reasonable and often performed for SCNs when they cause debilitating symptoms including refractory abdominal pain or pancreatitis. When resected and confirmed by pathology, no surveillance is required [14,78].

Conclusion

Pancreatic cysts are common incidental findings in clinical practice today. Many cause anxiety due to their association with pancreas cancer, but most are indolent and safe to observe. Even those cysts with malignant potential grow slowly and immediate surgery is often unnecessary. Several guidelines have been developed, and while there are similarities between them, there are enough critical differences unfortunately to cause some confusion among practitioners today. Further robust research is needed to help address and reconcile these differences. In the meantime, a multidisciplinary approach is highly recommended at dedicated centers of excellence for pancreatic diseases.

Corresponding author: Walter G. Park, MD, MS, 300 Pasteur Drive, MC: 5187, Stanford, CA 94305, [email protected].

Funding/support: Dr. Park is funded by an American College of Gastroenterology Junior Faculty Development Award and is a subcontinent for the National Cancer Institute's Early Detection Research Network.

Financial disclosures: None.

Author contributions: conception and design, TZ, WGP; analysis and interpretation of data, WGP; drafting of article, TZ, WGP; critical revision of the article, TZ, WGP.

From the Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Abstract

• Objective: To review the diagnosis and management of pancreatic cystic lesions.
• Methods: Narrative review of the literature.
• Results: Pancreatic cystic lesions are clinically relevant as some are precursor lesions to pancreatic adenocarcinoma. Mucinous cystic neoplasms and intraductal papillary mucinous neoplasms are 2 commonly encountered pre-cancerous pancreatic cysts. Many cysts are identified incidentally due to frequent use of high-resolution CT and MRI imaging technology. Proposed diagnostic and management algorithms exist to guide clinical practice but are limited by a lack of evidence and discordance among various guidelines. New cyst fluid biomarkers are under development to diagnose cyst types and risk of cancer.
• Conclusion: Pancreatic cysts are increasingly encountered in clinical practice and represent a growing problem. Diagnostic and management algorithms are available to assist practice but are limited by the available evidence. A multidisciplinary approach is recommended.

In the United States there were an estimated 46,420 new cases of pancreatic cancer in 2014 [1]. Of all major cancers, pancreatic cancer had the lowest 5-year survival rate at 6% [1]. Of the 3 known precursor lesions to pancreas adenocarcinoma, 2 are pancreatic cysts [2]. Correctly identifying those with cancer, those with cancer potential (premalignant), and those that are benign (harboring no malignant potential) can be difficult.

Case 1

A 57-year-old male had a 1.5-cm pancreatic cyst located in the head that was found on computed tomography (CT) imaging for suspected renal colic. He had no history or complaints suspicious for pancreatic disease. A CT pancreas protocol scan was obtained, which demonstrated a simple appearing cyst with no mural nodules. The pancreatic and biliary ducts were normal. His laboratory evaluations including liver function testing and lipase were normal.

• What is the approach to incidentally discovered pancreatic cysts?

While many pancreatic cysts are first discovered by cross sectional imaging (CT or MRI), the diagnostic accuracy of defining cyst type and the presence of malignancy is imperfect. The area under the curve (AUC) for differentiating malignant from benign pancreatic cysts ranges from 0.64 to 0.82 for CT and 0.73 to 0.91 for MRI, and no difference between the 2 were observed [12,13]. Several guidelines are currently available to offer guidance on management [6,14,15,16,17]. Much of the current evidence includes retrospective case series with no randomized control trials. The guidelines, therefore, mostly represent consensus-based expert extrapolation of available data.

The American Gastroenterological Association (AGA) recently produced guidelines in 2015 [14]. In comparison to the international consensus guidelines, there are a few key differences, which have now become a point of vigorous debate and disagreement among pancreatologists and confusion among general gastroenterologists and surgeons in the community. Where the international consensus guidelines have stricter criteria to define the appropriateness of surgery, the AGA guidelines are more liberal. AGA defined cysts appropriate for surgery as having 2 out of 3 of the following features: (1) cyst size ≥ 3 cm, (2) presence of a solid component in the cyst, and (3) dilation of the main pancreatic duct. Those having 1 out of 3 criteria were defined as needing further investigation with EUS [14]. These criteria are more relaxed and will likely lead to more surgical resections.

Another difference involves surveillance recommendations. The international consensus guidelines do not define a period when surveillance can be safely stopped. The AGA guidelines define 5 years as the period where if there is no significant change in the cyst from surveillance MRIs performed every 1 to 2 years, then surveillance can be stopped [14]. As the natural history of these cysts remain substantially uncertain, with evidence that malignant transformation occurs after 5 years, this particular recommendation by the AGA remains highly controversial [18,19]. Other differences between these 2 guidelines are summarized in Table 2 [6,14].

Until the surveillance recommendations by the AGA are validated with further studies, we generally follow the 2012 international consensus guidelines. We generally prefer MRI for initial and surveillance evaluations of pancreatic cysts. Besides the lack of radiation exposure, some studies show MRI to have better inter-reader variability [20], better resolution to show cyst communication with the main pancreatic duct [21], and better characterization of peripheral pancreatic cysts [22]. At our center, when a solid mass is suspected, a CT pancreas protocol is preferred in lieu of an MRI by our surgical team.

Case 1 Continued

Despite the reassuring CEA and cytology results, a high concern for a malignant cystic lesion remained based on cyst size, main pancreatic duct dilation, and atrophy noted in the distal pancreas. The patient underwent surgical resection including subtotal pancreatectomy, splenectomy, subtotal gastrectomy, and superior mesenteric and portal vein resection with reconstruction. Pathology revealed the cyst to be a benign pseudocyst.

This case reflects some of the critical challenges in current management of pancreatic cysts. By history, this patient had no suspicion for pancreatitis, making a pseudocyst less likely in a differential diagnosis. When the patient presented 7 years later, again with no reported history of pancreatitis, there was clinical concern for a branch duct IPMN. Although the cyst fluid CEA and cytology were reassuring, the patient met surgical criteria by the 2006 international consensus criteria and the more recent AGA guidelines. Interestingly, the narrowed 2012 international consensus guidelines for surgical resection would have recommended observation. This case highlights the need for better diagnostic tests.

• What is the epidemiology of pancreatic fluid collections and how do they present?

Pancreatic fluid collections are not true cysts as they lack an epithelial cell lining. They often occur in the context of either acute or chronic pancreatitis, and are considered benign or nonmucinous cysts [7,8]. Duct disruption occurs causing pancreatic fluid accumulation, initially defined as an acute peri-pancreatic fluid collection, or an acute necrotic collection if necrosis is present. Over about 4 weeks a more defined cyst wall forms and the cyst is now classified as either a pseudocyst or walled-off pancreatic necrosis [23]. In one review, the median age at presentation was 49 with a male:female ratio of 2:1. Only 52% of fluid collections were discovered following an acute attack of pancreatitis [24]. The risk factors for pancreatic fluid collections are similar to the risk factors for pancreatitis, with the most common being alcohol use and gallstones [24]. Potential symptoms include abdominal pain, weight loss, gastrointestinal bleeding from pseudoaneurysms, obstructive symptoms, sepsis from super infection, and obstructive jaundice [8,24,25,26,27].

• How are pancreatic fluid collections diagnosed and managed?

Clinical suspicion for pancreatic fluid collections should increase if a cyst is diagnosed in the context of acute or chronic pancreatitis [28]. However, other types of cysts can cause ductal obstruction and pancreatitis, so further investigation may be needed, including review of prior imaging if available. The presence of internal debris, the presence of imaging findings of acute or chronic pancreatitis, and fluid extension beyond the pancreas and taking the shape of the retroperitoneum are often characteristics found in pancreatic fluid collections [29,28,30]. If needed, FNA with assay of amylase may be helpful. An amylase value of 5680 IU/L or greater was 84% sensitive and 64% specific (AUC 0.69) for pseudocysts in one study [31].

Management of pancreatic fluid collections is largely based on surgical series. Drainage procedures for pancreatic fluid collections are often undertaken for intractable symptoms or concerns of infection [8,24,25,26]. Asymptomatic pseudocysts can be safely followed. Specific techniques used for pancreatic fluid collection management vary by institutional expertise. Endoscopic drainage can be done by transpapillary stenting if main duct communication is present, or transgastric/transduodenal stenting if the cyst wall is mature and accessible by these approaches [32]. If necrosis is present this can be debrided endoscopically [33]. Laparoscopic surgical options are preferred to open approaches, and can be performed in 1 procedure where endoscopic approaches may require multiple procedures. The most common approach is to drain the cyst by creating a cyst-gastrostomy, or when not feasible a cyst-duodenostomy or cyst-jejunostomy [26,34]. Percutaneous drainage is less commonly performed and used for unstable patients as it can lead to cutaneous fistulas [34]. The best technique for intervention should be decided in the context of a multidisciplinary team. The option for conservative management should be considered as well because about 60% of those managed conservatively will have resolution in 1 year [35].

Case 2

• What is the role of endoscopic ultrasound with FNA in the diagnosis of pancreatic cysts?

While more invasive than CT or MRI, EUS provides detailed imaging to characterize relevant clinical features and allows fine needle aspiration of the cyst fluid and tissue of intra-cystic masses (Table 2) [6,14]. While MRI imaging resolution is continuing to improve [22,36,37], EUS is generally considered superior [38] for diagnosing high-risk lesions. A limitation of EUS, however, is significant inter-observer variability when compared with MRI [37,39,40].

EUS enables FNA of the cyst, which offers unique oppor-tunities for diagnosis. Cyst fluid cytology unfortunately has limited diagnostic yield, with a recent meta-analysis showing sensitivity 63%, specificity 88%, and AUC of 0.89 in differentiating mucinous from nonmucinous cysts [41]. The low sensitivity is likely because cyst fluid is paucicellular. Techniques that include targeting the cyst wall are under investigation and may improve the diagnostic yield of cytological analysis [42]. Tumor markers such as CEA have been widely used in the cyst fluid, with a value > 192 ng/mL having 63% sensitivity and 88% specificity (AUC of 0.79) for mucinous pancreatic cysts [43]. Other cyst fluid markers have been or are being developed including mutated KRAS DNA [44], mutated GNAS DNA [45,46], micro RNA [47,48], glucose [49], proteomic analysis [50], and multiple other molecules [51]. At this time, many of these markers are under investigation.

Case 2 Continued

An endoscopic ultrasound was performed and showed normal main pancreatic and common bile ducts. No intra-cystic mural nodules were observed. FNA was performed. Cytology showed “paucicellular fluid” and the cyst fluid CEA was 319 ng/mL. Having met the original consensus criteria for surgical resection [17] based on size, the presence of mural nodules, and due to suspicion for a mucinous cyst based on the CEA level, the patient underwent a Whipple procedure. The final pathology was a branch-duct IPMN with moderate dysplasia.

• What interventions exist for treating pancreatic cysts?

Surgery is the mainstay of treatment for pancreatic cysts. The most common surgical procedure for worrisome cysts in the head of the pancreas is a pancreatoduodenectomy (Whipple procedure). For cysts in the distal pancreas, a laparoscopic distal pancreatectomy can be performed [52,53]. Middle pancreatectomy, total pancreatectomy, and enucleation are less commonly performed and remain under investigation. The most common complications after surgery are surgical site and nonsurgical site infection, bleeding, pancreatic fistula, and delayed gastric emptying [52,53]. Overall complication rate for pancreatic cyst surgery is 27% to 39%, and perioperative mortality is 0.5% to 4% at high-volume centers [52,53].

An area of active investigation involves EUS-directed chemical cyst ablation. Prior studies using ethanol intra-cystic injection alone showed cyst resolution in 33% of patients [54]. A combination of ethanol and paclitaxel showed cyst resolution in 62% of patients [55]. Though these techniques offer a less invasive alternative to surgery, the complete eradication of dysplastic cystic epithelium remains uncertain and long-term efficacy is unclear. Thus, these techniques should only be considered in the context of a clinical trial or perhaps in patients who are not surgical candidates [56].

Case 3

• What is the epidemiology of IPMNs and how do they present?

IPMNs are mucin-producing lesions (mucinous cysts) of the exocrine pancreas involving either the main or branch ducts that have the potential to develop into pancreatic adenocarcinoma [57]. The mean age at presentation for both branch duct IPMNs (BD-IPMNs) and main duct IPMNs (MD-IPMNs) is around 65 years [58,59]. In the United States, the male to female prevalence ratio is equal, though there is some geographic variation among different countries [58]. Risk factors for IPMN formation include diabetes, chronic pancreatitis, and a family history of pancreatic adenocarcinoma [60]. Presentation is often asymptomatic but may present with pancreatitis, abdominal pain, weight loss, jaundice, and pancreatic exocrine insufficiency [61]. They tend to occur in the pancreatic head [29]. IPMNs involve either the main pancreatic duct or branch duct or both [62], but this is not always visible by imaging [21]. MRI with MRCP is considered superior to CT in characterizing these lesions, specifically in identifying a connection with the pancreatic ducts [21].

• How are IPMNs diagnosed and managed?

MD-IPMNs harbor a higher risk of malignancy than BD-IPMNs. In one series, 64% of MD-IPMN resected specimens contained cancer [63]. Because of the high cancer risk, all guidelines recommend surgical resection for appropriate patients [6,14,15,16,17]. BD-IPMNs have a lower risk of cancer at diagnosis, present in 19.5% of resected specimens in one study [63]. As a surgical series, this may overstate the true prevalence, which is supported by another study. A cohort of 103 suspected BD-IPMNs patients were observed and those with high-risk features were resected. The overall rate of cancer at 5 years was 2.6%, and only 1 of 103 patients developed non-resectable disease [64]. For these reasons, suspected BD-IPMNs can often be safely monitored if they do not harbor any high risk stigmata as defined by the international consensus criteria (Table 2)[6]. Otherwise, suspected BD-IPMNs are managed in a similar manner to other pancreatic cysts (Table 2) [6,14].

