From the MetroHealth System, Cleveland, OH.

Abstract

• Objective: To describe risk factors for unplanned extubation (UE) among critically ill adults requiring mechanical ventilation and to identify strategies to reduce the occurrence of this adverse event.
• Methods: Review of the literature.
• Results: Inadvertent removal of an endotracheal tube, or a UE, occurs in 7% to 22.5% of mechanically ventilated adult patients and is often due to deliberate patient removal. Despite the multitude of research examining risk factors and predictors of UE, rates have remained unchanged for the past 2 decades. Risk factors can be classified by intensive care unit (ICU) type, including medical ICUs, surgical ICUs, and mixed medical-surgical ICUs. The majority of risk factors for UEs across ICUs may be amenable to changes in unit processes, such as programs for agitation management, use of weaning protocols, increased surveillance of patients, and ongoing education for patients and health care staff.
• Conclusion: Prevention of UE remains an elusive target. Changes in unit processes that target identified risk factors may be an effective method to decrease prevalence of UE.

Unplanned extubation (UE) is the inadvertent removal of an endotracheal tube, either by a patient (deliberate self-extubation), or by a member of the health care team providing routine care such as repositioning, suctioning, or procedures (accidental extubation). Approximately 7% to 22.5% of mechanically ventilated patients in the intensive care unit (ICU) experience UE [1–7]. Estimates are likely higher, as current regulatory and accreditation standards do not include mandatory reporting of this event. Despite numerous studies investigating risk factors associated with UE, it remains a prevalent problem with adverse outcomes for patients and hospitals. The purpose of this review is to provide a summary of the literature on risk factors for UE, review effects on patient and organizational outcomes, and identify evidence-based strategies for reducing occurrence of UE among mechanically ventilated patients.

Prevalence of Unplanned Exubation

There is substantial heterogeneity in how UE is calculated and reported in the research literature. UE is calculated as the number of UE events per 100 or 1000 patient days, or the number of UE per total ventilator days. Rates of UE are also reported as the proportion of patients who experience UE out of all intubated patients over a set time period [8]. Despite efforts aimed at mitigating risk factors for UE, rates have remained static over the past 2 decades. Reported UE rates from 1994–2002 were 2.6% to 14% [3,6,9–11], while rates from 2004–2014 ranged from 1% to 22% [3–5,8,12–15]. Interventions utilizing a multidisciplinary approach have been implemented with the aim of decreasing UE, yet few have proven successful on improving rates nationally.

Unplanned self-extubation by the patient (deliberate self-extubation) is the most common type of UE [3,10,12,16–18]. A multicenter trial of 426 patients from 11 medical centers indicates that 46 patients experienced UE, with 36 of these (78.2%) caused by patient self-extubation [6]. Prospective single-site studies report similar or higher estimates of patient self-extubation, ranging from 75.8% to 91.7% [3,5], while a multisite study of 10,112 patients revealed 32 of 35 UE (91.4%) were due to patient self-extubation [12]. Similarly, a 4-year analysis of 85 UEs reported 82 incidences (96.5%) were a result of deliberate patient removal [13]. Patients either physically pull out the endotracheal tube or use their tongue or coughing/gagging maneuvers to displace or intentionally remove the endotracheal tube [5]. Only 3% to 8% of UEs are caused by inadvertent removal by health care staff [3,5,12,13].

Effects on Patient and Organizational Outcomes

Regardless of the cause of the UE, there are adverse consequences for both patients and hospitals. Some patients who experience UE have higher rates of in-hospital mortality; however, this is often due to contributing factors associated with severity of injury, the need for reintubation, and underlying chronic diseases [13]. Patients who experience accidental UE have higher incidence of nosocomial pneumonia (27.6% vs. 138%, P = 0.002) [11], longer duration of mechanical ventilation, and increased length of stay (LOS) [7,13]. While some studies report UE can result in serious consequences such as respiratory distress, hypoxia [13], and even death [6,12], others report lower mortality and length of stay when UE occurs, likely due to the fact that many patients are ready for liberation from mechanical ventilation at the time of UE [5,15].

Despite the emergent nature of UE, not all patients experience immediate reintubation. Many instances of UE occur during patient weaning trials or in preparation for planned extubations [5,11], which explains why only 10% to 60% of patients require reintubation [3,5,10,11,15,19,20]. When reintubation is necessary, it results in increased number of ventilator days [10,11], and increased ICU and hospital LOS [1,11]. There is little evidence directly linking reintubation with in-hospital mortality; however, it can cause serious complications such as hypotension, hypertension, arrhythmias, and airway trauma [21]. For hospitals and health care organizations, the need for reintubation results in increased hospital costs, estimated to be $1000 per reintubation event [17,22]. This estimate does not take into account additional costs incurred with increased ICU care, longer periods of mechanical ventilation, and increased LOS. Estimates of these additional costs in pediatric patients are approximately $36,000 [23]. Costs are likely higher in adult patients, due to multiple comorbidities that often accompany the need for mechanical ventilation, as well as increased pharmacy, lab, and diagnostic charges [1].

Risk Factors for Unplanned Extubation

Medical ICU Risk Factors

MICUs traditionally have the highest rates of UE [4,8]. Data from a national prevalence study indicated that there were 23.4 episodes of UE in MICUs per 1000 ventilator days [4]. Approximately 9.5% to 15% of all ventilated patients in the MICU experience UE [4,5,8]. Patients in the MICU who require mechanical ventilation often have complex chronic illness with underlying respiratory disease, which can result in prolonged periods of ventilation and increased risk of UE. Specific risk factors investigated in UE research include patient specific factors (age, gender, diagnosis, comorbidities, agitation, level of consciousness, laboratory values), ventilatory factors (ventilator type and setting, type of tracheal tube, method of tube fixation), as well as type of sedation and use of protocols [5,6,24]. Surprisingly, few variables emerge as significant risk factors for UE among MICU patients. Risk factors associated with UE have included male gender [24], presence of chronic obstructive pulmonary disease (COPD) [24], increased level of consciousness [25], and use of weaning protocols [5]. While gender, COPD, and level of consciousness increase risk of UE, the presence of weaning protocols is shown to decrease risk of UE [5]. Although UE are reported most often in MICUs, few risk factors consistently emerge for this specific cohort, making definitive recommendations for prevention of UE difficult.

Surgical ICU Risk Factors

The prevalence of UE for mechanically ventilated patients in the SICU tend to be lower than those for MICU cohorts. Prevalence of UE in the SICU is reported at 1.41 episodes per 100 ventilator days [13], or 6.8 episodes per 1000 ventilator days [4]. Percentages of UE in the SICU range from 2% to 6% [4,8,19]. Similar to MICU patients, critically ill patients in the SICU often have specific risk factors placing them at risk for UE. Causative factors examined in research studies with this population include gender, age, sedation scale scores, need for reintubation, time from intubation to extubation, use of sedatives/analgesics, restraints, ICU nurse experience, location of staff at time of UE, and criteria for extubation [17,19]. Similar to MICU cohorts, few variables are identified as predictors of UE. Significant predictors include use of restraints, decreased sedation [17], and meeting criteria for extubation [19]. Among patients who experienced an UE, 87% were restrained at the time of the UE [17], and most had low levels of sedation (mean Ramsay sedation scale score = 2.42 in the hour preceding the UE). Approximately 64% of patients who experienced UE met criteria for planned extubation and did not require re-intubation [19], suggesting many patients were essentially ready for planned extubation.

Mixed ICU Risk Factors

The majority of research investigating risk factors for UE is conducted within medical-surgical or mixed/general ICUs. The prevalence of UE within this type of unit is reported at 1.59 episodes per 100 patient days [6], or approximately 2% to 10% [4,6,7]. Among this population, potential risk factors are similar to those included in solely MICU or SICU studies. Because of the high number of studies investigating UE in a mixed ICU setting, there are significantly more variables included in as potential risk factors. Variables include patient age, gender, admission diagnosis, injury severity using Acute Physiological and Chronic Health Evaluation (APACHE II), ICU and hospital LOS, patient level of consciousness, agitation, days of mechanical ventilation, ventilator settings, nosocomial infection, sedation, physical restraints, vital signs [7,14,26], laboratory values, medication types, and body mass index [15,26]. One study also included time of UE and ICU nurse level of experience [3]. Among all factors, several were significant predictors of UE: male gender [15], decreased sedation and increased level of consciousness [8], agitation [3,19,26], use of restraints [3,7], sedation practices (particularly use of benzodiazapines) [3,7,15,26,27], lack of strong tube fixation, absence of IV sedation, and orotracheal intubation [6]. UE were more likely to occur on the night shift and among staff that included nurses with fewer years of experience [3]. Many episodes of UE occurred during weaning [10] or among patients who could communicate and were alert [3]. One study reports 57% of patients who intentionally self-extubated explained they simply removed the tube because it was uncomfortable [3].

Strategies for Reducing Adverse Events

Agitation Management

The majority of studies cited agitation, altered level of consciousness, or inadequate sedation as risk factors for UE [3,6–8,15,17,18,25,26,28,29]. These factors directly impact restraint use, another common risk factor for UE [3,7,17]. A key recommendation for agitation management is to identify the source of agitation, which is often caused by delirium onset in the ICU [30–32]. Prevalence of delirium in the ICU ranges from 20% to 80% [33–35]. ICU patients are at high risk for delirium due to sleep deprivation, older age, restraints, abnormal lab values, medications, infection, and respiratory complications [31]. Treatment for delirium centers on prevention, early recognition, interdisciplinary and pharmacologic protocols, increased nursing presence, and use of short-acting sedation when necessary [30–32,36]. While there is no research specifically linking delirium to UE, a quality analysis of risk factors present at the time of UE using bow-tie analysis methods identified delirium as a key factor present in the majority of UE cases [36]. It is possible that agitation reported in other studies investigating risk factors for UE may actually be reflective of underlying delirium. Routine screening using validated tools, such as the Confusion Assessment Method-ICU (CAM-ICU) [37] would aid in early detection and management of delirium, and would provide a standardized method for exploring the relationship of delirium and UE in future trials.

Integration of Weaning Protocols

Protocol-directed weaning is beneficial for decreasing ventilator days, time to wean from mechanical ventilation, and ICU LOS [38]. A systematic review including 7 trials (2434 patients) comparing protocol/non-protocol for weaning from mechanical ventilation reported a 26% decrease in the mean duration of mechanical ventilation for the protocol groups (95% CI 13%–37%, P < 0.001), a 70% reduction in time to wean, (95% CI 27%–88%, P = 0.009), and a decrease in ICU LOS by 11% (95% CI 3%–19%, P = 0.01). Weaning protocols are also an important risk factor for UE [5]. Findings from a prospective cohort study specifically identify the presence of weaning protocols as an important factor for reducing UE; patients who had weaning protocols ordered and followed were least likely to experience UE (P = 0.02) [5]. A separate quality improvement initiative demonstrated an overall decrease in the number of UEs (from 5.2% to 0.9%) after implementing weaning protocols as standard of care [39]. Considering many UEs occur during weaning [10], integration of weaning protocols aids in expediting the process and ensuring timely extubation.

Increased Surveillance

Increasing surveillance and monitoring of ventilated patients is a recommendation based on risk factors presented at the time of UE. Specifically, staffing levels and shifts and the use of physical restraints are variables associated with UE that are amendable to changes in unit processes based on increased surveillance. It is reported that 40% to 76% of UEs occurred during the night shift [14,17,24,40]; many more occur during change of shift or when there is not a nurse present at the bedside [3,17]. Recent trends towards mandatory bedside reporting is a specific intervention that may positively impact UE among patients in the ICU [41]. Meta-analyses of observational studies investigating the effect of nurse staffing on hospital outcomes indicate that increasing the number of RNs is associated with decreased risk of adverse patient outcomes, including UE [42,43]. The addition of 1 additional nurse per patient day can result in a 51% decrease in UE, while a decrease in nursing workload could result in a 45% decrease in UE [42]. Data from a national prevalence study reports ICUs with fewer available resources, including staff, experienced a higher number of UEs [4].

Increasing surveillance by nursing and health care staff may also impact prevalence of physical restraint use. A significant number of patients who experience UE are physically restrained at the time of the incident, ranging from 40% to 90% of intubated patients [5–7,14,17,40]. It is well documented that UE continue to occur despite the use of restraints [5,7,28,29,44] Patients who are physically restrained often experience higher rates of unplanned extubation (42.9% vs. 16.5% , P < 0.001 in Chang et al’s study [7]), and longer ICU LOS (20.3 days vs. 15.8 days, P = 0.009) [7]. Soft wrist restraints are commonly used to prevent pulling of the endotracheal tube; however, research evidence on UE demonstrates this is not always an effective intervention. Increasing surveillance of ventilated patients, treating their agitation and screening for underlying delirium, and integration of weaning protocols are all interventions that may decrease UE and the need for routine use of physical restraints.

Ongoing Education for Patients and Health Care Staff

Initial and ongoing education about UE, risk factors, and effective interventions is beneficial for patients and health care staff. Although there are no trials investigating effects of educational interventions for patients on UE outcomes, pre-education of surgical patients regarding what to expect while intubated may aid in decreasing delirium risk, agitation, physical restraint use, and possibly UE. Verbal and written educational information during pre-admission testing is a feasible method easily integrated into pre-operative programs.

Because UEs often occur more frequently among less experienced staff, initial education about risk factors for UE is crucial to include in ICU staff orientation programs [3,7]. Educational initiatives should incorporate training on routine delirium screening and avoidance of agitation, use of protocols, and increased surveillance of patients receiving mechanical ventilation [5,15,17,39,45]. Ongoing education of staff regarding ventilatory equipment and risk factors for UE can be particularly effective in decreasing UE [46]. Initial educational efforts should be followed by routine updates for all members of the healthcare team about ongoing quality improvement efforts to monitor UE. Associated factors for UE that may be unit- or process-specific, including methods for endotracheal tube securement and intra-hospital transport, should be communicated with all individuals involved in patient care. Integration of continuous quality improvement programs can decrease UE rates by 22% to 53% [16]. Quality efforts typically focus on standardization of reporting and tracking tools, protocol implementations, and ongoing monitoring, auditing, and recording of UE.