Prognosis after resection is more favorable for IPMNs than for pancreatic adenocarcinoma, possibly due to earlier stage of detection. The 5-year survival for BD-IPMN is 90% after resection, and 47% for MD-IPMN after resection [62]. Survival rates for IPMNs with invasive adenocarcinoma are lower with a combined overall survival 24% to 42% at 5 years. Survival rates are similar to the survival rate for non-cystic pancreatic adenocarcinoma when controlling for size, invasiveness, and lymph node metastasis [65,66].

Guidelines for surveillance after resection have even fewer applicable studies. The 5-year postoperative recurrence rate is 0 to 20% for IPMNs [6]. The revised international consensus guidelines recommends surveillance 6 months after resection with CT or MRI for all IPMNs, but with no recommendation given on how long to continue surveillance [6]. For patients with invasive disease, the same follow up is recommended as for standard invasive adenocarcinoma [6]. The AGA recommends yearly MRI only for only patients with high-grade dysplasia or invasive disease, with consideration for lifelong surveillance [14].

Case 4

• What is the epidemiology of MCNs and how do they present?

MCNs are mucin-producing lesions (mucinous cysts) of the exocrine pancreas histologically defined by the presence of ovarian stroma [67]. They have the potential to develop into pancreatic adenocarcinoma. Unlike IPMNs, MCNs occur almost exclusively in women, and patients are generally younger. In one series, 99.7% of MCNs occurred in females, with a mean age of 47 [67]. Presenting symptoms, as with other cysts, are often vague. These include abdominal pain, fatigue, weight loss, pancreatitis, and a palpable mass. Only 25% of patients are asymptomatic [68].

• How are MCNs diagnosed and managed?

Approximately 95% of MCNs are located in the body or tail of the pancreas [67]. These lesions do not communicate with the pancreatic ducts unlike IPMNs, though they may still cause ductal obstruction and dilation [29]. They are often one large unilocular cyst with a thick cyst wall, but in 20% of cases they can have multiple septations [29]. Peripheral eggshell calcification on CT is present in roughly 25% of cases, which is sometimes helpful in differentiating these lesions from serous cystic neoplasms, which often have central calcification [69].

When diagnosed, MCNs are surgically removed [6,14]. A recent surgical series found that the rate of high-grade dysplasia in resected specimens was 5.5%, and the risk of invasive disease was 4.4% [70]. This data suggests that a more conservative approach of observation rather than immediate resection may be reasonable for some patients [70]. The prognosis is very good after MCN resection, with a 5-year survival of 97% to 100% for all comers [68,70]. However, invasive MCNs have a lower 5-year survival rate ranging from 15% to 75% [70,71]. Per the AGA guidelines, patients with invasive disease or dysplasia should undergo yearly surveillance with MRI [14]. This recommendation is based on a potential field defect described with IPMNs. However, the international consensus guidelines only recommends surveillance if invasive disease is present [6,68,71,72].

Case 5

A 59-year-old male presents for evaluation of sudden onset abdominal pain and an 8-pound weight loss over the past few months. Seven years ago a pancreatic cyst was diagnosed and has since been observed by serial imaging. His lipase was 400 U/L (normal < 82) with normal liver function tests. A CT scan of the abdomen and pelvis showed peri-pancreatic stranding consistent with pancreatitis and a large complex cyst in the head of the pancreas.

• What is the epidemiology of SCNs and how do they present?

SCNs are benign non–mucin-producing cystic lesions that are characterized by a glycogen-rich epithelium on histology [73]. Of patients with SCNs, 74% are female, with a median age 58 [10]. When diagnosed, most patients are usually asymptomatic (61%), but 27% present with abdominal pain. Other symptoms include jaundice, pancreatitis, nausea, and presence of a palpable abdominal mass. SCNs are more common in patients with von Hippel-Lindau syndrome [74].

• How are SCNs diagnosed and managed?

These cysts have fairly even distribution when discovered in the pancreas [53]. About 74% of lesions have smaller micro-cystic components [75]. About 20% of lesions have a characteristic honeycomb appearance, which is highly suggestive of an SCN [76]. About 30% of patients have a characteristic central stellate scar on CT which is also highly suggestive of an SCN [76]. Unlike mucinous neoplasms, peripheral calcification is usually not seen [69].

Malignancy associated with these cysts is very rare, with the largest cohort study reporting a rate of 0.1% [10]. The diagnosis can commonly be made by its unique imaging appearance [10]. Diagnostic biomarkers that may identify such cysts with more certainty are under active investigation [77]. Resection is reasonable and often performed for SCNs when they cause debilitating symptoms including refractory abdominal pain or pancreatitis. When resected and confirmed by pathology, no surveillance is required [14,78].

Conclusion

Pancreatic cysts are common incidental findings in clinical practice today. Many cause anxiety due to their association with pancreas cancer, but most are indolent and safe to observe. Even those cysts with malignant potential grow slowly and immediate surgery is often unnecessary. Several guidelines have been developed, and while there are similarities between them, there are enough critical differences unfortunately to cause some confusion among practitioners today. Further robust research is needed to help address and reconcile these differences. In the meantime, a multidisciplinary approach is highly recommended at dedicated centers of excellence for pancreatic diseases.

Corresponding author: Walter G. Park, MD, MS, 300 Pasteur Drive, MC: 5187, Stanford, CA 94305, [email protected].

Funding/support: Dr. Park is funded by an American College of Gastroenterology Junior Faculty Development Award and is a subcontinent for the National Cancer Institute's Early Detection Research Network.

Financial disclosures: None.

Author contributions: conception and design, TZ, WGP; analysis and interpretation of data, WGP; drafting of article, TZ, WGP; critical revision of the article, TZ, WGP.

As gynecologists are well aware, in November 2014, the FDA issued a safety communication, warning “against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids.” Now, a group of 46 experts in gynecologic surgery, including Dr. Eva Chalas, question the FDA’s decision and provide their own clinical recommendations for FDA consideration.

 Click here to read the open letter to the FDA.

As gynecologists are well aware, in November 2014, the FDA issued a safety communication, warning “against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids.” Now, a group of 46 experts in gynecologic surgery, including Dr. Eva Chalas, question the FDA’s decision and provide their own clinical recommendations for FDA consideration.

 Click here to read the open letter to the FDA.

As gynecologists are well aware, in November 2014, the FDA issued a safety communication, warning “against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids.” Now, a group of 46 experts in gynecologic surgery, including Dr. Eva Chalas, question the FDA’s decision and provide their own clinical recommendations for FDA consideration.

 Click here to read the open letter to the FDA.

From the Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ.

Abstract

• Objective: To provide a clinical summary of the available data evaluating the use of direct oral anticoagulants (DOACs) in geriatric patients with nonvalvular atrial fibrillation.
• Methods: MEDLINE, Web of Science, and Google Scholar were used to identify pertinent systematic reviews, randomized controlled trials, observational studies, and pharmacokinetic studies evaluating use of DOACs in the geriatric population.
• Results: A total of 8 systemic reviews, 5 randomized controlled trials, 2 observational trials, and 5 pharmacokinetic studies of relevance were identified for inclusion in this review. The landscape of anticoagulation has dramatically changed over the past 5 years beginning with the development and marketing of an oral direct thrombin inhibitor and followed by 3 oral direct factor Xa inhibitors. Despite significant advances in this oral anticoagulation arena, many questions remain as to the best therapeutic approach in the geriatric population as the literature is lacking. This population has a higher risk of stroke; however, due to the increased risk of bleeding clinicians may often defer anticoagulant therapy due to the fear of hemorrhagic complications. Clinicians must consider the risk-benefit ratio and the associated outcomes in geriatric patients compared to other patient populations.
• Conclusions: Interpreting the available literature and understanding the benefits and limitations of the DOACs is critical when selecting the most appropriate pharmacologic strategy in geriatric patients.

Anticoagulants are among the top 5 drug classes associated with patient harm in the US [1] and are commonly reported as contributing to hospitalizations [2]. In just one quarter in 2012 alone, warfarin, dabigatran, and rivaroxaban accounted for 1734 of 50,289 adverse events reported to the Food and Drug Administration (FDA), including 233 deaths [3]. Appropriate use of anticoagulant agents and consideration of individual patient risk factors are essential to mitigate the occurrence of adverse consequences, especially in the geriatric population. This population is more likely to have risk factors for adverse drug events, for example, polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics, and diminished organ function (ie, renal and hepatic) [4,5]. Another important consideration is the lack of consensus on the definition of a “geriatric” or “elderly” patient. Although many consider a chronological age of > 65 years as the defining variable for a geriatric individual, this definition does not account for overall health status [6,7]. Clinicians should consider this shortcoming when evaluating the quality of geriatric studies. For example, a study claiming to evaluate the pharmacokinetics of a drug in a geriatric population enrolling healthy subjects aged > 65 years may result in data that do not translate to clinical practice.

Compounding the concern for iatrogenic events is the frequency of anticoagulant use in the geriatric population, as several indications are found more commonly in this age-group. Stroke prevention in nonvalvular atrial fibrillation (AF), the most common arrhythmia in the elderly, is a common indication for long-term anticoagulation [8]. The prevalence of AF increases with age and is usually higher in men than in women [9,10]. AF is generally uncommon before 60 years of age, but the prevalence increases noticeably thereafter, affecting approximately 10% of the overall population by 80 years of age [11]. The median age of patients who have AF is 75 years with approximately 70% of patients between 65 and 85 years of age [8,12]. Currently in the United States, an estimated 2.3 million people are diagnosed with AF [8]. In 2020, the AF population is predicted to increase to 7.5 million individuals with an expected prevalence of 13.5% among individuals ≥ 75 years of age, and 18.2% for those ≥ 85 years of age [13]. These data underscore the importance of considering the influence of age on the balance between efficacy and safety of anticoagulant therapy.

Direct oral anticoagulants (DOACs) represent the first alternatives to warfarin in over 6 decades. Currently available products in US include apixaban, dabigatran, edoxaban, and rivaroxaban. DOACs possess many of the characteristics of an ideal anticoagulant, including predictable pharmacokinetics, a wider therapeutic window compared to warfarin, minimal drug interactions, a fixed dose, and no need for routine evaluation of coagulation parameters. The safety and efficacy of the DOACs for stroke prevention in nonvalvular AF have been substantiated in several landmark clinical trials [14–16]. Yet there are several important questions that need to be addressed, such as management of excessive anticoagulation, clinical outcome data with renally adjusted doses (an exclusion criterion in many landmark studies was a creatinine clearance of < 25–30 mL/min), whether monitoring of coagulation parameters could enhance efficacy and safety, and optimal dosing strategies in geriatric patients. This review provides clinicians a summary of data from landmark studies, post-marketing surveillance, and pharmacokinetic evaluations to support DOAC selection in the geriatric population.

Evaluating Bleeding Risk

These tools have been extensively evaluated with warfarin therapy, but their performance in predicting DOAC-related bleeding has not been definitively established. Nonetheless, until tools evaluated specifically for DOACs are developed, it is reasonable to use these for risk-prediction in combination with clinical judgment. As an example, the European Society of Cardiology guideline on the use of non–vitamin K antagonist (VKA) anticoagulants in patients with nonvalvular AF suggests that the HAS-BLED score may be used to identify risk factors for bleeding and correct those that are modifiable [20]. The HAS-BLED score is validated for VKA and non-VKA anticoagulants (early-generation oral direct thrombin inhibitor ximelgatran) [21] and is the only bleeding risk score predictive for intracranial hemorrhage [19]. In a 2013 “real world” comparison, HAS-BLED was easier to use and had better predictive accuracy that ATRIA [22].

One of the major challenges in geriatric patients is that those at highest risk for bleeding are those who would have the greatest benefit from anticoagulation [23]. The prediction scores can help clinicians balance the risk-benefit ratio for anticoagulation on a case by case basis. Although the scoring systems take into consideration several factors, including medical conditions that have been shown to significantly increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes, renal insufficiency, alcoholism and liver disease, not all are included in every scoring scheme [23]. These conditions are more common among elderly patients, and this should be taken into account when estimating the risk-benefit ratio of oral anticoagulation [15]. Patients’ preferences should also be taken into account. It is essential for clinicians to clearly discuss treatment options with patients as data suggest that clinician and patient perceptions of anticoagulation are often mismatched [24–26].

Performance of TSOACS in Landmark Studies

Some specific differences in outcomes seen in landmark studies that may facilitate selection among the DOACs include the risk of major bleeding, risk of gastrointestinal bleeding, risk of acute coronary syndrome, exclusion of valvular heart disease, and noninferiority versus superiority as the primary endpoint when compared to warfarin.

Major Bleeding

Gastrointestinal Bleeding

Among all of the DOACs, gastrointestinal (GI) bleeding was significantly greater with dabigatran, edoxaban, and rivaroxaban when compared to warfarin (HR, 1.49; 95% CI, 1.21–1.84; HR, 1.23; 95% CI, 1.02–1.50; and HR, 1.61; 95% CI, 1.30–1.99, respectively; P < 0.05 for all) [14–16] in landmark studies. Based on these data, clinicians may consider the selection of apixaban in patients with a previous history of GI pathology. GI bleeding may be more common in elderly patients due to the potential for preexisting GI pathology and high local concentrations of drug [29]. Clemens and colleagues suggested an “anticoagulation GI stress test” may predict GI malignancy [33]. They found that patients on DOACs that presented with a GI bleed were more likely to present with a GI malignancy. As such, it is reasonable to screen patients with a fecal occult blood test within the first month after initiating TSOAC treatment and then annually.

Acute Coronary Syndrome

A higher rate of myocardial infarction was observed with dabigatran 150 mg versus warfarin (0.74% vs 0.53% per year; P = 0.048) in the RE-LY study [16]. Whether the increase in myocardial infarction was due to dabigatran as a causative agent or warfarin’s ability to reduce the risk of myocardial infarction to a larger extent compared with dabigatran is unknown. Nonetheless, it may be prudent to use an alternative therapy in patients with a history of acute coronary syndrome.

Valvular Heart Disease

The risk of stroke and systemic embolism is higher in patients with valvular heart disease [34]. Patients with moderate to severe mitral stenosis or mechanical prosthetic heart valves were excluded from the DOAC landmark studies. Dabigatran was evaluated for prevention of stroke and systemic embolism in patients with valvular heart disease in the RE-ALIGN study [35,36]. Patients were randomized to warfarin titrated to a target INR of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk or dabigatran 150 mg, 220 mg, or 300 mg twice daily adjusted to a targeted trough of ≥ 50 ng/mL. The trial was terminated early due to a worse primary outcome (composite of stroke, systemic embolism, myocardial infarction, and death) with dabigatran versus warfarin (HR, 3.37, 95% CI, 0.76–14.95; P = 0.11). In addition, bleeding rates (any bleeding) was significantly greater with dabigatran (27%) versus warfarin (12%) (P = 0.01). Based on these data and the lack of data with the other TSOACs, warfarin remains the standard of care for valvular heart disease [37]. In patients with a previous bioprosthetic valve with AF, patients with mitral insufficiency, or aortic stensosis, TSOACs may be considered [37].

Landmark Study Efficacy Endpoints

The primary endpoint in each of the landmark studies was a composite of stroke (ischemic or hemorrhagic) and systemic embolism. For the primary endpoint only dabigatran 150 mg twice daily and apixaban 5 mg twice daily were found to be superior to warfarin for the prevention of stroke or systemic embolism in nonvalvular AF (HR, 0.66; 95% CI, 0.53–0.82; P < 0.001 and HR, 0.66; 95% CI, 0.66–0.95; P = 0.01, respectively). Both edoxaban (60 mg and 30 mg daily) and rivaroxaban were noninferior to warfarin for the primary endpoint. In terms of ischemic stroke, only dabigatran 150 mg twice daily was superior to warfarin for the reduction in ischemic stroke in patients with nonvalvular AF (HR, 0.76; 95% CI, 0.60–0.98; P = 0.03) [19]. All of the DOACs demonstrated a reduction in hemorrhagic stroke.

TSOAC Use in Elderly Patitents

Pharmacokinetic Evaluations

Several pharmacokinetic studies have evaluated the influence of age on DOAC disposition. In a study evaluating the influence of age on apixaban disposition, the area under the concentration-time curve to infinity was 32% higher in the elderly (aged 65 years or older) compared to the younger subjects (< age 40 years) [38]. These data provide the rationale for dosage adjustment in individuals aged 80 years or older with either low body mass (weight less than or equal to 60 kg) or renal impairment (serum creatinine 1.5 mg/dL or higher). In a pharmacokinetic study evaluating dabigatran in patients > 65 years of age, the time to steady state ranged from 2 to 3 days, correlating to a half-life of 12 to 14 hours, and peak concentrations (256 ng/mL females, 255 ng/mL males) were reached after a median of 3 hours (range, 2.0–4.0 hours) [39]. These data suggest a 1.7- to twofold increase in bioavailability. The area under the curve of rivaroxaban was significantly higher in subjects > 75 years versus subjects 18-45 years, while total and renal clearance were decreased [40].However, the time to maximum factor Xa inhibition and C_max were not influenced by age.

Clinical Evaluations

Dabigatran

In a post-hoc analysis of the RE-LY trial, Eikelboom and colleagues found that patients 75 years of age and older treated with dabigatran 150 mg twice daily had a greater incidence of GI bleeding irrespective of renal function compared with those on warfarin (1.85%/year vs. 1.25%/year; P < 0.001) [29]. A higher risk in major bleeding also was seen in dabigatran patients (5.10% versus 4.37%; P = 0.07). As a result, the 2012 Beer’s Criteria lists dabigatran as a potentially inappropriate medication. An analysis was conducted of 134,414 elderly Medicare patients (defined as age > 65 years) with 37,587 person-years of follow-up who were treated with dabigatran or warfarin [44]. Approximately 60% of patients included in the analysis were over age 75 years. Dabigatran was associated with a significant reduction in ischemic stroke: HR 0.80 (CI 0.67–0.96); intracranial hemorrhage: HR 0.34 (CI 0.26–0.46); and death: HR 0.86 (CI 0.77–0.96) when compared with warfarin. As in the Eikelboom study, major gastrointestinal bleeding was significantly increased with dabigatran (HR, 1.28 [95% CI, 1.14–1.44]).

Rivaroxaban

For rivaroxaban, a subgroup analysis of patients ≥ 75 years in the ROCKET-AF trial reported similar rates of major bleeding (HR, 1.11; 95% CI, 0.92–1.34) with rivaroxaban compared with warfarin [31]. Clinically relevant non-major bleeding was significantly higher for patients aged ≥ 75 years compared with patients aged < 75 years (P = 0.01).

Apixaban

Halvorsen and colleagues found that age did not influence the benefits of apixaban in terms of efficacy and safety [47]. In the cohort of patients aged 75 years or older, major bleeding was significantly reduced compared to warfarin (HR, 0.64; 95% CI, 0.52–0.79). The safety benefits persisted even in the setting of age greater than 75 years and renal impairment. A significant reduction in major bleeding (HR, 0.35; 95% CI, 0.14–0.86) was seen in elderly patients with a CrCl; ≤ 30 mL/min (n = 221) treated with apixaban versus warfarin. Similarly, in elderly patients with a CrCl 30 to 50 mL/min (n = 1898) a significant reduction in major bleeding was reported (HR, 0.53; 95% CI, 0.37–0.76). These data are consistent with a meta-regression analysis that found a linear relationship between the relative risk of major bleeding and the magnitude of renal excretion for the DOACs (r²=0.66, P = 0.03) [48]. In this analysis, apixaban had the most favorable outcomes in terms of major bleeding compared to the other DOACs and also has the least dependence on renal function for clearance. In a pooled analysis of data from landmark trials, Ng and colleagues found that in elderly patients (defined as age > 75 years) with nonvalvular AF, only apixaban was associated with a significant reduction in both stroke and major hemorrhage (Figure 1) [49,50].

Edoxaban

Kato and colleagues performed a subgroup analysis of patients aged 75 years or older enrolled in the ENGAGE TIMI 48 study [50]. Currently the results are only published in abstract form. Regardless of treatment, the risk of major bleeding and stroke significantly increased with age (P < 0.001). An absolute risk reduction in major bleeding was reported with both 60 mg and 30 mg of edoxaban versus warfarin (4.0%/year and 2.2%/year versus 4.8%/year, respectively; no P value provided).

Therapeuti Drug Monitoring

Collectively, the data on assessment of the anticoagulant activity of DOACs using coagulation assays is evolving. These tests include but are not limited to prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TT), dilute TT, activated clotting time (ACT), anti factor Xa, and ecarin clotting time (ECT) assays. Although routine monitoring is not desirable, the ability to assess degree of anticoagulation in select patient populations may prove beneficial. Future studies are essential to confirm whether assessing DOAC activity using coagulation assays in vulnerable populations such as the elderly improves clinical outcomes. Several reviews on this subject matter have been published [51–55]. The reader is encouraged to review these data as there are significant limitations to currently available assays and incorrect interpretation may lead to suboptimal treatment decisions.

Renal and Hepatic Dysfunction

Depending on the specific agents, DOACs renal clearance varies from 27% to 80% [56–59]. Clinical trials often use the Cockcroft-Gault formula (CG) based on actual body weight to estimate renal function. Landmark trials evaluating the DOACs differed in their strategy for estimation of renal function using CG. For example, RE-LY and ROCKET-AF used actual body weight for the estimation of renal function, while ARISTOTLE did not specify which body weight to use. Estimation of renal function or glomerular filtration rate (GFR) by CG is frequently in discordance with actual renal function in the elderly [60]. MDRD (modification of diet in renal disease) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) are also common estimations that provide an estimate of GFR. In a cross-sectional study, comparing the CG, MDRD, and EPI formulas in a clinical setting, data from potential kidney donors and adult patients who underwent a GFR measurement revealed that MDRD has the smallest mean bias. The influence of age was the absolute bias for estimation of renal function for all formulas. CG is additionally influenced by body weight and body mass index. When compared to CG, MDRD actually reported more accurate predictor of GFR in adults < 70 years old [61]. However, package inserts recommend dose adjustments based on estimation of CrCl using CG formula. This poses a problem in adjusting DOAC doses in elderly patients who are subject to overestimation of renal function with this antiquated equation. Among elderly patients with renal impairment, discordance between estimated and actual renal function was higher for dabigatran and rivaroxaban than for apixaban dosages [61].

Renal excretion of unchanged dabigatran is the predominant pathway for elimination (~80%) [58]. The FDA-approved dosing strategy in the US for dabigatran is 150 mg twice daily in patients with a CrCl ≥ 30 mL/min, 75 mg twice daily in patients with severe renal impairment (CrCl 15–30 mL/min), and is contraindicated in patients with a CrCl < 15 mL/min [58]. By comparison, the Canadian and the European Medicines Agency have listed patients with a CrCl < 30 mL/min (severe renal impairment) as a contraindication for use. The US-approved dosage for severe renal impairment was derived during the approval phase of dabigatran using a simulation pharmacokinetic model [62,63]. The dosage was estimated by pharmacokinetic simulation to provide similar C_max and C_min concentrations compared to the 150 mg twice-daily dosage in moderate renal impairment. Compared to patients with CrCl ≥ 80 mL/min, there was a 1.29- and a 1.47-fold increase in dabigatran trough plasma concentration in the CrCl 50–80 mL/min patients and the CrCl 30–50 mL/min patients, respectively. There have been many postmarketing reports of hemorrhage with dabigatran [36,84,85]. Although reporting bias is likely due to the novelty of the agent, clinicians may take key clinical pearls away from these reports. Patients often had risk factors, including low body weight, renal impairment, and polypharmacy with interacting drugs (eg, amiodarone). These risk factors are also important with the other DOACs.

A subgroup analysis of ROCKET-AF evaluating rivaroxaban 15 mg daily in patients with a CrCl of 30–49 mL/min did not identify any differences in endpoints with the exception of fatal bleeding, which occurred less often with rivaroxaban (0.28%/yr vs. 0.74%/yr; P = 0.047) [64].

Monitoring of renal function is essential to mitigate the risk of drug accumulation. Clinicians should consider obtaining a baseline renal assessment with annual reassessments in patients with normal (CrCl ≥ 80 mL/min) or mild (CrCl 50–79 mL/min) renal impairment, and 2 to 3 times per year in patients with moderate (CrCl 30–49 mL/min) renal impairment [65]. A summary of renal dose adjustments for DOAC therapy may be found in Table 5 [56–59].

In addition to renal function, hepatic impairment can also affect the metabolism of anticoagulants. Severe hepatic impairment can lead to prolonged PT. Therefore, patients who have liver dysfunction and are treated with anticoagulation have increased risk of hemorrhagic events. Large pivotal trials on the key indications of dabigatran, apixaban, and rivaroxaban excluded patients with significant signs of hepatic impairment. Table 5 provides dosing recommendations for the different DOACs in the setting of hepatic impairment [56–59].

Polypharmacy And The Potential For Adverse Consequences

Costs And Cost-Effectiveness of DOACS

With the high burden of AF and the aging population, analysis of cost and value is an important consideration [76]. There are limited publications comparing the cost-effectiveness between the anticoagulation options. However, numerous cost-effectiveness studies have evaluated the individual DOACs [71–79]. Overall, the studies suggest that the DOACs are a cost-effective alternative to warfarin in the general and elderly populations. One analysis reported that dabigatran may not be cost-effective in patients with a low CHADS2 score (≤ 2) [71].

Harrington et al [80] compared the cost-effectiveness of dabigatran, rivaroxaban, and apixaban versus warfarin. This cost-effectiveness study used published clinical trial data to build a decision model, and results indicated that for patients ≥ 70 years of age with an increased risk for stroke, normal renal function, and no previous contraindications to anticoagulant therapy, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were cost-effective substitutes for warfarin for the prevention of stroke in nonvalvular AF [80]. Apixaban was the preferred anticoagulant for their hypothetical cohort of 70-year-old patients with nonvalvular AF, as it was most likely to be the cost-effective treatment option at all willing-to-pay thresholds > $40,000 per quality-adjusted life-year gained [76,81].

Prescription costs may vary depending on payor and level of insurance. If a patient does not have prescription insurance, the annual price of generic warfarin is roughly $200 to $360, depending on dosage. Approximate annual costs for the DOACs are greater than 20 times the cost of warfarin (apixaban $4500, dabigatran $4500, and rivaroxaban $4800) [82]. However, most patients on these medications are over 65 years old and have prescription coverage through Medicare Part D. Of note, patients may have more of a burden if or when they reach the “donut hole” coverage gap. Currently, once patients spend $2960 (for 2015) and $3310 (for 2016) on covered drugs they will fall into the donut hole unless they qualify for additional assistance. At this point Medicare Part D will reimburse 45% of the cost of the newer anticoagulants since generics are currently unavailable. As a result, individual affordability may become an issue. Further complicating the scenario is the inability to apply coupon and rebate cards in the setting of government-funded prescription coverage. Clinicians should discuss these issues with their patients to help select the most valuable therapy.