Current Trends and Future Directions

Recent trends in critical care recommendations may mitigate potential risk factors identified in UE research. Integration of lightened sedation and daily wake up periods for intubated patients may decrease prevalence of risk factors for UE, specifically agitation, physical restraint use, and altered level of consciousness [30], while routine weaning protocols may improve ventilatory outcomes, including UE [5,38,40]. Nursing bedside report and purposeful hourly rounding are quickly emerging as mainstays of professional nursing care [41]. Inherent in these 2 initiatives are increased surveillance and vigilance by health care staff, which can result in timely extubation of those who indicate readiness, as well as decreased incidence of adverse events. Delirium remains a key factor that may be a likely cause for UE; recent trends towards early detection and proper management of delirium among ICU staff may result in improved ventilatory outcomes, including weaning, planned extubation, and the prevalence of UE.

Another important trend in critical care is the emergence of a neurocritical care specialty and routine admission of neurocritically ill patients to neuroscience ICUs [47,48]. However, there are no studies investigating prevalence of UE among these patients, who often have higher rates of agitation or restlessness due to cognitive impairment. Among general ICUs, patients with a primary respiratory diagnosis accounted for 23% of all UE in one study, while those with a neurological diagnosis accounted for the second highest percentage (12%) among the study population [15]. A separate study concluded that presence of neurological injury with a concomitant nosocomial infection increased risk of UE among patients in a mixed ICU [7]. A recent systematic review of weaning protocols highlights positive effects on ventilatory outcomes but cites lack of evidence for effectiveness of protocols among those with neurological injury [38]. Areas for future UE research should include factors specific to this patient population, as they may be at higher risk for adverse ventilatory outcomes due to the nature of the neurological injury.

Conclusion

Prevention of UE remains an elusive target, evidenced by little change in reported rates over 2 decades. Research provides data on risk factors that may be patient, unit, or process related. Structuring prevention efforts around modifiable risk factors for UE is a feasible approach amenable to ongoing monitoring for effectiveness. Integration of current trends in health care safety and quality may produce an added benefit of reducing the occurrence of UE in critical care units. Future research evaluating these trends and the prevalence of UE in subspecialty populations is warranted.

Corresponding author: Molly McNett, PhD, RN, CNRN, Attn: NBO, MetroHealth Medical Center, 2500 MetroHealth Drive; Cleveland, OH 44109, [email protected].

Financial disclosures: None.

From the MetroHealth System, Cleveland, OH.

Abstract

• Objective: To describe risk factors for unplanned extubation (UE) among critically ill adults requiring mechanical ventilation and to identify strategies to reduce the occurrence of this adverse event.
• Methods: Review of the literature.
• Results: Inadvertent removal of an endotracheal tube, or a UE, occurs in 7% to 22.5% of mechanically ventilated adult patients and is often due to deliberate patient removal. Despite the multitude of research examining risk factors and predictors of UE, rates have remained unchanged for the past 2 decades. Risk factors can be classified by intensive care unit (ICU) type, including medical ICUs, surgical ICUs, and mixed medical-surgical ICUs. The majority of risk factors for UEs across ICUs may be amenable to changes in unit processes, such as programs for agitation management, use of weaning protocols, increased surveillance of patients, and ongoing education for patients and health care staff.
• Conclusion: Prevention of UE remains an elusive target. Changes in unit processes that target identified risk factors may be an effective method to decrease prevalence of UE.

Unplanned extubation (UE) is the inadvertent removal of an endotracheal tube, either by a patient (deliberate self-extubation), or by a member of the health care team providing routine care such as repositioning, suctioning, or procedures (accidental extubation). Approximately 7% to 22.5% of mechanically ventilated patients in the intensive care unit (ICU) experience UE [1–7]. Estimates are likely higher, as current regulatory and accreditation standards do not include mandatory reporting of this event. Despite numerous studies investigating risk factors associated with UE, it remains a prevalent problem with adverse outcomes for patients and hospitals. The purpose of this review is to provide a summary of the literature on risk factors for UE, review effects on patient and organizational outcomes, and identify evidence-based strategies for reducing occurrence of UE among mechanically ventilated patients.

Prevalence of Unplanned Exubation

There is substantial heterogeneity in how UE is calculated and reported in the research literature. UE is calculated as the number of UE events per 100 or 1000 patient days, or the number of UE per total ventilator days. Rates of UE are also reported as the proportion of patients who experience UE out of all intubated patients over a set time period [8]. Despite efforts aimed at mitigating risk factors for UE, rates have remained static over the past 2 decades. Reported UE rates from 1994–2002 were 2.6% to 14% [3,6,9–11], while rates from 2004–2014 ranged from 1% to 22% [3–5,8,12–15]. Interventions utilizing a multidisciplinary approach have been implemented with the aim of decreasing UE, yet few have proven successful on improving rates nationally.

Unplanned self-extubation by the patient (deliberate self-extubation) is the most common type of UE [3,10,12,16–18]. A multicenter trial of 426 patients from 11 medical centers indicates that 46 patients experienced UE, with 36 of these (78.2%) caused by patient self-extubation [6]. Prospective single-site studies report similar or higher estimates of patient self-extubation, ranging from 75.8% to 91.7% [3,5], while a multisite study of 10,112 patients revealed 32 of 35 UE (91.4%) were due to patient self-extubation [12]. Similarly, a 4-year analysis of 85 UEs reported 82 incidences (96.5%) were a result of deliberate patient removal [13]. Patients either physically pull out the endotracheal tube or use their tongue or coughing/gagging maneuvers to displace or intentionally remove the endotracheal tube [5]. Only 3% to 8% of UEs are caused by inadvertent removal by health care staff [3,5,12,13].

Effects on Patient and Organizational Outcomes

Regardless of the cause of the UE, there are adverse consequences for both patients and hospitals. Some patients who experience UE have higher rates of in-hospital mortality; however, this is often due to contributing factors associated with severity of injury, the need for reintubation, and underlying chronic diseases [13]. Patients who experience accidental UE have higher incidence of nosocomial pneumonia (27.6% vs. 138%, P = 0.002) [11], longer duration of mechanical ventilation, and increased length of stay (LOS) [7,13]. While some studies report UE can result in serious consequences such as respiratory distress, hypoxia [13], and even death [6,12], others report lower mortality and length of stay when UE occurs, likely due to the fact that many patients are ready for liberation from mechanical ventilation at the time of UE [5,15].

Despite the emergent nature of UE, not all patients experience immediate reintubation. Many instances of UE occur during patient weaning trials or in preparation for planned extubations [5,11], which explains why only 10% to 60% of patients require reintubation [3,5,10,11,15,19,20]. When reintubation is necessary, it results in increased number of ventilator days [10,11], and increased ICU and hospital LOS [1,11]. There is little evidence directly linking reintubation with in-hospital mortality; however, it can cause serious complications such as hypotension, hypertension, arrhythmias, and airway trauma [21]. For hospitals and health care organizations, the need for reintubation results in increased hospital costs, estimated to be $1000 per reintubation event [17,22]. This estimate does not take into account additional costs incurred with increased ICU care, longer periods of mechanical ventilation, and increased LOS. Estimates of these additional costs in pediatric patients are approximately $36,000 [23]. Costs are likely higher in adult patients, due to multiple comorbidities that often accompany the need for mechanical ventilation, as well as increased pharmacy, lab, and diagnostic charges [1].

Risk Factors for Unplanned Extubation

Medical ICU Risk Factors

MICUs traditionally have the highest rates of UE [4,8]. Data from a national prevalence study indicated that there were 23.4 episodes of UE in MICUs per 1000 ventilator days [4]. Approximately 9.5% to 15% of all ventilated patients in the MICU experience UE [4,5,8]. Patients in the MICU who require mechanical ventilation often have complex chronic illness with underlying respiratory disease, which can result in prolonged periods of ventilation and increased risk of UE. Specific risk factors investigated in UE research include patient specific factors (age, gender, diagnosis, comorbidities, agitation, level of consciousness, laboratory values), ventilatory factors (ventilator type and setting, type of tracheal tube, method of tube fixation), as well as type of sedation and use of protocols [5,6,24]. Surprisingly, few variables emerge as significant risk factors for UE among MICU patients. Risk factors associated with UE have included male gender [24], presence of chronic obstructive pulmonary disease (COPD) [24], increased level of consciousness [25], and use of weaning protocols [5]. While gender, COPD, and level of consciousness increase risk of UE, the presence of weaning protocols is shown to decrease risk of UE [5]. Although UE are reported most often in MICUs, few risk factors consistently emerge for this specific cohort, making definitive recommendations for prevention of UE difficult.

Surgical ICU Risk Factors

The prevalence of UE for mechanically ventilated patients in the SICU tend to be lower than those for MICU cohorts. Prevalence of UE in the SICU is reported at 1.41 episodes per 100 ventilator days [13], or 6.8 episodes per 1000 ventilator days [4]. Percentages of UE in the SICU range from 2% to 6% [4,8,19]. Similar to MICU patients, critically ill patients in the SICU often have specific risk factors placing them at risk for UE. Causative factors examined in research studies with this population include gender, age, sedation scale scores, need for reintubation, time from intubation to extubation, use of sedatives/analgesics, restraints, ICU nurse experience, location of staff at time of UE, and criteria for extubation [17,19]. Similar to MICU cohorts, few variables are identified as predictors of UE. Significant predictors include use of restraints, decreased sedation [17], and meeting criteria for extubation [19]. Among patients who experienced an UE, 87% were restrained at the time of the UE [17], and most had low levels of sedation (mean Ramsay sedation scale score = 2.42 in the hour preceding the UE). Approximately 64% of patients who experienced UE met criteria for planned extubation and did not require re-intubation [19], suggesting many patients were essentially ready for planned extubation.

Mixed ICU Risk Factors

The majority of research investigating risk factors for UE is conducted within medical-surgical or mixed/general ICUs. The prevalence of UE within this type of unit is reported at 1.59 episodes per 100 patient days [6], or approximately 2% to 10% [4,6,7]. Among this population, potential risk factors are similar to those included in solely MICU or SICU studies. Because of the high number of studies investigating UE in a mixed ICU setting, there are significantly more variables included in as potential risk factors. Variables include patient age, gender, admission diagnosis, injury severity using Acute Physiological and Chronic Health Evaluation (APACHE II), ICU and hospital LOS, patient level of consciousness, agitation, days of mechanical ventilation, ventilator settings, nosocomial infection, sedation, physical restraints, vital signs [7,14,26], laboratory values, medication types, and body mass index [15,26]. One study also included time of UE and ICU nurse level of experience [3]. Among all factors, several were significant predictors of UE: male gender [15], decreased sedation and increased level of consciousness [8], agitation [3,19,26], use of restraints [3,7], sedation practices (particularly use of benzodiazapines) [3,7,15,26,27], lack of strong tube fixation, absence of IV sedation, and orotracheal intubation [6]. UE were more likely to occur on the night shift and among staff that included nurses with fewer years of experience [3]. Many episodes of UE occurred during weaning [10] or among patients who could communicate and were alert [3]. One study reports 57% of patients who intentionally self-extubated explained they simply removed the tube because it was uncomfortable [3].

Strategies for Reducing Adverse Events

Agitation Management

The majority of studies cited agitation, altered level of consciousness, or inadequate sedation as risk factors for UE [3,6–8,15,17,18,25,26,28,29]. These factors directly impact restraint use, another common risk factor for UE [3,7,17]. A key recommendation for agitation management is to identify the source of agitation, which is often caused by delirium onset in the ICU [30–32]. Prevalence of delirium in the ICU ranges from 20% to 80% [33–35]. ICU patients are at high risk for delirium due to sleep deprivation, older age, restraints, abnormal lab values, medications, infection, and respiratory complications [31]. Treatment for delirium centers on prevention, early recognition, interdisciplinary and pharmacologic protocols, increased nursing presence, and use of short-acting sedation when necessary [30–32,36]. While there is no research specifically linking delirium to UE, a quality analysis of risk factors present at the time of UE using bow-tie analysis methods identified delirium as a key factor present in the majority of UE cases [36]. It is possible that agitation reported in other studies investigating risk factors for UE may actually be reflective of underlying delirium. Routine screening using validated tools, such as the Confusion Assessment Method-ICU (CAM-ICU) [37] would aid in early detection and management of delirium, and would provide a standardized method for exploring the relationship of delirium and UE in future trials.

Integration of Weaning Protocols

Protocol-directed weaning is beneficial for decreasing ventilator days, time to wean from mechanical ventilation, and ICU LOS [38]. A systematic review including 7 trials (2434 patients) comparing protocol/non-protocol for weaning from mechanical ventilation reported a 26% decrease in the mean duration of mechanical ventilation for the protocol groups (95% CI 13%–37%, P < 0.001), a 70% reduction in time to wean, (95% CI 27%–88%, P = 0.009), and a decrease in ICU LOS by 11% (95% CI 3%–19%, P = 0.01). Weaning protocols are also an important risk factor for UE [5]. Findings from a prospective cohort study specifically identify the presence of weaning protocols as an important factor for reducing UE; patients who had weaning protocols ordered and followed were least likely to experience UE (P = 0.02) [5]. A separate quality improvement initiative demonstrated an overall decrease in the number of UEs (from 5.2% to 0.9%) after implementing weaning protocols as standard of care [39]. Considering many UEs occur during weaning [10], integration of weaning protocols aids in expediting the process and ensuring timely extubation.

Increased Surveillance

Increasing surveillance and monitoring of ventilated patients is a recommendation based on risk factors presented at the time of UE. Specifically, staffing levels and shifts and the use of physical restraints are variables associated with UE that are amendable to changes in unit processes based on increased surveillance. It is reported that 40% to 76% of UEs occurred during the night shift [14,17,24,40]; many more occur during change of shift or when there is not a nurse present at the bedside [3,17]. Recent trends towards mandatory bedside reporting is a specific intervention that may positively impact UE among patients in the ICU [41]. Meta-analyses of observational studies investigating the effect of nurse staffing on hospital outcomes indicate that increasing the number of RNs is associated with decreased risk of adverse patient outcomes, including UE [42,43]. The addition of 1 additional nurse per patient day can result in a 51% decrease in UE, while a decrease in nursing workload could result in a 45% decrease in UE [42]. Data from a national prevalence study reports ICUs with fewer available resources, including staff, experienced a higher number of UEs [4].

Increasing surveillance by nursing and health care staff may also impact prevalence of physical restraint use. A significant number of patients who experience UE are physically restrained at the time of the incident, ranging from 40% to 90% of intubated patients [5–7,14,17,40]. It is well documented that UE continue to occur despite the use of restraints [5,7,28,29,44] Patients who are physically restrained often experience higher rates of unplanned extubation (42.9% vs. 16.5% , P < 0.001 in Chang et al’s study [7]), and longer ICU LOS (20.3 days vs. 15.8 days, P = 0.009) [7]. Soft wrist restraints are commonly used to prevent pulling of the endotracheal tube; however, research evidence on UE demonstrates this is not always an effective intervention. Increasing surveillance of ventilated patients, treating their agitation and screening for underlying delirium, and integration of weaning protocols are all interventions that may decrease UE and the need for routine use of physical restraints.

Ongoing Education for Patients and Health Care Staff

Initial and ongoing education about UE, risk factors, and effective interventions is beneficial for patients and health care staff. Although there are no trials investigating effects of educational interventions for patients on UE outcomes, pre-education of surgical patients regarding what to expect while intubated may aid in decreasing delirium risk, agitation, physical restraint use, and possibly UE. Verbal and written educational information during pre-admission testing is a feasible method easily integrated into pre-operative programs.

Because UEs often occur more frequently among less experienced staff, initial education about risk factors for UE is crucial to include in ICU staff orientation programs [3,7]. Educational initiatives should incorporate training on routine delirium screening and avoidance of agitation, use of protocols, and increased surveillance of patients receiving mechanical ventilation [5,15,17,39,45]. Ongoing education of staff regarding ventilatory equipment and risk factors for UE can be particularly effective in decreasing UE [46]. Initial educational efforts should be followed by routine updates for all members of the healthcare team about ongoing quality improvement efforts to monitor UE. Associated factors for UE that may be unit- or process-specific, including methods for endotracheal tube securement and intra-hospital transport, should be communicated with all individuals involved in patient care. Integration of continuous quality improvement programs can decrease UE rates by 22% to 53% [16]. Quality efforts typically focus on standardization of reporting and tracking tools, protocol implementations, and ongoing monitoring, auditing, and recording of UE.

Current Trends and Future Directions

Recent trends in critical care recommendations may mitigate potential risk factors identified in UE research. Integration of lightened sedation and daily wake up periods for intubated patients may decrease prevalence of risk factors for UE, specifically agitation, physical restraint use, and altered level of consciousness [30], while routine weaning protocols may improve ventilatory outcomes, including UE [5,38,40]. Nursing bedside report and purposeful hourly rounding are quickly emerging as mainstays of professional nursing care [41]. Inherent in these 2 initiatives are increased surveillance and vigilance by health care staff, which can result in timely extubation of those who indicate readiness, as well as decreased incidence of adverse events. Delirium remains a key factor that may be a likely cause for UE; recent trends towards early detection and proper management of delirium among ICU staff may result in improved ventilatory outcomes, including weaning, planned extubation, and the prevalence of UE.

Another important trend in critical care is the emergence of a neurocritical care specialty and routine admission of neurocritically ill patients to neuroscience ICUs [47,48]. However, there are no studies investigating prevalence of UE among these patients, who often have higher rates of agitation or restlessness due to cognitive impairment. Among general ICUs, patients with a primary respiratory diagnosis accounted for 23% of all UE in one study, while those with a neurological diagnosis accounted for the second highest percentage (12%) among the study population [15]. A separate study concluded that presence of neurological injury with a concomitant nosocomial infection increased risk of UE among patients in a mixed ICU [7]. A recent systematic review of weaning protocols highlights positive effects on ventilatory outcomes but cites lack of evidence for effectiveness of protocols among those with neurological injury [38]. Areas for future UE research should include factors specific to this patient population, as they may be at higher risk for adverse ventilatory outcomes due to the nature of the neurological injury.

Conclusion

Prevention of UE remains an elusive target, evidenced by little change in reported rates over 2 decades. Research provides data on risk factors that may be patient, unit, or process related. Structuring prevention efforts around modifiable risk factors for UE is a feasible approach amenable to ongoing monitoring for effectiveness. Integration of current trends in health care safety and quality may produce an added benefit of reducing the occurrence of UE in critical care units. Future research evaluating these trends and the prevalence of UE in subspecialty populations is warranted.

Corresponding author: Molly McNett, PhD, RN, CNRN, Attn: NBO, MetroHealth Medical Center, 2500 MetroHealth Drive; Cleveland, OH 44109, [email protected].

Financial disclosures: None.

From the MetroHealth System, Cleveland, OH.

Abstract

• Objective: To describe risk factors for unplanned extubation (UE) among critically ill adults requiring mechanical ventilation and to identify strategies to reduce the occurrence of this adverse event.
• Methods: Review of the literature.
• Results: Inadvertent removal of an endotracheal tube, or a UE, occurs in 7% to 22.5% of mechanically ventilated adult patients and is often due to deliberate patient removal. Despite the multitude of research examining risk factors and predictors of UE, rates have remained unchanged for the past 2 decades. Risk factors can be classified by intensive care unit (ICU) type, including medical ICUs, surgical ICUs, and mixed medical-surgical ICUs. The majority of risk factors for UEs across ICUs may be amenable to changes in unit processes, such as programs for agitation management, use of weaning protocols, increased surveillance of patients, and ongoing education for patients and health care staff.
• Conclusion: Prevention of UE remains an elusive target. Changes in unit processes that target identified risk factors may be an effective method to decrease prevalence of UE.

Unplanned extubation (UE) is the inadvertent removal of an endotracheal tube, either by a patient (deliberate self-extubation), or by a member of the health care team providing routine care such as repositioning, suctioning, or procedures (accidental extubation). Approximately 7% to 22.5% of mechanically ventilated patients in the intensive care unit (ICU) experience UE [1–7]. Estimates are likely higher, as current regulatory and accreditation standards do not include mandatory reporting of this event. Despite numerous studies investigating risk factors associated with UE, it remains a prevalent problem with adverse outcomes for patients and hospitals. The purpose of this review is to provide a summary of the literature on risk factors for UE, review effects on patient and organizational outcomes, and identify evidence-based strategies for reducing occurrence of UE among mechanically ventilated patients.

Prevalence of Unplanned Exubation

There is substantial heterogeneity in how UE is calculated and reported in the research literature. UE is calculated as the number of UE events per 100 or 1000 patient days, or the number of UE per total ventilator days. Rates of UE are also reported as the proportion of patients who experience UE out of all intubated patients over a set time period [8]. Despite efforts aimed at mitigating risk factors for UE, rates have remained static over the past 2 decades. Reported UE rates from 1994–2002 were 2.6% to 14% [3,6,9–11], while rates from 2004–2014 ranged from 1% to 22% [3–5,8,12–15]. Interventions utilizing a multidisciplinary approach have been implemented with the aim of decreasing UE, yet few have proven successful on improving rates nationally.

Unplanned self-extubation by the patient (deliberate self-extubation) is the most common type of UE [3,10,12,16–18]. A multicenter trial of 426 patients from 11 medical centers indicates that 46 patients experienced UE, with 36 of these (78.2%) caused by patient self-extubation [6]. Prospective single-site studies report similar or higher estimates of patient self-extubation, ranging from 75.8% to 91.7% [3,5], while a multisite study of 10,112 patients revealed 32 of 35 UE (91.4%) were due to patient self-extubation [12]. Similarly, a 4-year analysis of 85 UEs reported 82 incidences (96.5%) were a result of deliberate patient removal [13]. Patients either physically pull out the endotracheal tube or use their tongue or coughing/gagging maneuvers to displace or intentionally remove the endotracheal tube [5]. Only 3% to 8% of UEs are caused by inadvertent removal by health care staff [3,5,12,13].

Effects on Patient and Organizational Outcomes

Regardless of the cause of the UE, there are adverse consequences for both patients and hospitals. Some patients who experience UE have higher rates of in-hospital mortality; however, this is often due to contributing factors associated with severity of injury, the need for reintubation, and underlying chronic diseases [13]. Patients who experience accidental UE have higher incidence of nosocomial pneumonia (27.6% vs. 138%, P = 0.002) [11], longer duration of mechanical ventilation, and increased length of stay (LOS) [7,13]. While some studies report UE can result in serious consequences such as respiratory distress, hypoxia [13], and even death [6,12], others report lower mortality and length of stay when UE occurs, likely due to the fact that many patients are ready for liberation from mechanical ventilation at the time of UE [5,15].

Despite the emergent nature of UE, not all patients experience immediate reintubation. Many instances of UE occur during patient weaning trials or in preparation for planned extubations [5,11], which explains why only 10% to 60% of patients require reintubation [3,5,10,11,15,19,20]. When reintubation is necessary, it results in increased number of ventilator days [10,11], and increased ICU and hospital LOS [1,11]. There is little evidence directly linking reintubation with in-hospital mortality; however, it can cause serious complications such as hypotension, hypertension, arrhythmias, and airway trauma [21]. For hospitals and health care organizations, the need for reintubation results in increased hospital costs, estimated to be $1000 per reintubation event [17,22]. This estimate does not take into account additional costs incurred with increased ICU care, longer periods of mechanical ventilation, and increased LOS. Estimates of these additional costs in pediatric patients are approximately $36,000 [23]. Costs are likely higher in adult patients, due to multiple comorbidities that often accompany the need for mechanical ventilation, as well as increased pharmacy, lab, and diagnostic charges [1].

Risk Factors for Unplanned Extubation

Medical ICU Risk Factors

MICUs traditionally have the highest rates of UE [4,8]. Data from a national prevalence study indicated that there were 23.4 episodes of UE in MICUs per 1000 ventilator days [4]. Approximately 9.5% to 15% of all ventilated patients in the MICU experience UE [4,5,8]. Patients in the MICU who require mechanical ventilation often have complex chronic illness with underlying respiratory disease, which can result in prolonged periods of ventilation and increased risk of UE. Specific risk factors investigated in UE research include patient specific factors (age, gender, diagnosis, comorbidities, agitation, level of consciousness, laboratory values), ventilatory factors (ventilator type and setting, type of tracheal tube, method of tube fixation), as well as type of sedation and use of protocols [5,6,24]. Surprisingly, few variables emerge as significant risk factors for UE among MICU patients. Risk factors associated with UE have included male gender [24], presence of chronic obstructive pulmonary disease (COPD) [24], increased level of consciousness [25], and use of weaning protocols [5]. While gender, COPD, and level of consciousness increase risk of UE, the presence of weaning protocols is shown to decrease risk of UE [5]. Although UE are reported most often in MICUs, few risk factors consistently emerge for this specific cohort, making definitive recommendations for prevention of UE difficult.

Surgical ICU Risk Factors

The prevalence of UE for mechanically ventilated patients in the SICU tend to be lower than those for MICU cohorts. Prevalence of UE in the SICU is reported at 1.41 episodes per 100 ventilator days [13], or 6.8 episodes per 1000 ventilator days [4]. Percentages of UE in the SICU range from 2% to 6% [4,8,19]. Similar to MICU patients, critically ill patients in the SICU often have specific risk factors placing them at risk for UE. Causative factors examined in research studies with this population include gender, age, sedation scale scores, need for reintubation, time from intubation to extubation, use of sedatives/analgesics, restraints, ICU nurse experience, location of staff at time of UE, and criteria for extubation [17,19]. Similar to MICU cohorts, few variables are identified as predictors of UE. Significant predictors include use of restraints, decreased sedation [17], and meeting criteria for extubation [19]. Among patients who experienced an UE, 87% were restrained at the time of the UE [17], and most had low levels of sedation (mean Ramsay sedation scale score = 2.42 in the hour preceding the UE). Approximately 64% of patients who experienced UE met criteria for planned extubation and did not require re-intubation [19], suggesting many patients were essentially ready for planned extubation.

Mixed ICU Risk Factors

The majority of research investigating risk factors for UE is conducted within medical-surgical or mixed/general ICUs. The prevalence of UE within this type of unit is reported at 1.59 episodes per 100 patient days [6], or approximately 2% to 10% [4,6,7]. Among this population, potential risk factors are similar to those included in solely MICU or SICU studies. Because of the high number of studies investigating UE in a mixed ICU setting, there are significantly more variables included in as potential risk factors. Variables include patient age, gender, admission diagnosis, injury severity using Acute Physiological and Chronic Health Evaluation (APACHE II), ICU and hospital LOS, patient level of consciousness, agitation, days of mechanical ventilation, ventilator settings, nosocomial infection, sedation, physical restraints, vital signs [7,14,26], laboratory values, medication types, and body mass index [15,26]. One study also included time of UE and ICU nurse level of experience [3]. Among all factors, several were significant predictors of UE: male gender [15], decreased sedation and increased level of consciousness [8], agitation [3,19,26], use of restraints [3,7], sedation practices (particularly use of benzodiazapines) [3,7,15,26,27], lack of strong tube fixation, absence of IV sedation, and orotracheal intubation [6]. UE were more likely to occur on the night shift and among staff that included nurses with fewer years of experience [3]. Many episodes of UE occurred during weaning [10] or among patients who could communicate and were alert [3]. One study reports 57% of patients who intentionally self-extubated explained they simply removed the tube because it was uncomfortable [3].