Conclusions And Recommendations

Corresponding author: Luigi Brunetti, PharmD, MPH, Rutgers University, 160 Frelinghuysen Rd, Piscataway, NJ 08854, [email protected].

From the Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ.

Abstract

• Objective: To provide a clinical summary of the available data evaluating the use of direct oral anticoagulants (DOACs) in geriatric patients with nonvalvular atrial fibrillation.
• Methods: MEDLINE, Web of Science, and Google Scholar were used to identify pertinent systematic reviews, randomized controlled trials, observational studies, and pharmacokinetic studies evaluating use of DOACs in the geriatric population.
• Results: A total of 8 systemic reviews, 5 randomized controlled trials, 2 observational trials, and 5 pharmacokinetic studies of relevance were identified for inclusion in this review. The landscape of anticoagulation has dramatically changed over the past 5 years beginning with the development and marketing of an oral direct thrombin inhibitor and followed by 3 oral direct factor Xa inhibitors. Despite significant advances in this oral anticoagulation arena, many questions remain as to the best therapeutic approach in the geriatric population as the literature is lacking. This population has a higher risk of stroke; however, due to the increased risk of bleeding clinicians may often defer anticoagulant therapy due to the fear of hemorrhagic complications. Clinicians must consider the risk-benefit ratio and the associated outcomes in geriatric patients compared to other patient populations.
• Conclusions: Interpreting the available literature and understanding the benefits and limitations of the DOACs is critical when selecting the most appropriate pharmacologic strategy in geriatric patients.

Anticoagulants are among the top 5 drug classes associated with patient harm in the US [1] and are commonly reported as contributing to hospitalizations [2]. In just one quarter in 2012 alone, warfarin, dabigatran, and rivaroxaban accounted for 1734 of 50,289 adverse events reported to the Food and Drug Administration (FDA), including 233 deaths [3]. Appropriate use of anticoagulant agents and consideration of individual patient risk factors are essential to mitigate the occurrence of adverse consequences, especially in the geriatric population. This population is more likely to have risk factors for adverse drug events, for example, polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics, and diminished organ function (ie, renal and hepatic) [4,5]. Another important consideration is the lack of consensus on the definition of a “geriatric” or “elderly” patient. Although many consider a chronological age of > 65 years as the defining variable for a geriatric individual, this definition does not account for overall health status [6,7]. Clinicians should consider this shortcoming when evaluating the quality of geriatric studies. For example, a study claiming to evaluate the pharmacokinetics of a drug in a geriatric population enrolling healthy subjects aged > 65 years may result in data that do not translate to clinical practice.

Compounding the concern for iatrogenic events is the frequency of anticoagulant use in the geriatric population, as several indications are found more commonly in this age-group. Stroke prevention in nonvalvular atrial fibrillation (AF), the most common arrhythmia in the elderly, is a common indication for long-term anticoagulation [8]. The prevalence of AF increases with age and is usually higher in men than in women [9,10]. AF is generally uncommon before 60 years of age, but the prevalence increases noticeably thereafter, affecting approximately 10% of the overall population by 80 years of age [11]. The median age of patients who have AF is 75 years with approximately 70% of patients between 65 and 85 years of age [8,12]. Currently in the United States, an estimated 2.3 million people are diagnosed with AF [8]. In 2020, the AF population is predicted to increase to 7.5 million individuals with an expected prevalence of 13.5% among individuals ≥ 75 years of age, and 18.2% for those ≥ 85 years of age [13]. These data underscore the importance of considering the influence of age on the balance between efficacy and safety of anticoagulant therapy.

Direct oral anticoagulants (DOACs) represent the first alternatives to warfarin in over 6 decades. Currently available products in US include apixaban, dabigatran, edoxaban, and rivaroxaban. DOACs possess many of the characteristics of an ideal anticoagulant, including predictable pharmacokinetics, a wider therapeutic window compared to warfarin, minimal drug interactions, a fixed dose, and no need for routine evaluation of coagulation parameters. The safety and efficacy of the DOACs for stroke prevention in nonvalvular AF have been substantiated in several landmark clinical trials [14–16]. Yet there are several important questions that need to be addressed, such as management of excessive anticoagulation, clinical outcome data with renally adjusted doses (an exclusion criterion in many landmark studies was a creatinine clearance of < 25–30 mL/min), whether monitoring of coagulation parameters could enhance efficacy and safety, and optimal dosing strategies in geriatric patients. This review provides clinicians a summary of data from landmark studies, post-marketing surveillance, and pharmacokinetic evaluations to support DOAC selection in the geriatric population.

Evaluating Bleeding Risk

These tools have been extensively evaluated with warfarin therapy, but their performance in predicting DOAC-related bleeding has not been definitively established. Nonetheless, until tools evaluated specifically for DOACs are developed, it is reasonable to use these for risk-prediction in combination with clinical judgment. As an example, the European Society of Cardiology guideline on the use of non–vitamin K antagonist (VKA) anticoagulants in patients with nonvalvular AF suggests that the HAS-BLED score may be used to identify risk factors for bleeding and correct those that are modifiable [20]. The HAS-BLED score is validated for VKA and non-VKA anticoagulants (early-generation oral direct thrombin inhibitor ximelgatran) [21] and is the only bleeding risk score predictive for intracranial hemorrhage [19]. In a 2013 “real world” comparison, HAS-BLED was easier to use and had better predictive accuracy that ATRIA [22].

One of the major challenges in geriatric patients is that those at highest risk for bleeding are those who would have the greatest benefit from anticoagulation [23]. The prediction scores can help clinicians balance the risk-benefit ratio for anticoagulation on a case by case basis. Although the scoring systems take into consideration several factors, including medical conditions that have been shown to significantly increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes, renal insufficiency, alcoholism and liver disease, not all are included in every scoring scheme [23]. These conditions are more common among elderly patients, and this should be taken into account when estimating the risk-benefit ratio of oral anticoagulation [15]. Patients’ preferences should also be taken into account. It is essential for clinicians to clearly discuss treatment options with patients as data suggest that clinician and patient perceptions of anticoagulation are often mismatched [24–26].

Performance of TSOACS in Landmark Studies

Some specific differences in outcomes seen in landmark studies that may facilitate selection among the DOACs include the risk of major bleeding, risk of gastrointestinal bleeding, risk of acute coronary syndrome, exclusion of valvular heart disease, and noninferiority versus superiority as the primary endpoint when compared to warfarin.

Major Bleeding

Gastrointestinal Bleeding

Among all of the DOACs, gastrointestinal (GI) bleeding was significantly greater with dabigatran, edoxaban, and rivaroxaban when compared to warfarin (HR, 1.49; 95% CI, 1.21–1.84; HR, 1.23; 95% CI, 1.02–1.50; and HR, 1.61; 95% CI, 1.30–1.99, respectively; P < 0.05 for all) [14–16] in landmark studies. Based on these data, clinicians may consider the selection of apixaban in patients with a previous history of GI pathology. GI bleeding may be more common in elderly patients due to the potential for preexisting GI pathology and high local concentrations of drug [29]. Clemens and colleagues suggested an “anticoagulation GI stress test” may predict GI malignancy [33]. They found that patients on DOACs that presented with a GI bleed were more likely to present with a GI malignancy. As such, it is reasonable to screen patients with a fecal occult blood test within the first month after initiating TSOAC treatment and then annually.

Acute Coronary Syndrome

A higher rate of myocardial infarction was observed with dabigatran 150 mg versus warfarin (0.74% vs 0.53% per year; P = 0.048) in the RE-LY study [16]. Whether the increase in myocardial infarction was due to dabigatran as a causative agent or warfarin’s ability to reduce the risk of myocardial infarction to a larger extent compared with dabigatran is unknown. Nonetheless, it may be prudent to use an alternative therapy in patients with a history of acute coronary syndrome.

Valvular Heart Disease

The risk of stroke and systemic embolism is higher in patients with valvular heart disease [34]. Patients with moderate to severe mitral stenosis or mechanical prosthetic heart valves were excluded from the DOAC landmark studies. Dabigatran was evaluated for prevention of stroke and systemic embolism in patients with valvular heart disease in the RE-ALIGN study [35,36]. Patients were randomized to warfarin titrated to a target INR of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk or dabigatran 150 mg, 220 mg, or 300 mg twice daily adjusted to a targeted trough of ≥ 50 ng/mL. The trial was terminated early due to a worse primary outcome (composite of stroke, systemic embolism, myocardial infarction, and death) with dabigatran versus warfarin (HR, 3.37, 95% CI, 0.76–14.95; P = 0.11). In addition, bleeding rates (any bleeding) was significantly greater with dabigatran (27%) versus warfarin (12%) (P = 0.01). Based on these data and the lack of data with the other TSOACs, warfarin remains the standard of care for valvular heart disease [37]. In patients with a previous bioprosthetic valve with AF, patients with mitral insufficiency, or aortic stensosis, TSOACs may be considered [37].

Landmark Study Efficacy Endpoints

The primary endpoint in each of the landmark studies was a composite of stroke (ischemic or hemorrhagic) and systemic embolism. For the primary endpoint only dabigatran 150 mg twice daily and apixaban 5 mg twice daily were found to be superior to warfarin for the prevention of stroke or systemic embolism in nonvalvular AF (HR, 0.66; 95% CI, 0.53–0.82; P < 0.001 and HR, 0.66; 95% CI, 0.66–0.95; P = 0.01, respectively). Both edoxaban (60 mg and 30 mg daily) and rivaroxaban were noninferior to warfarin for the primary endpoint. In terms of ischemic stroke, only dabigatran 150 mg twice daily was superior to warfarin for the reduction in ischemic stroke in patients with nonvalvular AF (HR, 0.76; 95% CI, 0.60–0.98; P = 0.03) [19]. All of the DOACs demonstrated a reduction in hemorrhagic stroke.

TSOAC Use in Elderly Patitents

Pharmacokinetic Evaluations

Several pharmacokinetic studies have evaluated the influence of age on DOAC disposition. In a study evaluating the influence of age on apixaban disposition, the area under the concentration-time curve to infinity was 32% higher in the elderly (aged 65 years or older) compared to the younger subjects (< age 40 years) [38]. These data provide the rationale for dosage adjustment in individuals aged 80 years or older with either low body mass (weight less than or equal to 60 kg) or renal impairment (serum creatinine 1.5 mg/dL or higher). In a pharmacokinetic study evaluating dabigatran in patients > 65 years of age, the time to steady state ranged from 2 to 3 days, correlating to a half-life of 12 to 14 hours, and peak concentrations (256 ng/mL females, 255 ng/mL males) were reached after a median of 3 hours (range, 2.0–4.0 hours) [39]. These data suggest a 1.7- to twofold increase in bioavailability. The area under the curve of rivaroxaban was significantly higher in subjects > 75 years versus subjects 18-45 years, while total and renal clearance were decreased [40].However, the time to maximum factor Xa inhibition and C_max were not influenced by age.

Clinical Evaluations

Dabigatran

In a post-hoc analysis of the RE-LY trial, Eikelboom and colleagues found that patients 75 years of age and older treated with dabigatran 150 mg twice daily had a greater incidence of GI bleeding irrespective of renal function compared with those on warfarin (1.85%/year vs. 1.25%/year; P < 0.001) [29]. A higher risk in major bleeding also was seen in dabigatran patients (5.10% versus 4.37%; P = 0.07). As a result, the 2012 Beer’s Criteria lists dabigatran as a potentially inappropriate medication. An analysis was conducted of 134,414 elderly Medicare patients (defined as age > 65 years) with 37,587 person-years of follow-up who were treated with dabigatran or warfarin [44]. Approximately 60% of patients included in the analysis were over age 75 years. Dabigatran was associated with a significant reduction in ischemic stroke: HR 0.80 (CI 0.67–0.96); intracranial hemorrhage: HR 0.34 (CI 0.26–0.46); and death: HR 0.86 (CI 0.77–0.96) when compared with warfarin. As in the Eikelboom study, major gastrointestinal bleeding was significantly increased with dabigatran (HR, 1.28 [95% CI, 1.14–1.44]).

Rivaroxaban

For rivaroxaban, a subgroup analysis of patients ≥ 75 years in the ROCKET-AF trial reported similar rates of major bleeding (HR, 1.11; 95% CI, 0.92–1.34) with rivaroxaban compared with warfarin [31]. Clinically relevant non-major bleeding was significantly higher for patients aged ≥ 75 years compared with patients aged < 75 years (P = 0.01).

Apixaban

Halvorsen and colleagues found that age did not influence the benefits of apixaban in terms of efficacy and safety [47]. In the cohort of patients aged 75 years or older, major bleeding was significantly reduced compared to warfarin (HR, 0.64; 95% CI, 0.52–0.79). The safety benefits persisted even in the setting of age greater than 75 years and renal impairment. A significant reduction in major bleeding (HR, 0.35; 95% CI, 0.14–0.86) was seen in elderly patients with a CrCl; ≤ 30 mL/min (n = 221) treated with apixaban versus warfarin. Similarly, in elderly patients with a CrCl 30 to 50 mL/min (n = 1898) a significant reduction in major bleeding was reported (HR, 0.53; 95% CI, 0.37–0.76). These data are consistent with a meta-regression analysis that found a linear relationship between the relative risk of major bleeding and the magnitude of renal excretion for the DOACs (r²=0.66, P = 0.03) [48]. In this analysis, apixaban had the most favorable outcomes in terms of major bleeding compared to the other DOACs and also has the least dependence on renal function for clearance. In a pooled analysis of data from landmark trials, Ng and colleagues found that in elderly patients (defined as age > 75 years) with nonvalvular AF, only apixaban was associated with a significant reduction in both stroke and major hemorrhage (Figure 1) [49,50].