Strategies for Reducing Adverse Events

Agitation Management

The majority of studies cited agitation, altered level of consciousness, or inadequate sedation as risk factors for UE [3,6–8,15,17,18,25,26,28,29]. These factors directly impact restraint use, another common risk factor for UE [3,7,17]. A key recommendation for agitation management is to identify the source of agitation, which is often caused by delirium onset in the ICU [30–32]. Prevalence of delirium in the ICU ranges from 20% to 80% [33–35]. ICU patients are at high risk for delirium due to sleep deprivation, older age, restraints, abnormal lab values, medications, infection, and respiratory complications [31]. Treatment for delirium centers on prevention, early recognition, interdisciplinary and pharmacologic protocols, increased nursing presence, and use of short-acting sedation when necessary [30–32,36]. While there is no research specifically linking delirium to UE, a quality analysis of risk factors present at the time of UE using bow-tie analysis methods identified delirium as a key factor present in the majority of UE cases [36]. It is possible that agitation reported in other studies investigating risk factors for UE may actually be reflective of underlying delirium. Routine screening using validated tools, such as the Confusion Assessment Method-ICU (CAM-ICU) [37] would aid in early detection and management of delirium, and would provide a standardized method for exploring the relationship of delirium and UE in future trials.

Integration of Weaning Protocols

Protocol-directed weaning is beneficial for decreasing ventilator days, time to wean from mechanical ventilation, and ICU LOS [38]. A systematic review including 7 trials (2434 patients) comparing protocol/non-protocol for weaning from mechanical ventilation reported a 26% decrease in the mean duration of mechanical ventilation for the protocol groups (95% CI 13%–37%, P < 0.001), a 70% reduction in time to wean, (95% CI 27%–88%, P = 0.009), and a decrease in ICU LOS by 11% (95% CI 3%–19%, P = 0.01). Weaning protocols are also an important risk factor for UE [5]. Findings from a prospective cohort study specifically identify the presence of weaning protocols as an important factor for reducing UE; patients who had weaning protocols ordered and followed were least likely to experience UE (P = 0.02) [5]. A separate quality improvement initiative demonstrated an overall decrease in the number of UEs (from 5.2% to 0.9%) after implementing weaning protocols as standard of care [39]. Considering many UEs occur during weaning [10], integration of weaning protocols aids in expediting the process and ensuring timely extubation.

Increased Surveillance

Increasing surveillance and monitoring of ventilated patients is a recommendation based on risk factors presented at the time of UE. Specifically, staffing levels and shifts and the use of physical restraints are variables associated with UE that are amendable to changes in unit processes based on increased surveillance. It is reported that 40% to 76% of UEs occurred during the night shift [14,17,24,40]; many more occur during change of shift or when there is not a nurse present at the bedside [3,17]. Recent trends towards mandatory bedside reporting is a specific intervention that may positively impact UE among patients in the ICU [41]. Meta-analyses of observational studies investigating the effect of nurse staffing on hospital outcomes indicate that increasing the number of RNs is associated with decreased risk of adverse patient outcomes, including UE [42,43]. The addition of 1 additional nurse per patient day can result in a 51% decrease in UE, while a decrease in nursing workload could result in a 45% decrease in UE [42]. Data from a national prevalence study reports ICUs with fewer available resources, including staff, experienced a higher number of UEs [4].

Increasing surveillance by nursing and health care staff may also impact prevalence of physical restraint use. A significant number of patients who experience UE are physically restrained at the time of the incident, ranging from 40% to 90% of intubated patients [5–7,14,17,40]. It is well documented that UE continue to occur despite the use of restraints [5,7,28,29,44] Patients who are physically restrained often experience higher rates of unplanned extubation (42.9% vs. 16.5% , P < 0.001 in Chang et al’s study [7]), and longer ICU LOS (20.3 days vs. 15.8 days, P = 0.009) [7]. Soft wrist restraints are commonly used to prevent pulling of the endotracheal tube; however, research evidence on UE demonstrates this is not always an effective intervention. Increasing surveillance of ventilated patients, treating their agitation and screening for underlying delirium, and integration of weaning protocols are all interventions that may decrease UE and the need for routine use of physical restraints.

Ongoing Education for Patients and Health Care Staff

Initial and ongoing education about UE, risk factors, and effective interventions is beneficial for patients and health care staff. Although there are no trials investigating effects of educational interventions for patients on UE outcomes, pre-education of surgical patients regarding what to expect while intubated may aid in decreasing delirium risk, agitation, physical restraint use, and possibly UE. Verbal and written educational information during pre-admission testing is a feasible method easily integrated into pre-operative programs.

Because UEs often occur more frequently among less experienced staff, initial education about risk factors for UE is crucial to include in ICU staff orientation programs [3,7]. Educational initiatives should incorporate training on routine delirium screening and avoidance of agitation, use of protocols, and increased surveillance of patients receiving mechanical ventilation [5,15,17,39,45]. Ongoing education of staff regarding ventilatory equipment and risk factors for UE can be particularly effective in decreasing UE [46]. Initial educational efforts should be followed by routine updates for all members of the healthcare team about ongoing quality improvement efforts to monitor UE. Associated factors for UE that may be unit- or process-specific, including methods for endotracheal tube securement and intra-hospital transport, should be communicated with all individuals involved in patient care. Integration of continuous quality improvement programs can decrease UE rates by 22% to 53% [16]. Quality efforts typically focus on standardization of reporting and tracking tools, protocol implementations, and ongoing monitoring, auditing, and recording of UE.

Current Trends and Future Directions

Recent trends in critical care recommendations may mitigate potential risk factors identified in UE research. Integration of lightened sedation and daily wake up periods for intubated patients may decrease prevalence of risk factors for UE, specifically agitation, physical restraint use, and altered level of consciousness [30], while routine weaning protocols may improve ventilatory outcomes, including UE [5,38,40]. Nursing bedside report and purposeful hourly rounding are quickly emerging as mainstays of professional nursing care [41]. Inherent in these 2 initiatives are increased surveillance and vigilance by health care staff, which can result in timely extubation of those who indicate readiness, as well as decreased incidence of adverse events. Delirium remains a key factor that may be a likely cause for UE; recent trends towards early detection and proper management of delirium among ICU staff may result in improved ventilatory outcomes, including weaning, planned extubation, and the prevalence of UE.

Another important trend in critical care is the emergence of a neurocritical care specialty and routine admission of neurocritically ill patients to neuroscience ICUs [47,48]. However, there are no studies investigating prevalence of UE among these patients, who often have higher rates of agitation or restlessness due to cognitive impairment. Among general ICUs, patients with a primary respiratory diagnosis accounted for 23% of all UE in one study, while those with a neurological diagnosis accounted for the second highest percentage (12%) among the study population [15]. A separate study concluded that presence of neurological injury with a concomitant nosocomial infection increased risk of UE among patients in a mixed ICU [7]. A recent systematic review of weaning protocols highlights positive effects on ventilatory outcomes but cites lack of evidence for effectiveness of protocols among those with neurological injury [38]. Areas for future UE research should include factors specific to this patient population, as they may be at higher risk for adverse ventilatory outcomes due to the nature of the neurological injury.

Conclusion

Prevention of UE remains an elusive target, evidenced by little change in reported rates over 2 decades. Research provides data on risk factors that may be patient, unit, or process related. Structuring prevention efforts around modifiable risk factors for UE is a feasible approach amenable to ongoing monitoring for effectiveness. Integration of current trends in health care safety and quality may produce an added benefit of reducing the occurrence of UE in critical care units. Future research evaluating these trends and the prevalence of UE in subspecialty populations is warranted.

Corresponding author: Molly McNett, PhD, RN, CNRN, Attn: NBO, MetroHealth Medical Center, 2500 MetroHealth Drive; Cleveland, OH 44109, [email protected].

Financial disclosures: None.

Study Overview

Objective. To investigate national trends in hospital admissions for malignant hypertension and hypertensive encephalopathy.

Study design. Retrospective cohort study. The Nation-wide Inpatient Sample [1] was used to identify all hospitalizations between January 2000 and December 2011 during which a primary diagnosis of malignant hypertension, hypertensive encephalopathy, or essential hypertension occurred. Time series models were estimated for these diagnoses and also for the combined series. A piecewise linear regression analysis was done to investigate whether there were changes in the trends of these series. In addition, the researchers compared patient characteristics.

Results. There was a gradual increase in the number of hypertension-related hospitalizations from 2000 to 2011. However, after 2007, the number of admissions for malignant hypertension and hypertensive encephalopathy increased dramatically, whereas diagnoses for essential hypertension fell (P < 0.001). Mortality for malignant hypertension significantly fell after the change point of 2007 (–36%, P = 0.02) but there was no significant difference in mortality for hypertensive encephalopathy or essential hypertension. The number of diagnoses and the adjusted average charges significantly increased after the change point for all hypertension series, although the increase in malignant hypertension and hypertensive encephalopathy was higher than in essential hypertension. Length of stay significantly decreased after 2007 for all series. Mean patient age and number of procedures for all series were similar before and after the change point.

Conclusion. Since the dramatic increase in the number of hospital admissions did not result in dramatic increases in morbidity, which would have been expected, the increase was most likely related to a change in coding practices that was implemented in 2007 and not actual changes in disease incidence.

Commentary

Hypertension is a major public health problem associated with significant morbidity and mortality [2]. In general, hypertension is asymptomatic; however, life-threatening manifestations of hypertension can develop. A hypertensive emergency is a situation in which uncontrolled hypertension is associated with acute end-organ damage.  Most patients presenting with hypertensive emergency have chronic hypertension, although the disorder can present in previously normotensive individuals [3]. The 2 major emergency syndromes are malignant hypertension and hypertensive encephalopathy. They usually require hospitalization, and therefore monitoring trends in admissions for these conditions is a reasonable population-based indicator for failures related to hypertension management.

In this epidemiologic study by Polgreen et al, the authors found a increasing trend in admissions for malig-nant hypertension and hypertensive emergencies, with a substantial increase after 2007. Although the authors considered the possibility that their findings represented a true change in the epidemiology of hypertensive emergencies, they concluded that this appears unlikely, as the diagnoses of essential hypertension fell, and in addition, an expected associated increase in morbidity was not seen. They attribute the shift to a change in assignment of administrative billing codes. In 2007, DRG codes were changed to medical severity DRG codes [4]. The authors acknowledge that there was a recession from 2007 to 2009 that led to an increase in the number of uninsured Americans [5]. However, they noted that the uninsured were no more likely to be diagnosed with malignant hypertension or hypertensive encephalopathy than essential hypertension and there is no reason to think that a change provider’s management of hypertension could have been responsible.

Limitations to this study were the use of administrative data only and the lack of data on outpatient medication use.

Applications for Clinical Practice

As the authors suggest, the study raised questions regarding the use of administrative data for monitoring hypertension outcomes. Future studies are needed to examine whether the rise in diagnoses for malignant hypertension and hypertensive encephalopathy are related to coding practices or other variables.

—Paloma Cesar de Sales, BN, RN, MS

Study Overview

Objective. To investigate national trends in hospital admissions for malignant hypertension and hypertensive encephalopathy.

Study design. Retrospective cohort study. The Nation-wide Inpatient Sample [1] was used to identify all hospitalizations between January 2000 and December 2011 during which a primary diagnosis of malignant hypertension, hypertensive encephalopathy, or essential hypertension occurred. Time series models were estimated for these diagnoses and also for the combined series. A piecewise linear regression analysis was done to investigate whether there were changes in the trends of these series. In addition, the researchers compared patient characteristics.

Results. There was a gradual increase in the number of hypertension-related hospitalizations from 2000 to 2011. However, after 2007, the number of admissions for malignant hypertension and hypertensive encephalopathy increased dramatically, whereas diagnoses for essential hypertension fell (P < 0.001). Mortality for malignant hypertension significantly fell after the change point of 2007 (–36%, P = 0.02) but there was no significant difference in mortality for hypertensive encephalopathy or essential hypertension. The number of diagnoses and the adjusted average charges significantly increased after the change point for all hypertension series, although the increase in malignant hypertension and hypertensive encephalopathy was higher than in essential hypertension. Length of stay significantly decreased after 2007 for all series. Mean patient age and number of procedures for all series were similar before and after the change point.

Conclusion. Since the dramatic increase in the number of hospital admissions did not result in dramatic increases in morbidity, which would have been expected, the increase was most likely related to a change in coding practices that was implemented in 2007 and not actual changes in disease incidence.

Commentary

Hypertension is a major public health problem associated with significant morbidity and mortality [2]. In general, hypertension is asymptomatic; however, life-threatening manifestations of hypertension can develop. A hypertensive emergency is a situation in which uncontrolled hypertension is associated with acute end-organ damage.  Most patients presenting with hypertensive emergency have chronic hypertension, although the disorder can present in previously normotensive individuals [3]. The 2 major emergency syndromes are malignant hypertension and hypertensive encephalopathy. They usually require hospitalization, and therefore monitoring trends in admissions for these conditions is a reasonable population-based indicator for failures related to hypertension management.

In this epidemiologic study by Polgreen et al, the authors found a increasing trend in admissions for malig-nant hypertension and hypertensive emergencies, with a substantial increase after 2007. Although the authors considered the possibility that their findings represented a true change in the epidemiology of hypertensive emergencies, they concluded that this appears unlikely, as the diagnoses of essential hypertension fell, and in addition, an expected associated increase in morbidity was not seen. They attribute the shift to a change in assignment of administrative billing codes. In 2007, DRG codes were changed to medical severity DRG codes [4]. The authors acknowledge that there was a recession from 2007 to 2009 that led to an increase in the number of uninsured Americans [5]. However, they noted that the uninsured were no more likely to be diagnosed with malignant hypertension or hypertensive encephalopathy than essential hypertension and there is no reason to think that a change provider’s management of hypertension could have been responsible.

Limitations to this study were the use of administrative data only and the lack of data on outpatient medication use.

Applications for Clinical Practice

As the authors suggest, the study raised questions regarding the use of administrative data for monitoring hypertension outcomes. Future studies are needed to examine whether the rise in diagnoses for malignant hypertension and hypertensive encephalopathy are related to coding practices or other variables.

—Paloma Cesar de Sales, BN, RN, MS

Study Overview

Objective. To investigate national trends in hospital admissions for malignant hypertension and hypertensive encephalopathy.

Study design. Retrospective cohort study. The Nation-wide Inpatient Sample [1] was used to identify all hospitalizations between January 2000 and December 2011 during which a primary diagnosis of malignant hypertension, hypertensive encephalopathy, or essential hypertension occurred. Time series models were estimated for these diagnoses and also for the combined series. A piecewise linear regression analysis was done to investigate whether there were changes in the trends of these series. In addition, the researchers compared patient characteristics.

Results. There was a gradual increase in the number of hypertension-related hospitalizations from 2000 to 2011. However, after 2007, the number of admissions for malignant hypertension and hypertensive encephalopathy increased dramatically, whereas diagnoses for essential hypertension fell (P < 0.001). Mortality for malignant hypertension significantly fell after the change point of 2007 (–36%, P = 0.02) but there was no significant difference in mortality for hypertensive encephalopathy or essential hypertension. The number of diagnoses and the adjusted average charges significantly increased after the change point for all hypertension series, although the increase in malignant hypertension and hypertensive encephalopathy was higher than in essential hypertension. Length of stay significantly decreased after 2007 for all series. Mean patient age and number of procedures for all series were similar before and after the change point.

Conclusion. Since the dramatic increase in the number of hospital admissions did not result in dramatic increases in morbidity, which would have been expected, the increase was most likely related to a change in coding practices that was implemented in 2007 and not actual changes in disease incidence.

Commentary

Hypertension is a major public health problem associated with significant morbidity and mortality [2]. In general, hypertension is asymptomatic; however, life-threatening manifestations of hypertension can develop. A hypertensive emergency is a situation in which uncontrolled hypertension is associated with acute end-organ damage.  Most patients presenting with hypertensive emergency have chronic hypertension, although the disorder can present in previously normotensive individuals [3]. The 2 major emergency syndromes are malignant hypertension and hypertensive encephalopathy. They usually require hospitalization, and therefore monitoring trends in admissions for these conditions is a reasonable population-based indicator for failures related to hypertension management.

In this epidemiologic study by Polgreen et al, the authors found a increasing trend in admissions for malig-nant hypertension and hypertensive emergencies, with a substantial increase after 2007. Although the authors considered the possibility that their findings represented a true change in the epidemiology of hypertensive emergencies, they concluded that this appears unlikely, as the diagnoses of essential hypertension fell, and in addition, an expected associated increase in morbidity was not seen. They attribute the shift to a change in assignment of administrative billing codes. In 2007, DRG codes were changed to medical severity DRG codes [4]. The authors acknowledge that there was a recession from 2007 to 2009 that led to an increase in the number of uninsured Americans [5]. However, they noted that the uninsured were no more likely to be diagnosed with malignant hypertension or hypertensive encephalopathy than essential hypertension and there is no reason to think that a change provider’s management of hypertension could have been responsible.

Limitations to this study were the use of administrative data only and the lack of data on outpatient medication use.

Applications for Clinical Practice

As the authors suggest, the study raised questions regarding the use of administrative data for monitoring hypertension outcomes. Future studies are needed to examine whether the rise in diagnoses for malignant hypertension and hypertensive encephalopathy are related to coding practices or other variables.

—Paloma Cesar de Sales, BN, RN, MS

Study Overview

Objective. To evaluate the association between intake of dietary fiber and type 2 diabetes.

Design. Case-cohort study (EPIC-InterAct Study), which is nested within the large prospective cohort study EPIC (European Prospective Investigation into Cancer & Nutrition) [1]. EPIC includes participants from 10 European countries and was designed to investigate the relationships between diet, nutritional status, lifestyle, and environmental factors and the incidence of cancer and other chronic disease [1].

Setting and participants. The EPIC-Interact study used data from 8 European countries (Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, and UK). The Interact sample includes 12,403 individuals who were identified as having developed type 2 diabetes, and a random subcohort of controls who were free of diabetes at baseline (n = 16,835, including 778 cases of incident diabetes) selected from 340,234 eligible EPIC participants. Of the 28,460 participants in the EPIC-InterAct study, excluded were those with prevalent diabetes, missing diabetes status information, post-censoring diabetes, extreme energy intake (top and bottom 1%), and missing values for education level, physical activity, smoking status, and BMI, leaving a final sample of 11,559 cases and 15,258 subcohort participants. No differences were observed in baseline characteristics between the included and excluded participants.

Analysis. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox proportional hazards models and were pooled using a random effects meta-analysis. Dietary intake over the previous 12 months before recruitment was assessed by country-specific or center-specific assessment methods (food-frequency questionnaire and dietary histories) that were developed and validated locally, and data were converted to nutrient intake.

Main outcome measure. Incident cases of diabetes.

Main results. During a median of 10.8 years of follow-up, total fiber intake was associated with a lower risk of diabetes after adjusting for lifestyle and dietary factors (hazard ratio for the highest quartile of fiber intake [> 26 g/day] vs the lowest [< 19 g/day], 0.82; 95% confidence interval, 0.69–0.97, P for trend = 0.02). When the researchers focused on specific types of fiber, they found that people who consumed the highest amounts of cereal and vegetable fiber were 19% and 16%, respectively, less likely to develop type 2 diabetes compared with those who consumed the lowest amounts (P < 0.001). Intake of fruit fiber was not associated with risk of diabetes. When the analyses were additionally adjusted for BMI, the inverse associations between intake of fiber and diabetes were attenuated and no longer statistically significant.

The researchers also conducted a meta-analysis that included 18 other cohorts in addition to the current EPIC-InterAct study. The summary relative risks per 10/g day increase in intake were 0.91 (95% CI, 0.87–0.96) for total fiber, 0.75 (95% CI, 0.65–0.86) for cereal fiber, 0.95 (95% CI, 0.87–1.03) for fruit fiber, and 0.93 (95% CI 0.82–1.05) for vegetable fiber.

Conclusion. Individuals with diets rich in fiber, in particular cereal fiber, may be at lower risk of type 2 diabetes.

Commentary

The current study by the European InterAct Consortium adds to the available evidence supporting the association of dietary fiber and risk of diabetes. Higher intake of dietary fiber, especially cereal fiber, has been consistently associated with a lower risk of diabetes [2,3].

This study showed that a high intake of total fiber (primarily cereal and vegetable fiber) was associated with an 18% lower risk of type 2 diabetes (adjusted for dietary and lifestyle factors). While there was no association after adjusting for BMI, their meta-analysis of 18 studies did support the an inverse association between total fiber and cereal fiber intake and risk of type 2 diabetes.

What is it about fiber that is protective? With regard to whole grains, a rich source of fiber, potential mechanisms have been identified [5], including the possible impact of improved postprandial glucose response. However, whole grains are rich in nutrients and phytochemicals, and new hypotheses for the health-protective mechanisms of whole grains beyond fiber are being proposed [6]. In addition, the beneficial effect of fiber seen in this and other studies may be partly mediated by a lower BMI. Dietary fiber may affect appetite and energy intake through a range of processes.

It should be noted that although the effect of whole-grain foods for the prevention of type 2 diabetes is strongly supported by numerous epidemiological studies, a 2008 systematic review by the Cochrane Collaboration [4], which included 1 low-quality RCT and 11 cohort studies, stated that the evidence is too weak to be able to draw a definite conclusion about the preventive effect of this dietary factor.

Strengths of the study included its prospective design and large sample size. Limitations of the study include that dietary intake was assessed only at baseline and measurement error through the use of a questionnaire may have occurred. Although food-frequency questionnaires are widely used, they are subjective estimates and subject to recall bias, and some researchers have questioned their value for use in epidemiologic studies [7]. In addition, the authors note that the inverse association for total fiber and cereal fiber intake in the meta-analysis could be due to residual confounding as fiber intake has been associated with healthier diet, lower BMI, and greater physical activity.

Applications for Clinical Practice

The prevalence of type 2 diabetes has increased rapidly during the past decades in the United States. Dietary guidelines recommend the consumption of whole grains to prevent chronic diseases. The results presented in the current study strengthen the evidence supporting cereal fiber as an important determinant of type 2 diabetes risk. Randomized controlled trials are needed and should elucidate this matter.

Study Overview

Objective. To evaluate the association between intake of dietary fiber and type 2 diabetes.

Design. Case-cohort study (EPIC-InterAct Study), which is nested within the large prospective cohort study EPIC (European Prospective Investigation into Cancer & Nutrition) [1]. EPIC includes participants from 10 European countries and was designed to investigate the relationships between diet, nutritional status, lifestyle, and environmental factors and the incidence of cancer and other chronic disease [1].

Setting and participants. The EPIC-Interact study used data from 8 European countries (Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, and UK). The Interact sample includes 12,403 individuals who were identified as having developed type 2 diabetes, and a random subcohort of controls who were free of diabetes at baseline (n = 16,835, including 778 cases of incident diabetes) selected from 340,234 eligible EPIC participants. Of the 28,460 participants in the EPIC-InterAct study, excluded were those with prevalent diabetes, missing diabetes status information, post-censoring diabetes, extreme energy intake (top and bottom 1%), and missing values for education level, physical activity, smoking status, and BMI, leaving a final sample of 11,559 cases and 15,258 subcohort participants. No differences were observed in baseline characteristics between the included and excluded participants.

Analysis. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox proportional hazards models and were pooled using a random effects meta-analysis. Dietary intake over the previous 12 months before recruitment was assessed by country-specific or center-specific assessment methods (food-frequency questionnaire and dietary histories) that were developed and validated locally, and data were converted to nutrient intake.

Main outcome measure. Incident cases of diabetes.

Main results. During a median of 10.8 years of follow-up, total fiber intake was associated with a lower risk of diabetes after adjusting for lifestyle and dietary factors (hazard ratio for the highest quartile of fiber intake [> 26 g/day] vs the lowest [< 19 g/day], 0.82; 95% confidence interval, 0.69–0.97, P for trend = 0.02). When the researchers focused on specific types of fiber, they found that people who consumed the highest amounts of cereal and vegetable fiber were 19% and 16%, respectively, less likely to develop type 2 diabetes compared with those who consumed the lowest amounts (P < 0.001). Intake of fruit fiber was not associated with risk of diabetes. When the analyses were additionally adjusted for BMI, the inverse associations between intake of fiber and diabetes were attenuated and no longer statistically significant.

The researchers also conducted a meta-analysis that included 18 other cohorts in addition to the current EPIC-InterAct study. The summary relative risks per 10/g day increase in intake were 0.91 (95% CI, 0.87–0.96) for total fiber, 0.75 (95% CI, 0.65–0.86) for cereal fiber, 0.95 (95% CI, 0.87–1.03) for fruit fiber, and 0.93 (95% CI 0.82–1.05) for vegetable fiber.

Conclusion. Individuals with diets rich in fiber, in particular cereal fiber, may be at lower risk of type 2 diabetes.

Commentary

The current study by the European InterAct Consortium adds to the available evidence supporting the association of dietary fiber and risk of diabetes. Higher intake of dietary fiber, especially cereal fiber, has been consistently associated with a lower risk of diabetes [2,3].

This study showed that a high intake of total fiber (primarily cereal and vegetable fiber) was associated with an 18% lower risk of type 2 diabetes (adjusted for dietary and lifestyle factors). While there was no association after adjusting for BMI, their meta-analysis of 18 studies did support the an inverse association between total fiber and cereal fiber intake and risk of type 2 diabetes.

What is it about fiber that is protective? With regard to whole grains, a rich source of fiber, potential mechanisms have been identified [5], including the possible impact of improved postprandial glucose response. However, whole grains are rich in nutrients and phytochemicals, and new hypotheses for the health-protective mechanisms of whole grains beyond fiber are being proposed [6]. In addition, the beneficial effect of fiber seen in this and other studies may be partly mediated by a lower BMI. Dietary fiber may affect appetite and energy intake through a range of processes.

It should be noted that although the effect of whole-grain foods for the prevention of type 2 diabetes is strongly supported by numerous epidemiological studies, a 2008 systematic review by the Cochrane Collaboration [4], which included 1 low-quality RCT and 11 cohort studies, stated that the evidence is too weak to be able to draw a definite conclusion about the preventive effect of this dietary factor.

Strengths of the study included its prospective design and large sample size. Limitations of the study include that dietary intake was assessed only at baseline and measurement error through the use of a questionnaire may have occurred. Although food-frequency questionnaires are widely used, they are subjective estimates and subject to recall bias, and some researchers have questioned their value for use in epidemiologic studies [7]. In addition, the authors note that the inverse association for total fiber and cereal fiber intake in the meta-analysis could be due to residual confounding as fiber intake has been associated with healthier diet, lower BMI, and greater physical activity.

Applications for Clinical Practice

The prevalence of type 2 diabetes has increased rapidly during the past decades in the United States. Dietary guidelines recommend the consumption of whole grains to prevent chronic diseases. The results presented in the current study strengthen the evidence supporting cereal fiber as an important determinant of type 2 diabetes risk. Randomized controlled trials are needed and should elucidate this matter.

Study Overview

Objective. To evaluate the association between intake of dietary fiber and type 2 diabetes.

Design. Case-cohort study (EPIC-InterAct Study), which is nested within the large prospective cohort study EPIC (European Prospective Investigation into Cancer & Nutrition) [1]. EPIC includes participants from 10 European countries and was designed to investigate the relationships between diet, nutritional status, lifestyle, and environmental factors and the incidence of cancer and other chronic disease [1].