Edoxaban

Kato and colleagues performed a subgroup analysis of patients aged 75 years or older enrolled in the ENGAGE TIMI 48 study [50]. Currently the results are only published in abstract form. Regardless of treatment, the risk of major bleeding and stroke significantly increased with age (P < 0.001). An absolute risk reduction in major bleeding was reported with both 60 mg and 30 mg of edoxaban versus warfarin (4.0%/year and 2.2%/year versus 4.8%/year, respectively; no P value provided).

Therapeuti Drug Monitoring

Collectively, the data on assessment of the anticoagulant activity of DOACs using coagulation assays is evolving. These tests include but are not limited to prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TT), dilute TT, activated clotting time (ACT), anti factor Xa, and ecarin clotting time (ECT) assays. Although routine monitoring is not desirable, the ability to assess degree of anticoagulation in select patient populations may prove beneficial. Future studies are essential to confirm whether assessing DOAC activity using coagulation assays in vulnerable populations such as the elderly improves clinical outcomes. Several reviews on this subject matter have been published [51–55]. The reader is encouraged to review these data as there are significant limitations to currently available assays and incorrect interpretation may lead to suboptimal treatment decisions.

Renal and Hepatic Dysfunction

Depending on the specific agents, DOACs renal clearance varies from 27% to 80% [56–59]. Clinical trials often use the Cockcroft-Gault formula (CG) based on actual body weight to estimate renal function. Landmark trials evaluating the DOACs differed in their strategy for estimation of renal function using CG. For example, RE-LY and ROCKET-AF used actual body weight for the estimation of renal function, while ARISTOTLE did not specify which body weight to use. Estimation of renal function or glomerular filtration rate (GFR) by CG is frequently in discordance with actual renal function in the elderly [60]. MDRD (modification of diet in renal disease) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) are also common estimations that provide an estimate of GFR. In a cross-sectional study, comparing the CG, MDRD, and EPI formulas in a clinical setting, data from potential kidney donors and adult patients who underwent a GFR measurement revealed that MDRD has the smallest mean bias. The influence of age was the absolute bias for estimation of renal function for all formulas. CG is additionally influenced by body weight and body mass index. When compared to CG, MDRD actually reported more accurate predictor of GFR in adults < 70 years old [61]. However, package inserts recommend dose adjustments based on estimation of CrCl using CG formula. This poses a problem in adjusting DOAC doses in elderly patients who are subject to overestimation of renal function with this antiquated equation. Among elderly patients with renal impairment, discordance between estimated and actual renal function was higher for dabigatran and rivaroxaban than for apixaban dosages [61].

Renal excretion of unchanged dabigatran is the predominant pathway for elimination (~80%) [58]. The FDA-approved dosing strategy in the US for dabigatran is 150 mg twice daily in patients with a CrCl ≥ 30 mL/min, 75 mg twice daily in patients with severe renal impairment (CrCl 15–30 mL/min), and is contraindicated in patients with a CrCl < 15 mL/min [58]. By comparison, the Canadian and the European Medicines Agency have listed patients with a CrCl < 30 mL/min (severe renal impairment) as a contraindication for use. The US-approved dosage for severe renal impairment was derived during the approval phase of dabigatran using a simulation pharmacokinetic model [62,63]. The dosage was estimated by pharmacokinetic simulation to provide similar C_max and C_min concentrations compared to the 150 mg twice-daily dosage in moderate renal impairment. Compared to patients with CrCl ≥ 80 mL/min, there was a 1.29- and a 1.47-fold increase in dabigatran trough plasma concentration in the CrCl 50–80 mL/min patients and the CrCl 30–50 mL/min patients, respectively. There have been many postmarketing reports of hemorrhage with dabigatran [36,84,85]. Although reporting bias is likely due to the novelty of the agent, clinicians may take key clinical pearls away from these reports. Patients often had risk factors, including low body weight, renal impairment, and polypharmacy with interacting drugs (eg, amiodarone). These risk factors are also important with the other DOACs.

A subgroup analysis of ROCKET-AF evaluating rivaroxaban 15 mg daily in patients with a CrCl of 30–49 mL/min did not identify any differences in endpoints with the exception of fatal bleeding, which occurred less often with rivaroxaban (0.28%/yr vs. 0.74%/yr; P = 0.047) [64].

Monitoring of renal function is essential to mitigate the risk of drug accumulation. Clinicians should consider obtaining a baseline renal assessment with annual reassessments in patients with normal (CrCl ≥ 80 mL/min) or mild (CrCl 50–79 mL/min) renal impairment, and 2 to 3 times per year in patients with moderate (CrCl 30–49 mL/min) renal impairment [65]. A summary of renal dose adjustments for DOAC therapy may be found in Table 5 [56–59].

In addition to renal function, hepatic impairment can also affect the metabolism of anticoagulants. Severe hepatic impairment can lead to prolonged PT. Therefore, patients who have liver dysfunction and are treated with anticoagulation have increased risk of hemorrhagic events. Large pivotal trials on the key indications of dabigatran, apixaban, and rivaroxaban excluded patients with significant signs of hepatic impairment. Table 5 provides dosing recommendations for the different DOACs in the setting of hepatic impairment [56–59].

Polypharmacy And The Potential For Adverse Consequences

Costs And Cost-Effectiveness of DOACS

With the high burden of AF and the aging population, analysis of cost and value is an important consideration [76]. There are limited publications comparing the cost-effectiveness between the anticoagulation options. However, numerous cost-effectiveness studies have evaluated the individual DOACs [71–79]. Overall, the studies suggest that the DOACs are a cost-effective alternative to warfarin in the general and elderly populations. One analysis reported that dabigatran may not be cost-effective in patients with a low CHADS2 score (≤ 2) [71].

Harrington et al [80] compared the cost-effectiveness of dabigatran, rivaroxaban, and apixaban versus warfarin. This cost-effectiveness study used published clinical trial data to build a decision model, and results indicated that for patients ≥ 70 years of age with an increased risk for stroke, normal renal function, and no previous contraindications to anticoagulant therapy, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were cost-effective substitutes for warfarin for the prevention of stroke in nonvalvular AF [80]. Apixaban was the preferred anticoagulant for their hypothetical cohort of 70-year-old patients with nonvalvular AF, as it was most likely to be the cost-effective treatment option at all willing-to-pay thresholds > $40,000 per quality-adjusted life-year gained [76,81].

Prescription costs may vary depending on payor and level of insurance. If a patient does not have prescription insurance, the annual price of generic warfarin is roughly $200 to $360, depending on dosage. Approximate annual costs for the DOACs are greater than 20 times the cost of warfarin (apixaban $4500, dabigatran $4500, and rivaroxaban $4800) [82]. However, most patients on these medications are over 65 years old and have prescription coverage through Medicare Part D. Of note, patients may have more of a burden if or when they reach the “donut hole” coverage gap. Currently, once patients spend $2960 (for 2015) and $3310 (for 2016) on covered drugs they will fall into the donut hole unless they qualify for additional assistance. At this point Medicare Part D will reimburse 45% of the cost of the newer anticoagulants since generics are currently unavailable. As a result, individual affordability may become an issue. Further complicating the scenario is the inability to apply coupon and rebate cards in the setting of government-funded prescription coverage. Clinicians should discuss these issues with their patients to help select the most valuable therapy.

Conclusions And Recommendations

Corresponding author: Luigi Brunetti, PharmD, MPH, Rutgers University, 160 Frelinghuysen Rd, Piscataway, NJ 08854, [email protected].

From the Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ.

Abstract

• Objective: To provide a clinical summary of the available data evaluating the use of direct oral anticoagulants (DOACs) in geriatric patients with nonvalvular atrial fibrillation.
• Methods: MEDLINE, Web of Science, and Google Scholar were used to identify pertinent systematic reviews, randomized controlled trials, observational studies, and pharmacokinetic studies evaluating use of DOACs in the geriatric population.
• Results: A total of 8 systemic reviews, 5 randomized controlled trials, 2 observational trials, and 5 pharmacokinetic studies of relevance were identified for inclusion in this review. The landscape of anticoagulation has dramatically changed over the past 5 years beginning with the development and marketing of an oral direct thrombin inhibitor and followed by 3 oral direct factor Xa inhibitors. Despite significant advances in this oral anticoagulation arena, many questions remain as to the best therapeutic approach in the geriatric population as the literature is lacking. This population has a higher risk of stroke; however, due to the increased risk of bleeding clinicians may often defer anticoagulant therapy due to the fear of hemorrhagic complications. Clinicians must consider the risk-benefit ratio and the associated outcomes in geriatric patients compared to other patient populations.
• Conclusions: Interpreting the available literature and understanding the benefits and limitations of the DOACs is critical when selecting the most appropriate pharmacologic strategy in geriatric patients.

Anticoagulants are among the top 5 drug classes associated with patient harm in the US [1] and are commonly reported as contributing to hospitalizations [2]. In just one quarter in 2012 alone, warfarin, dabigatran, and rivaroxaban accounted for 1734 of 50,289 adverse events reported to the Food and Drug Administration (FDA), including 233 deaths [3]. Appropriate use of anticoagulant agents and consideration of individual patient risk factors are essential to mitigate the occurrence of adverse consequences, especially in the geriatric population. This population is more likely to have risk factors for adverse drug events, for example, polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics, and diminished organ function (ie, renal and hepatic) [4,5]. Another important consideration is the lack of consensus on the definition of a “geriatric” or “elderly” patient. Although many consider a chronological age of > 65 years as the defining variable for a geriatric individual, this definition does not account for overall health status [6,7]. Clinicians should consider this shortcoming when evaluating the quality of geriatric studies. For example, a study claiming to evaluate the pharmacokinetics of a drug in a geriatric population enrolling healthy subjects aged > 65 years may result in data that do not translate to clinical practice.

Compounding the concern for iatrogenic events is the frequency of anticoagulant use in the geriatric population, as several indications are found more commonly in this age-group. Stroke prevention in nonvalvular atrial fibrillation (AF), the most common arrhythmia in the elderly, is a common indication for long-term anticoagulation [8]. The prevalence of AF increases with age and is usually higher in men than in women [9,10]. AF is generally uncommon before 60 years of age, but the prevalence increases noticeably thereafter, affecting approximately 10% of the overall population by 80 years of age [11]. The median age of patients who have AF is 75 years with approximately 70% of patients between 65 and 85 years of age [8,12]. Currently in the United States, an estimated 2.3 million people are diagnosed with AF [8]. In 2020, the AF population is predicted to increase to 7.5 million individuals with an expected prevalence of 13.5% among individuals ≥ 75 years of age, and 18.2% for those ≥ 85 years of age [13]. These data underscore the importance of considering the influence of age on the balance between efficacy and safety of anticoagulant therapy.

Direct oral anticoagulants (DOACs) represent the first alternatives to warfarin in over 6 decades. Currently available products in US include apixaban, dabigatran, edoxaban, and rivaroxaban. DOACs possess many of the characteristics of an ideal anticoagulant, including predictable pharmacokinetics, a wider therapeutic window compared to warfarin, minimal drug interactions, a fixed dose, and no need for routine evaluation of coagulation parameters. The safety and efficacy of the DOACs for stroke prevention in nonvalvular AF have been substantiated in several landmark clinical trials [14–16]. Yet there are several important questions that need to be addressed, such as management of excessive anticoagulation, clinical outcome data with renally adjusted doses (an exclusion criterion in many landmark studies was a creatinine clearance of < 25–30 mL/min), whether monitoring of coagulation parameters could enhance efficacy and safety, and optimal dosing strategies in geriatric patients. This review provides clinicians a summary of data from landmark studies, post-marketing surveillance, and pharmacokinetic evaluations to support DOAC selection in the geriatric population.

Evaluating Bleeding Risk

These tools have been extensively evaluated with warfarin therapy, but their performance in predicting DOAC-related bleeding has not been definitively established. Nonetheless, until tools evaluated specifically for DOACs are developed, it is reasonable to use these for risk-prediction in combination with clinical judgment. As an example, the European Society of Cardiology guideline on the use of non–vitamin K antagonist (VKA) anticoagulants in patients with nonvalvular AF suggests that the HAS-BLED score may be used to identify risk factors for bleeding and correct those that are modifiable [20]. The HAS-BLED score is validated for VKA and non-VKA anticoagulants (early-generation oral direct thrombin inhibitor ximelgatran) [21] and is the only bleeding risk score predictive for intracranial hemorrhage [19]. In a 2013 “real world” comparison, HAS-BLED was easier to use and had better predictive accuracy that ATRIA [22].

One of the major challenges in geriatric patients is that those at highest risk for bleeding are those who would have the greatest benefit from anticoagulation [23]. The prediction scores can help clinicians balance the risk-benefit ratio for anticoagulation on a case by case basis. Although the scoring systems take into consideration several factors, including medical conditions that have been shown to significantly increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes, renal insufficiency, alcoholism and liver disease, not all are included in every scoring scheme [23]. These conditions are more common among elderly patients, and this should be taken into account when estimating the risk-benefit ratio of oral anticoagulation [15]. Patients’ preferences should also be taken into account. It is essential for clinicians to clearly discuss treatment options with patients as data suggest that clinician and patient perceptions of anticoagulation are often mismatched [24–26].