Setting and participants. The EPIC-Interact study used data from 8 European countries (Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, and UK). The Interact sample includes 12,403 individuals who were identified as having developed type 2 diabetes, and a random subcohort of controls who were free of diabetes at baseline (n = 16,835, including 778 cases of incident diabetes) selected from 340,234 eligible EPIC participants. Of the 28,460 participants in the EPIC-InterAct study, excluded were those with prevalent diabetes, missing diabetes status information, post-censoring diabetes, extreme energy intake (top and bottom 1%), and missing values for education level, physical activity, smoking status, and BMI, leaving a final sample of 11,559 cases and 15,258 subcohort participants. No differences were observed in baseline characteristics between the included and excluded participants.

Analysis. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox proportional hazards models and were pooled using a random effects meta-analysis. Dietary intake over the previous 12 months before recruitment was assessed by country-specific or center-specific assessment methods (food-frequency questionnaire and dietary histories) that were developed and validated locally, and data were converted to nutrient intake.

Main outcome measure. Incident cases of diabetes.

Main results. During a median of 10.8 years of follow-up, total fiber intake was associated with a lower risk of diabetes after adjusting for lifestyle and dietary factors (hazard ratio for the highest quartile of fiber intake [> 26 g/day] vs the lowest [< 19 g/day], 0.82; 95% confidence interval, 0.69–0.97, P for trend = 0.02). When the researchers focused on specific types of fiber, they found that people who consumed the highest amounts of cereal and vegetable fiber were 19% and 16%, respectively, less likely to develop type 2 diabetes compared with those who consumed the lowest amounts (P < 0.001). Intake of fruit fiber was not associated with risk of diabetes. When the analyses were additionally adjusted for BMI, the inverse associations between intake of fiber and diabetes were attenuated and no longer statistically significant.

The researchers also conducted a meta-analysis that included 18 other cohorts in addition to the current EPIC-InterAct study. The summary relative risks per 10/g day increase in intake were 0.91 (95% CI, 0.87–0.96) for total fiber, 0.75 (95% CI, 0.65–0.86) for cereal fiber, 0.95 (95% CI, 0.87–1.03) for fruit fiber, and 0.93 (95% CI 0.82–1.05) for vegetable fiber.

Conclusion. Individuals with diets rich in fiber, in particular cereal fiber, may be at lower risk of type 2 diabetes.

Commentary

The current study by the European InterAct Consortium adds to the available evidence supporting the association of dietary fiber and risk of diabetes. Higher intake of dietary fiber, especially cereal fiber, has been consistently associated with a lower risk of diabetes [2,3].

This study showed that a high intake of total fiber (primarily cereal and vegetable fiber) was associated with an 18% lower risk of type 2 diabetes (adjusted for dietary and lifestyle factors). While there was no association after adjusting for BMI, their meta-analysis of 18 studies did support the an inverse association between total fiber and cereal fiber intake and risk of type 2 diabetes.

What is it about fiber that is protective? With regard to whole grains, a rich source of fiber, potential mechanisms have been identified [5], including the possible impact of improved postprandial glucose response. However, whole grains are rich in nutrients and phytochemicals, and new hypotheses for the health-protective mechanisms of whole grains beyond fiber are being proposed [6]. In addition, the beneficial effect of fiber seen in this and other studies may be partly mediated by a lower BMI. Dietary fiber may affect appetite and energy intake through a range of processes.

It should be noted that although the effect of whole-grain foods for the prevention of type 2 diabetes is strongly supported by numerous epidemiological studies, a 2008 systematic review by the Cochrane Collaboration [4], which included 1 low-quality RCT and 11 cohort studies, stated that the evidence is too weak to be able to draw a definite conclusion about the preventive effect of this dietary factor.

Strengths of the study included its prospective design and large sample size. Limitations of the study include that dietary intake was assessed only at baseline and measurement error through the use of a questionnaire may have occurred. Although food-frequency questionnaires are widely used, they are subjective estimates and subject to recall bias, and some researchers have questioned their value for use in epidemiologic studies [7]. In addition, the authors note that the inverse association for total fiber and cereal fiber intake in the meta-analysis could be due to residual confounding as fiber intake has been associated with healthier diet, lower BMI, and greater physical activity.

Applications for Clinical Practice

The prevalence of type 2 diabetes has increased rapidly during the past decades in the United States. Dietary guidelines recommend the consumption of whole grains to prevent chronic diseases. The results presented in the current study strengthen the evidence supporting cereal fiber as an important determinant of type 2 diabetes risk. Randomized controlled trials are needed and should elucidate this matter.

TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.

Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).

Courtesy International Society on Thrombosis and Haemostasis

“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.

In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.

Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.

“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.

Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.

“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”

In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”

“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.

Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.

Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.

“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.

“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.

Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.

Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.

TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.

Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).

Courtesy International Society on Thrombosis and Haemostasis

“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.

In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.

Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.

“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.

Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.

“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”

In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”

“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.

Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.

Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.

“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.

“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.

Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.

Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.

TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.

Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).

Courtesy International Society on Thrombosis and Haemostasis

“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.

In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.

Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.

“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.

Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.

“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”

In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”

“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.

Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.

Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.

“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.

“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.

Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.

Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.

Cangrelor became the first intravenous antiplatelet agent acting on ADP receptors for adult patients undergoing percutaneous coronary intervention to receive marketing approval from the Food and Drug Administration, The Medicines Company announced on June 22.

While cangrelor’s unique delivery route and rapid onset and off-set of action set it apart and may give it certain clinical advantages over the three approved oral drugs that target the same platelet receptor – clopidogrel, prasugrel (Effient), and ticagrelor (Brilinta) – cangrelor will also be distinguished by its much higher price. The standard dosage to treat one patient undergoing percutaneous coronary intervention (PCI) with cangrelor (Kengreal) will have a wholesale acquisition cost of $749, Raymond Russo, senior vice president of The Medicines Company, said at a June 23 press briefing. That prices cangrelor substantially above its brand-name competition, which costs roughly $10 for similar treatment, as well as generic clopidogrel, which costs about $3 for the same indication.

“I believe in the strength of the data that showed that cangrelor was superior to the comparator drug [clopidogrel], and if cost were not an issue I’d use cangrelor routinely, but I am not naive; cost is an issue,” said Dr. Deepak L. Bhatt, professor of medicine at Harvard University and executive director of interventional cardiology programs at Brigham and Women’s Hospital in Boston, and co–lead investigator for the CHAMPION PHOENIX pivotal trial that led to cangrelor’s approval (N. Engl. J. Med. 2013;368:1303-13).

Whether or not interventional cardiologists and the centers where they work decide to use cangrelor or one of the oral antiplatelet drugs for coronary artery disease (CAD) patients undergoing PCI will likely depend on a series of considerations that will need to take into account not just drug cost but also practice strategies, a patient’s clinical state, and the potential for ancillary costs from following an entirely different management approach.

The first issue is whether the interventionalist decides to pretreat a patient scheduled for angioplasty and possible immediate PCI following angiography with an ADP-receptor antagonist (also known as a P2Y12-receptor inhibitor) prior to the start of angiography or opts to defer that treatment until the angiography results are available and a decision is made to proceed with PCI. Recent nationwide registry data suggest that roughly half of U.S. interventionalists treat their patients upfront with an ADP-receptor antagonist, usually clopidogrel for patients with stable angina or prasugrel or ticagrelor if they have either a non-ST-elevation MI or a ST-elevation MI, while the other 50% of interventionalists will wait to administer the ADP-receptor antagonist until angiography is complete, Dr. Bhatt explained in an interview.

The advantage to upfront treatment is that by the time the patient is ready for PCI an oral ADP-receptor antagonist is fully absorbed and on board. The disadvantage is that if the coronary anatomy demands a surgical approach to revascularization many surgeons would elect not to operate on a patient freshly dosed with an antiplatelet agent, and these patients often remain hospitalized for several days until the ADP-receptor antagonist clears and the patient’s platelet function returns to normal. Angiography generally identifies 10%-15% of these patients with a CAD distribution that necessitates surgical coronary bypass, and the potential hospitalization expense of waiting for their ADP-receptor antagonist to clear could be a major cost to counterbalance the price of cangrelor, which would obviate this expense if the quick-to-start-and-to-clear cangrelor were used instead of a more lumbering oral drug, he noted.

The other 50% of U.S. interventionalists, Dr. Bhatt included, take a different approach. Recognizing the potential downside of upfront oral antiplatelet therapy if the patient is pegged for bypass surgery following angiography, they elect to wait until the angiography results are in hand. If the angiography results show the patient is destined for surgery or for medical management, then the patient receives no ADP-receptor antagonist. The cardiologist administers an ADP-receptor antagonist only if the patient’s CAD is appropriate for PCI, the fate for most of these CAD patients following angiography. It’s under these circumstances that the advantages of cangrelor kick in, as shown in the results from CHAMPION PHOENIX.

This trial randomized patients to two different types of ADP-receptor antagonist treatment while they were in the coronary catheterization laboratory. The study results showed a statistically significant, 22% relative-risk reduction in the primary endpoint in favor of intravenous cangrelor compared with oral clopidogrel delivered while patients were “on the table” in the interval between angiography and PCI. That 22% relative improvement in outcomes, driven primarily by reductions in periprocedural MIs and stent thrombosis, improved to a 31% relative-risk reduction when The Medicines Company performed a new analysis of the study results at the FDA’s request using a more stringent and conventional definition of periprocedural MIs and stent thrombosis. The time needed to perform this and other FDA-requested analyses largely caused the greater than 2-year gap between the 2013 publication of the CHAMPION PHOENIX results and the FDA’s approval.

But the editorial that accompanied the 2013 publication highlighted what the editorialists perceived as flaws in the study’s design, such as an inadequate loading dose of clopidogrel delivered to a quarter of the patients randomized to that arm, inadequate time allowed for the clopidogrel to fully kick in before PCI began in a third of patients, and the use of clopidogrel as the comparator drug and not a more potent alternative drug, either prasugrel or ticagrelor (N. Engl. J. Med. 2013;368:1356-7).

“Cangrelor was never tested against prasugrel or ticagrelor, and it was compared with inadequate clopidogrel treatment. That was a problem,” reiterated Dr. Richard A. Lange, one of the 2013 editorialists, when interviewed following news of cangrelor’s FDA approval. CHAMPION PHOENIX “wasn’t really a comparison [of two drugs], it was a study of an intravenous strategy, and it’s not a strategy that is needed very often,” said Dr. Lange, an interventional cardiologist and president of the Texas Tech University Health Sciences Center in El Paso. In Dr. Lange’s opinion, the only real need for an intravenous ADP-receptor antagonist is for CAD patients undergoing PCI who are unable to take an oral agent, for example because they are on a ventilator, unable to hold down an oral pill, or unconscious, which collectively are “rare” situations, he said.

Dr. Bhatt noted that another clear indication for an intravenous agent is when MI patients receive morphine for their pain, a situation recently documented to interfere with absorption of oral ADP-receptor antagonists.

From Dr. Bhatt’s perspective, the major issue is practice patterns: “Do the interventionalists treat [with an ADP-receptor antagonist] upstream or not. If they do, then they should do the math,” and determine if the expense of holding a significant minority of patients in the hospital just to allow them to clear the ADP-receptor antagonist prior to coronary bypass surgery outweighs the cost for delaying this treatment and administering cangrelor later only to patients scheduled for PCI. At the center where he practices, Brigham and Women’s Hospital in Boston, he sees a roughly equal mix of interventionalists who prefer to treat patients with clopidogrel upfront, those who treat with ticagrelor upfront, and those who practice as he does and wait until the PCI is a go.

“For my personal practice, cangrelor will fit in quite nicely,” Dr. Bhatt said.

[email protected]

On Twitter@mitchelzoler

Cangrelor became the first intravenous antiplatelet agent acting on ADP receptors for adult patients undergoing percutaneous coronary intervention to receive marketing approval from the Food and Drug Administration, The Medicines Company announced on June 22.

While cangrelor’s unique delivery route and rapid onset and off-set of action set it apart and may give it certain clinical advantages over the three approved oral drugs that target the same platelet receptor – clopidogrel, prasugrel (Effient), and ticagrelor (Brilinta) – cangrelor will also be distinguished by its much higher price. The standard dosage to treat one patient undergoing percutaneous coronary intervention (PCI) with cangrelor (Kengreal) will have a wholesale acquisition cost of $749, Raymond Russo, senior vice president of The Medicines Company, said at a June 23 press briefing. That prices cangrelor substantially above its brand-name competition, which costs roughly $10 for similar treatment, as well as generic clopidogrel, which costs about $3 for the same indication.

“I believe in the strength of the data that showed that cangrelor was superior to the comparator drug [clopidogrel], and if cost were not an issue I’d use cangrelor routinely, but I am not naive; cost is an issue,” said Dr. Deepak L. Bhatt, professor of medicine at Harvard University and executive director of interventional cardiology programs at Brigham and Women’s Hospital in Boston, and co–lead investigator for the CHAMPION PHOENIX pivotal trial that led to cangrelor’s approval (N. Engl. J. Med. 2013;368:1303-13).

Whether or not interventional cardiologists and the centers where they work decide to use cangrelor or one of the oral antiplatelet drugs for coronary artery disease (CAD) patients undergoing PCI will likely depend on a series of considerations that will need to take into account not just drug cost but also practice strategies, a patient’s clinical state, and the potential for ancillary costs from following an entirely different management approach.

The first issue is whether the interventionalist decides to pretreat a patient scheduled for angioplasty and possible immediate PCI following angiography with an ADP-receptor antagonist (also known as a P2Y12-receptor inhibitor) prior to the start of angiography or opts to defer that treatment until the angiography results are available and a decision is made to proceed with PCI. Recent nationwide registry data suggest that roughly half of U.S. interventionalists treat their patients upfront with an ADP-receptor antagonist, usually clopidogrel for patients with stable angina or prasugrel or ticagrelor if they have either a non-ST-elevation MI or a ST-elevation MI, while the other 50% of interventionalists will wait to administer the ADP-receptor antagonist until angiography is complete, Dr. Bhatt explained in an interview.