Performance of TSOACS in Landmark Studies

Some specific differences in outcomes seen in landmark studies that may facilitate selection among the DOACs include the risk of major bleeding, risk of gastrointestinal bleeding, risk of acute coronary syndrome, exclusion of valvular heart disease, and noninferiority versus superiority as the primary endpoint when compared to warfarin.

Major Bleeding

Gastrointestinal Bleeding

Among all of the DOACs, gastrointestinal (GI) bleeding was significantly greater with dabigatran, edoxaban, and rivaroxaban when compared to warfarin (HR, 1.49; 95% CI, 1.21–1.84; HR, 1.23; 95% CI, 1.02–1.50; and HR, 1.61; 95% CI, 1.30–1.99, respectively; P < 0.05 for all) [14–16] in landmark studies. Based on these data, clinicians may consider the selection of apixaban in patients with a previous history of GI pathology. GI bleeding may be more common in elderly patients due to the potential for preexisting GI pathology and high local concentrations of drug [29]. Clemens and colleagues suggested an “anticoagulation GI stress test” may predict GI malignancy [33]. They found that patients on DOACs that presented with a GI bleed were more likely to present with a GI malignancy. As such, it is reasonable to screen patients with a fecal occult blood test within the first month after initiating TSOAC treatment and then annually.

Acute Coronary Syndrome

A higher rate of myocardial infarction was observed with dabigatran 150 mg versus warfarin (0.74% vs 0.53% per year; P = 0.048) in the RE-LY study [16]. Whether the increase in myocardial infarction was due to dabigatran as a causative agent or warfarin’s ability to reduce the risk of myocardial infarction to a larger extent compared with dabigatran is unknown. Nonetheless, it may be prudent to use an alternative therapy in patients with a history of acute coronary syndrome.

Valvular Heart Disease

The risk of stroke and systemic embolism is higher in patients with valvular heart disease [34]. Patients with moderate to severe mitral stenosis or mechanical prosthetic heart valves were excluded from the DOAC landmark studies. Dabigatran was evaluated for prevention of stroke and systemic embolism in patients with valvular heart disease in the RE-ALIGN study [35,36]. Patients were randomized to warfarin titrated to a target INR of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk or dabigatran 150 mg, 220 mg, or 300 mg twice daily adjusted to a targeted trough of ≥ 50 ng/mL. The trial was terminated early due to a worse primary outcome (composite of stroke, systemic embolism, myocardial infarction, and death) with dabigatran versus warfarin (HR, 3.37, 95% CI, 0.76–14.95; P = 0.11). In addition, bleeding rates (any bleeding) was significantly greater with dabigatran (27%) versus warfarin (12%) (P = 0.01). Based on these data and the lack of data with the other TSOACs, warfarin remains the standard of care for valvular heart disease [37]. In patients with a previous bioprosthetic valve with AF, patients with mitral insufficiency, or aortic stensosis, TSOACs may be considered [37].

Landmark Study Efficacy Endpoints

The primary endpoint in each of the landmark studies was a composite of stroke (ischemic or hemorrhagic) and systemic embolism. For the primary endpoint only dabigatran 150 mg twice daily and apixaban 5 mg twice daily were found to be superior to warfarin for the prevention of stroke or systemic embolism in nonvalvular AF (HR, 0.66; 95% CI, 0.53–0.82; P < 0.001 and HR, 0.66; 95% CI, 0.66–0.95; P = 0.01, respectively). Both edoxaban (60 mg and 30 mg daily) and rivaroxaban were noninferior to warfarin for the primary endpoint. In terms of ischemic stroke, only dabigatran 150 mg twice daily was superior to warfarin for the reduction in ischemic stroke in patients with nonvalvular AF (HR, 0.76; 95% CI, 0.60–0.98; P = 0.03) [19]. All of the DOACs demonstrated a reduction in hemorrhagic stroke.

TSOAC Use in Elderly Patitents

Pharmacokinetic Evaluations

Several pharmacokinetic studies have evaluated the influence of age on DOAC disposition. In a study evaluating the influence of age on apixaban disposition, the area under the concentration-time curve to infinity was 32% higher in the elderly (aged 65 years or older) compared to the younger subjects (< age 40 years) [38]. These data provide the rationale for dosage adjustment in individuals aged 80 years or older with either low body mass (weight less than or equal to 60 kg) or renal impairment (serum creatinine 1.5 mg/dL or higher). In a pharmacokinetic study evaluating dabigatran in patients > 65 years of age, the time to steady state ranged from 2 to 3 days, correlating to a half-life of 12 to 14 hours, and peak concentrations (256 ng/mL females, 255 ng/mL males) were reached after a median of 3 hours (range, 2.0–4.0 hours) [39]. These data suggest a 1.7- to twofold increase in bioavailability. The area under the curve of rivaroxaban was significantly higher in subjects > 75 years versus subjects 18-45 years, while total and renal clearance were decreased [40].However, the time to maximum factor Xa inhibition and C_max were not influenced by age.

Clinical Evaluations

Dabigatran

In a post-hoc analysis of the RE-LY trial, Eikelboom and colleagues found that patients 75 years of age and older treated with dabigatran 150 mg twice daily had a greater incidence of GI bleeding irrespective of renal function compared with those on warfarin (1.85%/year vs. 1.25%/year; P < 0.001) [29]. A higher risk in major bleeding also was seen in dabigatran patients (5.10% versus 4.37%; P = 0.07). As a result, the 2012 Beer’s Criteria lists dabigatran as a potentially inappropriate medication. An analysis was conducted of 134,414 elderly Medicare patients (defined as age > 65 years) with 37,587 person-years of follow-up who were treated with dabigatran or warfarin [44]. Approximately 60% of patients included in the analysis were over age 75 years. Dabigatran was associated with a significant reduction in ischemic stroke: HR 0.80 (CI 0.67–0.96); intracranial hemorrhage: HR 0.34 (CI 0.26–0.46); and death: HR 0.86 (CI 0.77–0.96) when compared with warfarin. As in the Eikelboom study, major gastrointestinal bleeding was significantly increased with dabigatran (HR, 1.28 [95% CI, 1.14–1.44]).

Rivaroxaban

For rivaroxaban, a subgroup analysis of patients ≥ 75 years in the ROCKET-AF trial reported similar rates of major bleeding (HR, 1.11; 95% CI, 0.92–1.34) with rivaroxaban compared with warfarin [31]. Clinically relevant non-major bleeding was significantly higher for patients aged ≥ 75 years compared with patients aged < 75 years (P = 0.01).

Apixaban

Halvorsen and colleagues found that age did not influence the benefits of apixaban in terms of efficacy and safety [47]. In the cohort of patients aged 75 years or older, major bleeding was significantly reduced compared to warfarin (HR, 0.64; 95% CI, 0.52–0.79). The safety benefits persisted even in the setting of age greater than 75 years and renal impairment. A significant reduction in major bleeding (HR, 0.35; 95% CI, 0.14–0.86) was seen in elderly patients with a CrCl; ≤ 30 mL/min (n = 221) treated with apixaban versus warfarin. Similarly, in elderly patients with a CrCl 30 to 50 mL/min (n = 1898) a significant reduction in major bleeding was reported (HR, 0.53; 95% CI, 0.37–0.76). These data are consistent with a meta-regression analysis that found a linear relationship between the relative risk of major bleeding and the magnitude of renal excretion for the DOACs (r²=0.66, P = 0.03) [48]. In this analysis, apixaban had the most favorable outcomes in terms of major bleeding compared to the other DOACs and also has the least dependence on renal function for clearance. In a pooled analysis of data from landmark trials, Ng and colleagues found that in elderly patients (defined as age > 75 years) with nonvalvular AF, only apixaban was associated with a significant reduction in both stroke and major hemorrhage (Figure 1) [49,50].

Edoxaban

Kato and colleagues performed a subgroup analysis of patients aged 75 years or older enrolled in the ENGAGE TIMI 48 study [50]. Currently the results are only published in abstract form. Regardless of treatment, the risk of major bleeding and stroke significantly increased with age (P < 0.001). An absolute risk reduction in major bleeding was reported with both 60 mg and 30 mg of edoxaban versus warfarin (4.0%/year and 2.2%/year versus 4.8%/year, respectively; no P value provided).

Therapeuti Drug Monitoring

Collectively, the data on assessment of the anticoagulant activity of DOACs using coagulation assays is evolving. These tests include but are not limited to prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TT), dilute TT, activated clotting time (ACT), anti factor Xa, and ecarin clotting time (ECT) assays. Although routine monitoring is not desirable, the ability to assess degree of anticoagulation in select patient populations may prove beneficial. Future studies are essential to confirm whether assessing DOAC activity using coagulation assays in vulnerable populations such as the elderly improves clinical outcomes. Several reviews on this subject matter have been published [51–55]. The reader is encouraged to review these data as there are significant limitations to currently available assays and incorrect interpretation may lead to suboptimal treatment decisions.

Renal and Hepatic Dysfunction

Depending on the specific agents, DOACs renal clearance varies from 27% to 80% [56–59]. Clinical trials often use the Cockcroft-Gault formula (CG) based on actual body weight to estimate renal function. Landmark trials evaluating the DOACs differed in their strategy for estimation of renal function using CG. For example, RE-LY and ROCKET-AF used actual body weight for the estimation of renal function, while ARISTOTLE did not specify which body weight to use. Estimation of renal function or glomerular filtration rate (GFR) by CG is frequently in discordance with actual renal function in the elderly [60]. MDRD (modification of diet in renal disease) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) are also common estimations that provide an estimate of GFR. In a cross-sectional study, comparing the CG, MDRD, and EPI formulas in a clinical setting, data from potential kidney donors and adult patients who underwent a GFR measurement revealed that MDRD has the smallest mean bias. The influence of age was the absolute bias for estimation of renal function for all formulas. CG is additionally influenced by body weight and body mass index. When compared to CG, MDRD actually reported more accurate predictor of GFR in adults < 70 years old [61]. However, package inserts recommend dose adjustments based on estimation of CrCl using CG formula. This poses a problem in adjusting DOAC doses in elderly patients who are subject to overestimation of renal function with this antiquated equation. Among elderly patients with renal impairment, discordance between estimated and actual renal function was higher for dabigatran and rivaroxaban than for apixaban dosages [61].

Renal excretion of unchanged dabigatran is the predominant pathway for elimination (~80%) [58]. The FDA-approved dosing strategy in the US for dabigatran is 150 mg twice daily in patients with a CrCl ≥ 30 mL/min, 75 mg twice daily in patients with severe renal impairment (CrCl 15–30 mL/min), and is contraindicated in patients with a CrCl < 15 mL/min [58]. By comparison, the Canadian and the European Medicines Agency have listed patients with a CrCl < 30 mL/min (severe renal impairment) as a contraindication for use. The US-approved dosage for severe renal impairment was derived during the approval phase of dabigatran using a simulation pharmacokinetic model [62,63]. The dosage was estimated by pharmacokinetic simulation to provide similar C_max and C_min concentrations compared to the 150 mg twice-daily dosage in moderate renal impairment. Compared to patients with CrCl ≥ 80 mL/min, there was a 1.29- and a 1.47-fold increase in dabigatran trough plasma concentration in the CrCl 50–80 mL/min patients and the CrCl 30–50 mL/min patients, respectively. There have been many postmarketing reports of hemorrhage with dabigatran [36,84,85]. Although reporting bias is likely due to the novelty of the agent, clinicians may take key clinical pearls away from these reports. Patients often had risk factors, including low body weight, renal impairment, and polypharmacy with interacting drugs (eg, amiodarone). These risk factors are also important with the other DOACs.

A subgroup analysis of ROCKET-AF evaluating rivaroxaban 15 mg daily in patients with a CrCl of 30–49 mL/min did not identify any differences in endpoints with the exception of fatal bleeding, which occurred less often with rivaroxaban (0.28%/yr vs. 0.74%/yr; P = 0.047) [64].

Monitoring of renal function is essential to mitigate the risk of drug accumulation. Clinicians should consider obtaining a baseline renal assessment with annual reassessments in patients with normal (CrCl ≥ 80 mL/min) or mild (CrCl 50–79 mL/min) renal impairment, and 2 to 3 times per year in patients with moderate (CrCl 30–49 mL/min) renal impairment [65]. A summary of renal dose adjustments for DOAC therapy may be found in Table 5 [56–59].

In addition to renal function, hepatic impairment can also affect the metabolism of anticoagulants. Severe hepatic impairment can lead to prolonged PT. Therefore, patients who have liver dysfunction and are treated with anticoagulation have increased risk of hemorrhagic events. Large pivotal trials on the key indications of dabigatran, apixaban, and rivaroxaban excluded patients with significant signs of hepatic impairment. Table 5 provides dosing recommendations for the different DOACs in the setting of hepatic impairment [56–59].

Polypharmacy And The Potential For Adverse Consequences

Costs And Cost-Effectiveness of DOACS

With the high burden of AF and the aging population, analysis of cost and value is an important consideration [76]. There are limited publications comparing the cost-effectiveness between the anticoagulation options. However, numerous cost-effectiveness studies have evaluated the individual DOACs [71–79]. Overall, the studies suggest that the DOACs are a cost-effective alternative to warfarin in the general and elderly populations. One analysis reported that dabigatran may not be cost-effective in patients with a low CHADS2 score (≤ 2) [71].

Harrington et al [80] compared the cost-effectiveness of dabigatran, rivaroxaban, and apixaban versus warfarin. This cost-effectiveness study used published clinical trial data to build a decision model, and results indicated that for patients ≥ 70 years of age with an increased risk for stroke, normal renal function, and no previous contraindications to anticoagulant therapy, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were cost-effective substitutes for warfarin for the prevention of stroke in nonvalvular AF [80]. Apixaban was the preferred anticoagulant for their hypothetical cohort of 70-year-old patients with nonvalvular AF, as it was most likely to be the cost-effective treatment option at all willing-to-pay thresholds > $40,000 per quality-adjusted life-year gained [76,81].