The advantage to upfront treatment is that by the time the patient is ready for PCI an oral ADP-receptor antagonist is fully absorbed and on board. The disadvantage is that if the coronary anatomy demands a surgical approach to revascularization many surgeons would elect not to operate on a patient freshly dosed with an antiplatelet agent, and these patients often remain hospitalized for several days until the ADP-receptor antagonist clears and the patient’s platelet function returns to normal. Angiography generally identifies 10%-15% of these patients with a CAD distribution that necessitates surgical coronary bypass, and the potential hospitalization expense of waiting for their ADP-receptor antagonist to clear could be a major cost to counterbalance the price of cangrelor, which would obviate this expense if the quick-to-start-and-to-clear cangrelor were used instead of a more lumbering oral drug, he noted.

The other 50% of U.S. interventionalists, Dr. Bhatt included, take a different approach. Recognizing the potential downside of upfront oral antiplatelet therapy if the patient is pegged for bypass surgery following angiography, they elect to wait until the angiography results are in hand. If the angiography results show the patient is destined for surgery or for medical management, then the patient receives no ADP-receptor antagonist. The cardiologist administers an ADP-receptor antagonist only if the patient’s CAD is appropriate for PCI, the fate for most of these CAD patients following angiography. It’s under these circumstances that the advantages of cangrelor kick in, as shown in the results from CHAMPION PHOENIX.

This trial randomized patients to two different types of ADP-receptor antagonist treatment while they were in the coronary catheterization laboratory. The study results showed a statistically significant, 22% relative-risk reduction in the primary endpoint in favor of intravenous cangrelor compared with oral clopidogrel delivered while patients were “on the table” in the interval between angiography and PCI. That 22% relative improvement in outcomes, driven primarily by reductions in periprocedural MIs and stent thrombosis, improved to a 31% relative-risk reduction when The Medicines Company performed a new analysis of the study results at the FDA’s request using a more stringent and conventional definition of periprocedural MIs and stent thrombosis. The time needed to perform this and other FDA-requested analyses largely caused the greater than 2-year gap between the 2013 publication of the CHAMPION PHOENIX results and the FDA’s approval.

But the editorial that accompanied the 2013 publication highlighted what the editorialists perceived as flaws in the study’s design, such as an inadequate loading dose of clopidogrel delivered to a quarter of the patients randomized to that arm, inadequate time allowed for the clopidogrel to fully kick in before PCI began in a third of patients, and the use of clopidogrel as the comparator drug and not a more potent alternative drug, either prasugrel or ticagrelor (N. Engl. J. Med. 2013;368:1356-7).

“Cangrelor was never tested against prasugrel or ticagrelor, and it was compared with inadequate clopidogrel treatment. That was a problem,” reiterated Dr. Richard A. Lange, one of the 2013 editorialists, when interviewed following news of cangrelor’s FDA approval. CHAMPION PHOENIX “wasn’t really a comparison [of two drugs], it was a study of an intravenous strategy, and it’s not a strategy that is needed very often,” said Dr. Lange, an interventional cardiologist and president of the Texas Tech University Health Sciences Center in El Paso. In Dr. Lange’s opinion, the only real need for an intravenous ADP-receptor antagonist is for CAD patients undergoing PCI who are unable to take an oral agent, for example because they are on a ventilator, unable to hold down an oral pill, or unconscious, which collectively are “rare” situations, he said.

Dr. Bhatt noted that another clear indication for an intravenous agent is when MI patients receive morphine for their pain, a situation recently documented to interfere with absorption of oral ADP-receptor antagonists.

From Dr. Bhatt’s perspective, the major issue is practice patterns: “Do the interventionalists treat [with an ADP-receptor antagonist] upstream or not. If they do, then they should do the math,” and determine if the expense of holding a significant minority of patients in the hospital just to allow them to clear the ADP-receptor antagonist prior to coronary bypass surgery outweighs the cost for delaying this treatment and administering cangrelor later only to patients scheduled for PCI. At the center where he practices, Brigham and Women’s Hospital in Boston, he sees a roughly equal mix of interventionalists who prefer to treat patients with clopidogrel upfront, those who treat with ticagrelor upfront, and those who practice as he does and wait until the PCI is a go.

“For my personal practice, cangrelor will fit in quite nicely,” Dr. Bhatt said.

[email protected]

On Twitter@mitchelzoler

Cangrelor became the first intravenous antiplatelet agent acting on ADP receptors for adult patients undergoing percutaneous coronary intervention to receive marketing approval from the Food and Drug Administration, The Medicines Company announced on June 22.

While cangrelor’s unique delivery route and rapid onset and off-set of action set it apart and may give it certain clinical advantages over the three approved oral drugs that target the same platelet receptor – clopidogrel, prasugrel (Effient), and ticagrelor (Brilinta) – cangrelor will also be distinguished by its much higher price. The standard dosage to treat one patient undergoing percutaneous coronary intervention (PCI) with cangrelor (Kengreal) will have a wholesale acquisition cost of $749, Raymond Russo, senior vice president of The Medicines Company, said at a June 23 press briefing. That prices cangrelor substantially above its brand-name competition, which costs roughly $10 for similar treatment, as well as generic clopidogrel, which costs about $3 for the same indication.

“I believe in the strength of the data that showed that cangrelor was superior to the comparator drug [clopidogrel], and if cost were not an issue I’d use cangrelor routinely, but I am not naive; cost is an issue,” said Dr. Deepak L. Bhatt, professor of medicine at Harvard University and executive director of interventional cardiology programs at Brigham and Women’s Hospital in Boston, and co–lead investigator for the CHAMPION PHOENIX pivotal trial that led to cangrelor’s approval (N. Engl. J. Med. 2013;368:1303-13).

Whether or not interventional cardiologists and the centers where they work decide to use cangrelor or one of the oral antiplatelet drugs for coronary artery disease (CAD) patients undergoing PCI will likely depend on a series of considerations that will need to take into account not just drug cost but also practice strategies, a patient’s clinical state, and the potential for ancillary costs from following an entirely different management approach.

The first issue is whether the interventionalist decides to pretreat a patient scheduled for angioplasty and possible immediate PCI following angiography with an ADP-receptor antagonist (also known as a P2Y12-receptor inhibitor) prior to the start of angiography or opts to defer that treatment until the angiography results are available and a decision is made to proceed with PCI. Recent nationwide registry data suggest that roughly half of U.S. interventionalists treat their patients upfront with an ADP-receptor antagonist, usually clopidogrel for patients with stable angina or prasugrel or ticagrelor if they have either a non-ST-elevation MI or a ST-elevation MI, while the other 50% of interventionalists will wait to administer the ADP-receptor antagonist until angiography is complete, Dr. Bhatt explained in an interview.

The advantage to upfront treatment is that by the time the patient is ready for PCI an oral ADP-receptor antagonist is fully absorbed and on board. The disadvantage is that if the coronary anatomy demands a surgical approach to revascularization many surgeons would elect not to operate on a patient freshly dosed with an antiplatelet agent, and these patients often remain hospitalized for several days until the ADP-receptor antagonist clears and the patient’s platelet function returns to normal. Angiography generally identifies 10%-15% of these patients with a CAD distribution that necessitates surgical coronary bypass, and the potential hospitalization expense of waiting for their ADP-receptor antagonist to clear could be a major cost to counterbalance the price of cangrelor, which would obviate this expense if the quick-to-start-and-to-clear cangrelor were used instead of a more lumbering oral drug, he noted.

The other 50% of U.S. interventionalists, Dr. Bhatt included, take a different approach. Recognizing the potential downside of upfront oral antiplatelet therapy if the patient is pegged for bypass surgery following angiography, they elect to wait until the angiography results are in hand. If the angiography results show the patient is destined for surgery or for medical management, then the patient receives no ADP-receptor antagonist. The cardiologist administers an ADP-receptor antagonist only if the patient’s CAD is appropriate for PCI, the fate for most of these CAD patients following angiography. It’s under these circumstances that the advantages of cangrelor kick in, as shown in the results from CHAMPION PHOENIX.

This trial randomized patients to two different types of ADP-receptor antagonist treatment while they were in the coronary catheterization laboratory. The study results showed a statistically significant, 22% relative-risk reduction in the primary endpoint in favor of intravenous cangrelor compared with oral clopidogrel delivered while patients were “on the table” in the interval between angiography and PCI. That 22% relative improvement in outcomes, driven primarily by reductions in periprocedural MIs and stent thrombosis, improved to a 31% relative-risk reduction when The Medicines Company performed a new analysis of the study results at the FDA’s request using a more stringent and conventional definition of periprocedural MIs and stent thrombosis. The time needed to perform this and other FDA-requested analyses largely caused the greater than 2-year gap between the 2013 publication of the CHAMPION PHOENIX results and the FDA’s approval.

But the editorial that accompanied the 2013 publication highlighted what the editorialists perceived as flaws in the study’s design, such as an inadequate loading dose of clopidogrel delivered to a quarter of the patients randomized to that arm, inadequate time allowed for the clopidogrel to fully kick in before PCI began in a third of patients, and the use of clopidogrel as the comparator drug and not a more potent alternative drug, either prasugrel or ticagrelor (N. Engl. J. Med. 2013;368:1356-7).

“Cangrelor was never tested against prasugrel or ticagrelor, and it was compared with inadequate clopidogrel treatment. That was a problem,” reiterated Dr. Richard A. Lange, one of the 2013 editorialists, when interviewed following news of cangrelor’s FDA approval. CHAMPION PHOENIX “wasn’t really a comparison [of two drugs], it was a study of an intravenous strategy, and it’s not a strategy that is needed very often,” said Dr. Lange, an interventional cardiologist and president of the Texas Tech University Health Sciences Center in El Paso. In Dr. Lange’s opinion, the only real need for an intravenous ADP-receptor antagonist is for CAD patients undergoing PCI who are unable to take an oral agent, for example because they are on a ventilator, unable to hold down an oral pill, or unconscious, which collectively are “rare” situations, he said.

Dr. Bhatt noted that another clear indication for an intravenous agent is when MI patients receive morphine for their pain, a situation recently documented to interfere with absorption of oral ADP-receptor antagonists.

From Dr. Bhatt’s perspective, the major issue is practice patterns: “Do the interventionalists treat [with an ADP-receptor antagonist] upstream or not. If they do, then they should do the math,” and determine if the expense of holding a significant minority of patients in the hospital just to allow them to clear the ADP-receptor antagonist prior to coronary bypass surgery outweighs the cost for delaying this treatment and administering cangrelor later only to patients scheduled for PCI. At the center where he practices, Brigham and Women’s Hospital in Boston, he sees a roughly equal mix of interventionalists who prefer to treat patients with clopidogrel upfront, those who treat with ticagrelor upfront, and those who practice as he does and wait until the PCI is a go.

“For my personal practice, cangrelor will fit in quite nicely,” Dr. Bhatt said.

[email protected]

On Twitter@mitchelzoler

Recently, there have been several news stories about physicians committing suicide. This is across all levels of the profession, including medical students, residents, and attendings.

Historically, doctors have had a higher rate of suicide than most professions. I’m not sure if that number has crept up recently, or if events are garnering more attention than before. They’re certainly mentioned prominently on various medical blogs.

Why do you see this in medicine? There are probably a number of factors that overlap:

• A high pressure job, where mistakes aren’t allowed (which isn’t humanly possible).

• A culture of litigation, where even minor mistakes are taken to court.

• Declining financial reimbursement, making it harder to support a practice and family, especially when you’re already six figures in debt coming out of medical school.

• Pressure to work longer hours and see far more patients than is possible, which increases the potential for mistakes. This further reduces the amount of family and recreational time available to balance ourselves.

• An increase in “empowered patients” demanding unnecessary tests and treatments because it said so on the Internet.

• A general lack of respect for the profession, to where we’re now “providers” who are vilified for political reasons by insurance companies, consumer groups, and both major parties.

• The need for us not to admit or seek treatment for human vulnerabilities. Our own health (mental and physical) is neglected because we can’t take time off to address it and a fear that doing so may result in us having our licenses penalized.

Any of the above makes life unpleasant, but when you combine them … it can be a perfect storm that tips a person over the edge.

In medicine, seeking help is often seen as a weakness, and even the most rational person under difficult circumstances can snap. None of the physicians who’ve ended their lives started out saying that was how they wanted their medical career to wind up. But when stressors pile up, it may appear to them to be the only way out. In that frame of mind, you think doing something so drastic is better for everyone around you. It isn’t true, but at that point you don’t believe it.

A physician’s suicide, even outside of its effects on their family, is a loss. A physician is a community resource, leaving behind relationships with patients in various stages of work-ups and treatments. There’s always another doctor, but it’s not easy, or immediate, to find someone who’s a good fit for the area.

I don’t know if this is a peculiarly American phenomenon or if my colleagues in Canada, Europe, and elsewhere face similar challenges. If the suicide rate elsewhere is lower, what can we learn from them to make things better here? If it’s the same, what can we do collectively to find an answer? Every country needs doctors and can’t afford to lose them.

Is there an easy solution? Probably not. Too many factors to fix. But it’s a serious problem and needs attention.

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

Recently, there have been several news stories about physicians committing suicide. This is across all levels of the profession, including medical students, residents, and attendings.

Historically, doctors have had a higher rate of suicide than most professions. I’m not sure if that number has crept up recently, or if events are garnering more attention than before. They’re certainly mentioned prominently on various medical blogs.

Why do you see this in medicine? There are probably a number of factors that overlap:

• A high pressure job, where mistakes aren’t allowed (which isn’t humanly possible).

• A culture of litigation, where even minor mistakes are taken to court.