Prescription costs may vary depending on payor and level of insurance. If a patient does not have prescription insurance, the annual price of generic warfarin is roughly $200 to $360, depending on dosage. Approximate annual costs for the DOACs are greater than 20 times the cost of warfarin (apixaban $4500, dabigatran $4500, and rivaroxaban $4800) [82]. However, most patients on these medications are over 65 years old and have prescription coverage through Medicare Part D. Of note, patients may have more of a burden if or when they reach the “donut hole” coverage gap. Currently, once patients spend $2960 (for 2015) and $3310 (for 2016) on covered drugs they will fall into the donut hole unless they qualify for additional assistance. At this point Medicare Part D will reimburse 45% of the cost of the newer anticoagulants since generics are currently unavailable. As a result, individual affordability may become an issue. Further complicating the scenario is the inability to apply coupon and rebate cards in the setting of government-funded prescription coverage. Clinicians should discuss these issues with their patients to help select the most valuable therapy.

Conclusions And Recommendations

Corresponding author: Luigi Brunetti, PharmD, MPH, Rutgers University, 160 Frelinghuysen Rd, Piscataway, NJ 08854, [email protected].

1. About a year ago, this 40-year-old man developed scaling on the distal one-third of his thumbnail. The condition began to worsen, leaving most of his thumb covered by thick adherent white scales on a pinkish base with sharply defined margins. The adjacent thumbnail has focal areas of pitting in the nail plate, as well as yellowish discoloration on the distal edge.

Diagnosis: The most likely diagnosis is psoriasis, which can manifest with localized involvement.

For more information, see “Thumb: Scaling with Pitted Nail Plate.” Clin Rev. 2013 March;23(3):11.

For the next photograph, proceed to the next page >>

2. A 10-year-old girl has had patches of dry skin appearing and disappearing on her arms, legs, and neck for years. Recently manifested on her extensor forearm is an annular, distinctly salmon-pink plaque with a tenacious white scale. Scaly areas are observed in both postauricular sulci; several tiny pits are seen on her fingernails.

Diagnosis: It would be difficult to imagine a more clear-cut case of psoriasis, not only manifesting with a classic plaque on the extensor forearm but also with corroboratory stigmata behind the ears and classic fingernail pits.

It’s helpful to know that psoriasis affects almost 3% of the white population in the United States, meaning that you will see it with considerable frequency. It would also help if you knew the diagnosis can be corroborated by identification of other, lesser known features.

For more information, see “Girl, 10, Asks Tough Questions About Skin Problem.” Clin Rev. 2015;25(8):W2.

For the next photograph, proceed to the next page >>

3. A 62-year-old woman complained bitterly of itching on the soles of both feet. Both insteps are covered with discrete, confluent papules and tiny pustules on an erythematous and hyperpigmented (brown), sharply demarcated, and highly symmetrical base. No such lesions appear elsewhere.

Diagnosis: Palmoplantar pustulosis is the term most often used to describe a fairly common form of psoriasis typified by this case. Many patients are genetically predisposed to psoriasis, but they may require a trigger to set it off, such as strep infection or occasionally, medication. Notable among the latter are the b-blockers and lithium. Stress is often involved as well.

The bilateral symmetrical involvement of both insteps is highly suggestive of this diagnosis, which often also affects either peripheral or central palms. A secondary form of neurodermatitis (itch–scratch–itch cycle) can follow, complicating the picture and perpetuating the problem.

For more information, see “Pruritic Rash on Both Soles.” Clin Rev. 2012 Jan;22(1).

For the next photograph, proceed to the next page >>

4. The patient presented with fiery red, burned looking skin covering ≥90% of the skin surface and shedding in large "sheets" instead of smaller scales. He was monitored for fever, systemic symptoms, and multiorgan dysfunction.

Photo courtesy of Peter A. Lio, MD, and Alisa McQueen, MD

Diagnosis: This patient was given a diagnosis of erythrodermic psoriasis. This form of psoriasis can be life-threatening.

For more information, see “Derm emergencies— detecting early signs of trouble.” J Fam Pract. 2012 February;61(2):71-78. 

For the next photograph, proceed to the next page >>

5. This 18-year-old patient had multiple, erythematous papules and plaques with a fine scale over her face, neck, trunk, and lower legs. She noted that the eruption had developed after a sore throat 2 weeks earlier and that it was itchy.

Photos courtesy of David A. Boyd, MD

Diagnosis: Guttate psoriasis was diagnosed in this patient based on her history and physical exam, a throat culture that was positive for group A beta-hemolytic streptococci, and blood work that showed an elevated antistreptolysin O titer. Further confirmation was obtained via punch biopsy.

Guttate psoriasis is a fairly uncommon form of psoriasis, affecting approximately 2% of patients with psoriasis.¹ It is characterized by the abrupt onset of pruritic, salmon-pink 1- to 10-mm droplike lesions with fine scale that may spread to the face, but spare the palms and soles. It’s uncommon for this sub-type of psoriasis to involve the nails.

Guttate psoriasis affects individuals younger than 30; there appears to be no gender predilection.² The rash usually appears 2 to 3 weeks after an upper respiratory group A beta-hemolytic streptococci infection. Although less common, there have also been reports of guttate psoriasis associated with perianal streptococcal disease.²

1. Habif TP. Clinical Dermatology. 4th ed. St. Louis, Mo: Mosby; 2004;209-239
2. Honig PJ. Guttate psoriasis associated with perianal streptococcal disease. J Pediatr. 1988;113:1037-1039.

For more information, see “Teen with a diffuse erythematous, pruritic eruption.” J Fam Pract. 2011 January;60(1):37-39.

1. About a year ago, this 40-year-old man developed scaling on the distal one-third of his thumbnail. The condition began to worsen, leaving most of his thumb covered by thick adherent white scales on a pinkish base with sharply defined margins. The adjacent thumbnail has focal areas of pitting in the nail plate, as well as yellowish discoloration on the distal edge.

Diagnosis: The most likely diagnosis is psoriasis, which can manifest with localized involvement.

For more information, see “Thumb: Scaling with Pitted Nail Plate.” Clin Rev. 2013 March;23(3):11.

For the next photograph, proceed to the next page >>

2. A 10-year-old girl has had patches of dry skin appearing and disappearing on her arms, legs, and neck for years. Recently manifested on her extensor forearm is an annular, distinctly salmon-pink plaque with a tenacious white scale. Scaly areas are observed in both postauricular sulci; several tiny pits are seen on her fingernails.

Diagnosis: It would be difficult to imagine a more clear-cut case of psoriasis, not only manifesting with a classic plaque on the extensor forearm but also with corroboratory stigmata behind the ears and classic fingernail pits.

It’s helpful to know that psoriasis affects almost 3% of the white population in the United States, meaning that you will see it with considerable frequency. It would also help if you knew the diagnosis can be corroborated by identification of other, lesser known features.

For more information, see “Girl, 10, Asks Tough Questions About Skin Problem.” Clin Rev. 2015;25(8):W2.

For the next photograph, proceed to the next page >>

3. A 62-year-old woman complained bitterly of itching on the soles of both feet. Both insteps are covered with discrete, confluent papules and tiny pustules on an erythematous and hyperpigmented (brown), sharply demarcated, and highly symmetrical base. No such lesions appear elsewhere.

Diagnosis: Palmoplantar pustulosis is the term most often used to describe a fairly common form of psoriasis typified by this case. Many patients are genetically predisposed to psoriasis, but they may require a trigger to set it off, such as strep infection or occasionally, medication. Notable among the latter are the b-blockers and lithium. Stress is often involved as well.

The bilateral symmetrical involvement of both insteps is highly suggestive of this diagnosis, which often also affects either peripheral or central palms. A secondary form of neurodermatitis (itch–scratch–itch cycle) can follow, complicating the picture and perpetuating the problem.

For more information, see “Pruritic Rash on Both Soles.” Clin Rev. 2012 Jan;22(1).

For the next photograph, proceed to the next page >>

4. The patient presented with fiery red, burned looking skin covering ≥90% of the skin surface and shedding in large "sheets" instead of smaller scales. He was monitored for fever, systemic symptoms, and multiorgan dysfunction.

Photo courtesy of Peter A. Lio, MD, and Alisa McQueen, MD

Diagnosis: This patient was given a diagnosis of erythrodermic psoriasis. This form of psoriasis can be life-threatening.

For more information, see “Derm emergencies— detecting early signs of trouble.” J Fam Pract. 2012 February;61(2):71-78. 

For the next photograph, proceed to the next page >>

5. This 18-year-old patient had multiple, erythematous papules and plaques with a fine scale over her face, neck, trunk, and lower legs. She noted that the eruption had developed after a sore throat 2 weeks earlier and that it was itchy.

Photos courtesy of David A. Boyd, MD

Diagnosis: Guttate psoriasis was diagnosed in this patient based on her history and physical exam, a throat culture that was positive for group A beta-hemolytic streptococci, and blood work that showed an elevated antistreptolysin O titer. Further confirmation was obtained via punch biopsy.

Guttate psoriasis is a fairly uncommon form of psoriasis, affecting approximately 2% of patients with psoriasis.¹ It is characterized by the abrupt onset of pruritic, salmon-pink 1- to 10-mm droplike lesions with fine scale that may spread to the face, but spare the palms and soles. It’s uncommon for this sub-type of psoriasis to involve the nails.

Guttate psoriasis affects individuals younger than 30; there appears to be no gender predilection.² The rash usually appears 2 to 3 weeks after an upper respiratory group A beta-hemolytic streptococci infection. Although less common, there have also been reports of guttate psoriasis associated with perianal streptococcal disease.²

1. Habif TP. Clinical Dermatology. 4th ed. St. Louis, Mo: Mosby; 2004;209-239
2. Honig PJ. Guttate psoriasis associated with perianal streptococcal disease. J Pediatr. 1988;113:1037-1039.

For more information, see “Teen with a diffuse erythematous, pruritic eruption.” J Fam Pract. 2011 January;60(1):37-39.

1. About a year ago, this 40-year-old man developed scaling on the distal one-third of his thumbnail. The condition began to worsen, leaving most of his thumb covered by thick adherent white scales on a pinkish base with sharply defined margins. The adjacent thumbnail has focal areas of pitting in the nail plate, as well as yellowish discoloration on the distal edge.

Diagnosis: The most likely diagnosis is psoriasis, which can manifest with localized involvement.

For more information, see “Thumb: Scaling with Pitted Nail Plate.” Clin Rev. 2013 March;23(3):11.

For the next photograph, proceed to the next page >>

2. A 10-year-old girl has had patches of dry skin appearing and disappearing on her arms, legs, and neck for years. Recently manifested on her extensor forearm is an annular, distinctly salmon-pink plaque with a tenacious white scale. Scaly areas are observed in both postauricular sulci; several tiny pits are seen on her fingernails.

Diagnosis: It would be difficult to imagine a more clear-cut case of psoriasis, not only manifesting with a classic plaque on the extensor forearm but also with corroboratory stigmata behind the ears and classic fingernail pits.

It’s helpful to know that psoriasis affects almost 3% of the white population in the United States, meaning that you will see it with considerable frequency. It would also help if you knew the diagnosis can be corroborated by identification of other, lesser known features.

For more information, see “Girl, 10, Asks Tough Questions About Skin Problem.” Clin Rev. 2015;25(8):W2.

For the next photograph, proceed to the next page >>

3. A 62-year-old woman complained bitterly of itching on the soles of both feet. Both insteps are covered with discrete, confluent papules and tiny pustules on an erythematous and hyperpigmented (brown), sharply demarcated, and highly symmetrical base. No such lesions appear elsewhere.

Diagnosis: Palmoplantar pustulosis is the term most often used to describe a fairly common form of psoriasis typified by this case. Many patients are genetically predisposed to psoriasis, but they may require a trigger to set it off, such as strep infection or occasionally, medication. Notable among the latter are the b-blockers and lithium. Stress is often involved as well.

The bilateral symmetrical involvement of both insteps is highly suggestive of this diagnosis, which often also affects either peripheral or central palms. A secondary form of neurodermatitis (itch–scratch–itch cycle) can follow, complicating the picture and perpetuating the problem.

For more information, see “Pruritic Rash on Both Soles.” Clin Rev. 2012 Jan;22(1).

For the next photograph, proceed to the next page >>

4. The patient presented with fiery red, burned looking skin covering ≥90% of the skin surface and shedding in large "sheets" instead of smaller scales. He was monitored for fever, systemic symptoms, and multiorgan dysfunction.

Photo courtesy of Peter A. Lio, MD, and Alisa McQueen, MD

Diagnosis: This patient was given a diagnosis of erythrodermic psoriasis. This form of psoriasis can be life-threatening.

For more information, see “Derm emergencies— detecting early signs of trouble.” J Fam Pract. 2012 February;61(2):71-78. 

For the next photograph, proceed to the next page >>

5. This 18-year-old patient had multiple, erythematous papules and plaques with a fine scale over her face, neck, trunk, and lower legs. She noted that the eruption had developed after a sore throat 2 weeks earlier and that it was itchy.

Photos courtesy of David A. Boyd, MD

Diagnosis: Guttate psoriasis was diagnosed in this patient based on her history and physical exam, a throat culture that was positive for group A beta-hemolytic streptococci, and blood work that showed an elevated antistreptolysin O titer. Further confirmation was obtained via punch biopsy.

Guttate psoriasis is a fairly uncommon form of psoriasis, affecting approximately 2% of patients with psoriasis.¹ It is characterized by the abrupt onset of pruritic, salmon-pink 1- to 10-mm droplike lesions with fine scale that may spread to the face, but spare the palms and soles. It’s uncommon for this sub-type of psoriasis to involve the nails.

Guttate psoriasis affects individuals younger than 30; there appears to be no gender predilection.² The rash usually appears 2 to 3 weeks after an upper respiratory group A beta-hemolytic streptococci infection. Although less common, there have also been reports of guttate psoriasis associated with perianal streptococcal disease.²

1. Habif TP. Clinical Dermatology. 4th ed. St. Louis, Mo: Mosby; 2004;209-239
2. Honig PJ. Guttate psoriasis associated with perianal streptococcal disease. J Pediatr. 1988;113:1037-1039.

For more information, see “Teen with a diffuse erythematous, pruritic eruption.” J Fam Pract. 2011 January;60(1):37-39.

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

[email protected]

On Twitter @maryjodales

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

[email protected]

On Twitter @maryjodales

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

[email protected]

On Twitter @maryjodales

ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.

Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).

The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.

Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.

“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”

To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.

[email protected]

ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.

Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).

The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.

Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.

“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”

To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.

[email protected]

ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.

Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).

The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.

Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.

“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”

To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.

[email protected]

NEW YORK - Restenosis rates are similar one year after implantation of an everolimus-eluting bioresorbable vascular scaffold or an everolimus-eluting metallic stent, but the scaffold has a higher risk of device thrombosis within 30 days, a new meta-analysis shows.

The meta-analysis suggests that the two interventions have a "similar requirement of repeat revascularization out to 1-year follow-up, despite inferior angiographic performance," first author Dr. Salvatore Cassese said by email.

This higher risk of stent thrombosis, twice as high with the bioresorbable device compared with the metallic stent after one year, "is somewhat surprising," said Dr. Cassese, of the Technical University of Munich's German Heart Center Munich. "The higher risk of scaffold thrombosis in relatively simple clinical (lesion) settings represents the new important finding showed by this meta-analysis."

A number of recently completed randomized trials showed comparable mid-term outcomes with the two devices, but data from routine clinical practice suggests a "somewhat higher rate of adverse events" with the bioresorbable scaffold, he said.

Most randomized trials comparing the two types of devices were small and not adequately powered to assess clinical endpoints, the authors noted. For their meta-analysis, they identified six trials involving 3,738 patients (mainly men, median age 62.3 years) that met their inclusion criteria (randomized design, an analysis by intention to treat, and a follow-up of at least six months).

The meta-analysis included 2,337 patients who received a bioresorbable scaffold and 1,401 who received a metallic stent. Median follow-up was 12 months.

Both groups had a 3% rate of target lesion revascularization, the primary efficacy outcome, the researchers noted in a report online November 16 in The Lancet.

The risk of the primary safety outcome, definite or probable stent/scaffold thrombosis, was significantly higher for those treated with a bioresorbable scaffold compared with those who received a metallic stent (1.3% versus 0.5%; odds ratio, 1.99), with the highest risk within 30 days after implantation.

In-device late lumen loss was also significantly greater in lesions treated with the bioresorbable device compared with the metallic stent.

Risk of myocardial infarction appeared to be higher in patients with the bioresorbable scaffolds than in those with metallic stents, but the difference was not statistically significant (5.2% versus 3.5%, p=0.06). The groups had similar rates of target lesion failure and risk of death.

The authors noted that their finding of at least similar efficacy of the bioresorbable scaffold versus the existing best-in-class drug-eluting stent at 12 months was achieved in a highly selected population that included mainly stable patients with single de-novo non-complex target lesions and excluded patients who had a higher risk for device failure.

Two large-scale randomized trials are under way that are expected to shed more light on the devices' relative efficacy in higher-risk populations.

Although the study's findings "should heighten concerns about the current generation of bioresorbable vascular scaffold technology, they should by no means be interpreted to mean that bioresorbable scaffolds are not worth pursuing," noted an editorial that accompanied the new meta-analysis. "Just as with first-generation drug-eluting stents, a complete understanding of the limitations of such technology is necessary before further advancements can be made."

"Little information appears available regarding the incidence of symptoms of angina in the comparison groups," Dr. Richard Chazal, who was not involved in the study, said in an email.

"This is important, as the principal utility of stents in stable patients is the relief of such symptoms," noted Dr. Chazal, president-elect of the American College of Cardiology and medical director of the Lee Memorial Health Systems' Heart and Vascular Institute in Fort Myers, Fla.

"Disappearing" bioresorbable scaffolds are viewed as a possible solution to potential problems of leaving metallic stents permanently inside a coronary vessel. These problems include impairing the function of the wall of the artery and limiting future options for treating the artery, especially with a bypass operation, explained Dr. Chazal.

Emergence of their anticipated benefit over metallic stents is expected several years after implantation, when elution of the anti-restenotic drug has stopped and the scaffold has dissolved.

"Longer-term follow-up will be needed to clarify whether these newer devices provide hoped-for advantages over metallic stents, or whether the early issues with thrombosis/clotting and vessel narrowing eventually results in more clinical problems," Dr. Chazal said.

The study had no funding source. Two of the 10 coauthors reported receiving fees from stent manufacturers or holding patents related to drug-eluting stent technologies, "outside the submitted work." A third coauthor is a member of the advisory board of Abbott, which includes a division that makes an everolimus-eluting bioresorbable vascular scaffold.

NEW YORK - Restenosis rates are similar one year after implantation of an everolimus-eluting bioresorbable vascular scaffold or an everolimus-eluting metallic stent, but the scaffold has a higher risk of device thrombosis within 30 days, a new meta-analysis shows.

The meta-analysis suggests that the two interventions have a "similar requirement of repeat revascularization out to 1-year follow-up, despite inferior angiographic performance," first author Dr. Salvatore Cassese said by email.

This higher risk of stent thrombosis, twice as high with the bioresorbable device compared with the metallic stent after one year, "is somewhat surprising," said Dr. Cassese, of the Technical University of Munich's German Heart Center Munich. "The higher risk of scaffold thrombosis in relatively simple clinical (lesion) settings represents the new important finding showed by this meta-analysis."

A number of recently completed randomized trials showed comparable mid-term outcomes with the two devices, but data from routine clinical practice suggests a "somewhat higher rate of adverse events" with the bioresorbable scaffold, he said.

Most randomized trials comparing the two types of devices were small and not adequately powered to assess clinical endpoints, the authors noted. For their meta-analysis, they identified six trials involving 3,738 patients (mainly men, median age 62.3 years) that met their inclusion criteria (randomized design, an analysis by intention to treat, and a follow-up of at least six months).

The meta-analysis included 2,337 patients who received a bioresorbable scaffold and 1,401 who received a metallic stent. Median follow-up was 12 months.

Both groups had a 3% rate of target lesion revascularization, the primary efficacy outcome, the researchers noted in a report online November 16 in The Lancet.

The risk of the primary safety outcome, definite or probable stent/scaffold thrombosis, was significantly higher for those treated with a bioresorbable scaffold compared with those who received a metallic stent (1.3% versus 0.5%; odds ratio, 1.99), with the highest risk within 30 days after implantation.

In-device late lumen loss was also significantly greater in lesions treated with the bioresorbable device compared with the metallic stent.

Risk of myocardial infarction appeared to be higher in patients with the bioresorbable scaffolds than in those with metallic stents, but the difference was not statistically significant (5.2% versus 3.5%, p=0.06). The groups had similar rates of target lesion failure and risk of death.

The authors noted that their finding of at least similar efficacy of the bioresorbable scaffold versus the existing best-in-class drug-eluting stent at 12 months was achieved in a highly selected population that included mainly stable patients with single de-novo non-complex target lesions and excluded patients who had a higher risk for device failure.

Two large-scale randomized trials are under way that are expected to shed more light on the devices' relative efficacy in higher-risk populations.

Although the study's findings "should heighten concerns about the current generation of bioresorbable vascular scaffold technology, they should by no means be interpreted to mean that bioresorbable scaffolds are not worth pursuing," noted an editorial that accompanied the new meta-analysis. "Just as with first-generation drug-eluting stents, a complete understanding of the limitations of such technology is necessary before further advancements can be made."

"Little information appears available regarding the incidence of symptoms of angina in the comparison groups," Dr. Richard Chazal, who was not involved in the study, said in an email.

"This is important, as the principal utility of stents in stable patients is the relief of such symptoms," noted Dr. Chazal, president-elect of the American College of Cardiology and medical director of the Lee Memorial Health Systems' Heart and Vascular Institute in Fort Myers, Fla.

"Disappearing" bioresorbable scaffolds are viewed as a possible solution to potential problems of leaving metallic stents permanently inside a coronary vessel. These problems include impairing the function of the wall of the artery and limiting future options for treating the artery, especially with a bypass operation, explained Dr. Chazal.

Emergence of their anticipated benefit over metallic stents is expected several years after implantation, when elution of the anti-restenotic drug has stopped and the scaffold has dissolved.

"Longer-term follow-up will be needed to clarify whether these newer devices provide hoped-for advantages over metallic stents, or whether the early issues with thrombosis/clotting and vessel narrowing eventually results in more clinical problems," Dr. Chazal said.

The study had no funding source. Two of the 10 coauthors reported receiving fees from stent manufacturers or holding patents related to drug-eluting stent technologies, "outside the submitted work." A third coauthor is a member of the advisory board of Abbott, which includes a division that makes an everolimus-eluting bioresorbable vascular scaffold.

NEW YORK - Restenosis rates are similar one year after implantation of an everolimus-eluting bioresorbable vascular scaffold or an everolimus-eluting metallic stent, but the scaffold has a higher risk of device thrombosis within 30 days, a new meta-analysis shows.

The meta-analysis suggests that the two interventions have a "similar requirement of repeat revascularization out to 1-year follow-up, despite inferior angiographic performance," first author Dr. Salvatore Cassese said by email.

This higher risk of stent thrombosis, twice as high with the bioresorbable device compared with the metallic stent after one year, "is somewhat surprising," said Dr. Cassese, of the Technical University of Munich's German Heart Center Munich. "The higher risk of scaffold thrombosis in relatively simple clinical (lesion) settings represents the new important finding showed by this meta-analysis."

A number of recently completed randomized trials showed comparable mid-term outcomes with the two devices, but data from routine clinical practice suggests a "somewhat higher rate of adverse events" with the bioresorbable scaffold, he said.

Most randomized trials comparing the two types of devices were small and not adequately powered to assess clinical endpoints, the authors noted. For their meta-analysis, they identified six trials involving 3,738 patients (mainly men, median age 62.3 years) that met their inclusion criteria (randomized design, an analysis by intention to treat, and a follow-up of at least six months).

The meta-analysis included 2,337 patients who received a bioresorbable scaffold and 1,401 who received a metallic stent. Median follow-up was 12 months.

Both groups had a 3% rate of target lesion revascularization, the primary efficacy outcome, the researchers noted in a report online November 16 in The Lancet.

The risk of the primary safety outcome, definite or probable stent/scaffold thrombosis, was significantly higher for those treated with a bioresorbable scaffold compared with those who received a metallic stent (1.3% versus 0.5%; odds ratio, 1.99), with the highest risk within 30 days after implantation.

In-device late lumen loss was also significantly greater in lesions treated with the bioresorbable device compared with the metallic stent.

Risk of myocardial infarction appeared to be higher in patients with the bioresorbable scaffolds than in those with metallic stents, but the difference was not statistically significant (5.2% versus 3.5%, p=0.06). The groups had similar rates of target lesion failure and risk of death.

The authors noted that their finding of at least similar efficacy of the bioresorbable scaffold versus the existing best-in-class drug-eluting stent at 12 months was achieved in a highly selected population that included mainly stable patients with single de-novo non-complex target lesions and excluded patients who had a higher risk for device failure.

Two large-scale randomized trials are under way that are expected to shed more light on the devices' relative efficacy in higher-risk populations.

Although the study's findings "should heighten concerns about the current generation of bioresorbable vascular scaffold technology, they should by no means be interpreted to mean that bioresorbable scaffolds are not worth pursuing," noted an editorial that accompanied the new meta-analysis. "Just as with first-generation drug-eluting stents, a complete understanding of the limitations of such technology is necessary before further advancements can be made."

"Little information appears available regarding the incidence of symptoms of angina in the comparison groups," Dr. Richard Chazal, who was not involved in the study, said in an email.

"This is important, as the principal utility of stents in stable patients is the relief of such symptoms," noted Dr. Chazal, president-elect of the American College of Cardiology and medical director of the Lee Memorial Health Systems' Heart and Vascular Institute in Fort Myers, Fla.

"Disappearing" bioresorbable scaffolds are viewed as a possible solution to potential problems of leaving metallic stents permanently inside a coronary vessel. These problems include impairing the function of the wall of the artery and limiting future options for treating the artery, especially with a bypass operation, explained Dr. Chazal.

Emergence of their anticipated benefit over metallic stents is expected several years after implantation, when elution of the anti-restenotic drug has stopped and the scaffold has dissolved.

"Longer-term follow-up will be needed to clarify whether these newer devices provide hoped-for advantages over metallic stents, or whether the early issues with thrombosis/clotting and vessel narrowing eventually results in more clinical problems," Dr. Chazal said.

The study had no funding source. Two of the 10 coauthors reported receiving fees from stent manufacturers or holding patents related to drug-eluting stent technologies, "outside the submitted work." A third coauthor is a member of the advisory board of Abbott, which includes a division that makes an everolimus-eluting bioresorbable vascular scaffold.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.