• Declining financial reimbursement, making it harder to support a practice and family, especially when you’re already six figures in debt coming out of medical school.

• Pressure to work longer hours and see far more patients than is possible, which increases the potential for mistakes. This further reduces the amount of family and recreational time available to balance ourselves.

• An increase in “empowered patients” demanding unnecessary tests and treatments because it said so on the Internet.

• A general lack of respect for the profession, to where we’re now “providers” who are vilified for political reasons by insurance companies, consumer groups, and both major parties.

• The need for us not to admit or seek treatment for human vulnerabilities. Our own health (mental and physical) is neglected because we can’t take time off to address it and a fear that doing so may result in us having our licenses penalized.

Any of the above makes life unpleasant, but when you combine them … it can be a perfect storm that tips a person over the edge.

In medicine, seeking help is often seen as a weakness, and even the most rational person under difficult circumstances can snap. None of the physicians who’ve ended their lives started out saying that was how they wanted their medical career to wind up. But when stressors pile up, it may appear to them to be the only way out. In that frame of mind, you think doing something so drastic is better for everyone around you. It isn’t true, but at that point you don’t believe it.

A physician’s suicide, even outside of its effects on their family, is a loss. A physician is a community resource, leaving behind relationships with patients in various stages of work-ups and treatments. There’s always another doctor, but it’s not easy, or immediate, to find someone who’s a good fit for the area.

I don’t know if this is a peculiarly American phenomenon or if my colleagues in Canada, Europe, and elsewhere face similar challenges. If the suicide rate elsewhere is lower, what can we learn from them to make things better here? If it’s the same, what can we do collectively to find an answer? Every country needs doctors and can’t afford to lose them.

Is there an easy solution? Probably not. Too many factors to fix. But it’s a serious problem and needs attention.

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

Recently, there have been several news stories about physicians committing suicide. This is across all levels of the profession, including medical students, residents, and attendings.

Historically, doctors have had a higher rate of suicide than most professions. I’m not sure if that number has crept up recently, or if events are garnering more attention than before. They’re certainly mentioned prominently on various medical blogs.

Why do you see this in medicine? There are probably a number of factors that overlap:

• A high pressure job, where mistakes aren’t allowed (which isn’t humanly possible).

• A culture of litigation, where even minor mistakes are taken to court.

• Declining financial reimbursement, making it harder to support a practice and family, especially when you’re already six figures in debt coming out of medical school.

• Pressure to work longer hours and see far more patients than is possible, which increases the potential for mistakes. This further reduces the amount of family and recreational time available to balance ourselves.

• An increase in “empowered patients” demanding unnecessary tests and treatments because it said so on the Internet.

• A general lack of respect for the profession, to where we’re now “providers” who are vilified for political reasons by insurance companies, consumer groups, and both major parties.

• The need for us not to admit or seek treatment for human vulnerabilities. Our own health (mental and physical) is neglected because we can’t take time off to address it and a fear that doing so may result in us having our licenses penalized.

Any of the above makes life unpleasant, but when you combine them … it can be a perfect storm that tips a person over the edge.

In medicine, seeking help is often seen as a weakness, and even the most rational person under difficult circumstances can snap. None of the physicians who’ve ended their lives started out saying that was how they wanted their medical career to wind up. But when stressors pile up, it may appear to them to be the only way out. In that frame of mind, you think doing something so drastic is better for everyone around you. It isn’t true, but at that point you don’t believe it.

A physician’s suicide, even outside of its effects on their family, is a loss. A physician is a community resource, leaving behind relationships with patients in various stages of work-ups and treatments. There’s always another doctor, but it’s not easy, or immediate, to find someone who’s a good fit for the area.

I don’t know if this is a peculiarly American phenomenon or if my colleagues in Canada, Europe, and elsewhere face similar challenges. If the suicide rate elsewhere is lower, what can we learn from them to make things better here? If it’s the same, what can we do collectively to find an answer? Every country needs doctors and can’t afford to lose them.

Is there an easy solution? Probably not. Too many factors to fix. But it’s a serious problem and needs attention.

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

The recent endorsements by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee of the new genetically manufactured, subcutaneously administered cholesterol-lowering agents alirocumab (Sanofi-Regeneron) and evolocumab (Pfizer) have sent a jolt through the world of cholesterol therapy. Proposed for the treatment of patients with high-risk cardiovascular disease and homozygous familial hypercholesterolemia (HoFH), the decisions suggest that the committee has developed a severe case of scientific amnesia.

A case can be made for the approval for the very-high-risk and untreatable patients with HoFH, but the decision to treat millions of Americans based on the paucity of clinical data available would be disturbing, if not irresponsible.

It is clear that these proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a powerful therapy for reducing LDL cholesterol, with a reported decrease of about 60% after only 12 or 52 weeks of treatment. Based on four small studies lasting 10-12 weeks and without any clinical outcome data, the committee recommended approving evolocumab for lifetime therapy without anything to support its clinical effectiveness or safety.

Dr. Robert J. Smith, who chaired the advisory committee meeting, faced with approving the drug or delaying a decision until a randomized clinical trial can be completed said, “I am unwilling to subject patients to the wait.” A publication of the American College of Cardiology suggested that these two monoclonal antibody drugs could replace generic statins in 70 million Americans at an estimated cost of $7,000-$12,000 a year. Talk about breaking the bank.

Only recently, we decided that the appropriate statin therapy for cholesterol control should use the dosing from the original clinical trials rather than chasing LDL levels to the lowest level possible. We now have a class of drugs that clearly can lower the cholesterol to a level never seen before, and we are about to discard that therapeutic advice.

We have experience in chasing blood levels with uncertain outcomes. Reducing blood sugar to a very low hemoglobin A_1c level led to adverse clinical events and increased mortality in type 2 diabetes. Raising HDL with the cholesterol ester transfer protein (CETP) inhibitor torcetrapib in a study of 15,000 patients in an outcome trial carried out over a number of years led to increased blood pressure and mortality by 58%, which was associated with a 25% decrease in LDL cholesterol and a 72% increase in HDL, both effects presumed to be remarkably beneficial (N. Engl. J. Med. 2007;357:2109-22).

It is quite possible that these new agents can further decrease coronary vascular mortality. A healthy controversy has raged for some time in regard to the “LDL hypothesis,” compared with therapy based upon the clinical trial outcome. The recent IMPROVE-IT report (N. Engl. J. Med. 2015;372:2387-97) provides some data to support the LDL hypothesis. In that study, the addition of 10 mg of ezetimibe to 40 mg of simvastatin in 18,144 patients followed for up to 6 years resulted in a 2% decrease in mortality associated with a 15.8-mg decrease in serum LDL.

Would it not be prudent to have similar data with the new drug on the street? If it is as potent as it appears to be, a trial of much shorter duration might demonstrate its potency and safety before it is offered to 70 million Americans. The FDA has been reluctant to use surrogate endpoints for approving drugs, but its position has not always been consistent. For some time the FDA has, on occasion, approved drugs that can lower cholesterol with limited outcome data as it did with ezetimibe. However, the decision in regard to the PCSK9 inhibitors will have a much larger impact on care than an add-on drug like ezetimibe. Let’s hope that the FDA shows better judgment than its advisory committee.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The recent endorsements by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee of the new genetically manufactured, subcutaneously administered cholesterol-lowering agents alirocumab (Sanofi-Regeneron) and evolocumab (Pfizer) have sent a jolt through the world of cholesterol therapy. Proposed for the treatment of patients with high-risk cardiovascular disease and homozygous familial hypercholesterolemia (HoFH), the decisions suggest that the committee has developed a severe case of scientific amnesia.

A case can be made for the approval for the very-high-risk and untreatable patients with HoFH, but the decision to treat millions of Americans based on the paucity of clinical data available would be disturbing, if not irresponsible.

It is clear that these proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a powerful therapy for reducing LDL cholesterol, with a reported decrease of about 60% after only 12 or 52 weeks of treatment. Based on four small studies lasting 10-12 weeks and without any clinical outcome data, the committee recommended approving evolocumab for lifetime therapy without anything to support its clinical effectiveness or safety.

Dr. Robert J. Smith, who chaired the advisory committee meeting, faced with approving the drug or delaying a decision until a randomized clinical trial can be completed said, “I am unwilling to subject patients to the wait.” A publication of the American College of Cardiology suggested that these two monoclonal antibody drugs could replace generic statins in 70 million Americans at an estimated cost of $7,000-$12,000 a year. Talk about breaking the bank.

Only recently, we decided that the appropriate statin therapy for cholesterol control should use the dosing from the original clinical trials rather than chasing LDL levels to the lowest level possible. We now have a class of drugs that clearly can lower the cholesterol to a level never seen before, and we are about to discard that therapeutic advice.

We have experience in chasing blood levels with uncertain outcomes. Reducing blood sugar to a very low hemoglobin A_1c level led to adverse clinical events and increased mortality in type 2 diabetes. Raising HDL with the cholesterol ester transfer protein (CETP) inhibitor torcetrapib in a study of 15,000 patients in an outcome trial carried out over a number of years led to increased blood pressure and mortality by 58%, which was associated with a 25% decrease in LDL cholesterol and a 72% increase in HDL, both effects presumed to be remarkably beneficial (N. Engl. J. Med. 2007;357:2109-22).

It is quite possible that these new agents can further decrease coronary vascular mortality. A healthy controversy has raged for some time in regard to the “LDL hypothesis,” compared with therapy based upon the clinical trial outcome. The recent IMPROVE-IT report (N. Engl. J. Med. 2015;372:2387-97) provides some data to support the LDL hypothesis. In that study, the addition of 10 mg of ezetimibe to 40 mg of simvastatin in 18,144 patients followed for up to 6 years resulted in a 2% decrease in mortality associated with a 15.8-mg decrease in serum LDL.

Would it not be prudent to have similar data with the new drug on the street? If it is as potent as it appears to be, a trial of much shorter duration might demonstrate its potency and safety before it is offered to 70 million Americans. The FDA has been reluctant to use surrogate endpoints for approving drugs, but its position has not always been consistent. For some time the FDA has, on occasion, approved drugs that can lower cholesterol with limited outcome data as it did with ezetimibe. However, the decision in regard to the PCSK9 inhibitors will have a much larger impact on care than an add-on drug like ezetimibe. Let’s hope that the FDA shows better judgment than its advisory committee.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The recent endorsements by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee of the new genetically manufactured, subcutaneously administered cholesterol-lowering agents alirocumab (Sanofi-Regeneron) and evolocumab (Pfizer) have sent a jolt through the world of cholesterol therapy. Proposed for the treatment of patients with high-risk cardiovascular disease and homozygous familial hypercholesterolemia (HoFH), the decisions suggest that the committee has developed a severe case of scientific amnesia.

A case can be made for the approval for the very-high-risk and untreatable patients with HoFH, but the decision to treat millions of Americans based on the paucity of clinical data available would be disturbing, if not irresponsible.

It is clear that these proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a powerful therapy for reducing LDL cholesterol, with a reported decrease of about 60% after only 12 or 52 weeks of treatment. Based on four small studies lasting 10-12 weeks and without any clinical outcome data, the committee recommended approving evolocumab for lifetime therapy without anything to support its clinical effectiveness or safety.

Dr. Robert J. Smith, who chaired the advisory committee meeting, faced with approving the drug or delaying a decision until a randomized clinical trial can be completed said, “I am unwilling to subject patients to the wait.” A publication of the American College of Cardiology suggested that these two monoclonal antibody drugs could replace generic statins in 70 million Americans at an estimated cost of $7,000-$12,000 a year. Talk about breaking the bank.

Only recently, we decided that the appropriate statin therapy for cholesterol control should use the dosing from the original clinical trials rather than chasing LDL levels to the lowest level possible. We now have a class of drugs that clearly can lower the cholesterol to a level never seen before, and we are about to discard that therapeutic advice.

We have experience in chasing blood levels with uncertain outcomes. Reducing blood sugar to a very low hemoglobin A_1c level led to adverse clinical events and increased mortality in type 2 diabetes. Raising HDL with the cholesterol ester transfer protein (CETP) inhibitor torcetrapib in a study of 15,000 patients in an outcome trial carried out over a number of years led to increased blood pressure and mortality by 58%, which was associated with a 25% decrease in LDL cholesterol and a 72% increase in HDL, both effects presumed to be remarkably beneficial (N. Engl. J. Med. 2007;357:2109-22).

It is quite possible that these new agents can further decrease coronary vascular mortality. A healthy controversy has raged for some time in regard to the “LDL hypothesis,” compared with therapy based upon the clinical trial outcome. The recent IMPROVE-IT report (N. Engl. J. Med. 2015;372:2387-97) provides some data to support the LDL hypothesis. In that study, the addition of 10 mg of ezetimibe to 40 mg of simvastatin in 18,144 patients followed for up to 6 years resulted in a 2% decrease in mortality associated with a 15.8-mg decrease in serum LDL.

Would it not be prudent to have similar data with the new drug on the street? If it is as potent as it appears to be, a trial of much shorter duration might demonstrate its potency and safety before it is offered to 70 million Americans. The FDA has been reluctant to use surrogate endpoints for approving drugs, but its position has not always been consistent. For some time the FDA has, on occasion, approved drugs that can lower cholesterol with limited outcome data as it did with ezetimibe. However, the decision in regard to the PCSK9 inhibitors will have a much larger impact on care than an add-on drug like ezetimibe. Let’s hope that the FDA shows better judgment than its advisory committee.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment for adults with chronic insomnia, according to a review published online ahead of print June 9 in Annals of Internal Medicine. Researchers analyzed 20 randomized controlled trials that included 1,162 participants, of whom 64% were female, with a mean age of 56. Approaches to CBT-I incorporated techniques such as cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. At the post-treatment time point, sleep onset latency improved by an average of 19.03 minutes, wake after sleep onset improved by 26.00 minutes, total sleep time improved by 7.61 minutes, and sleep efficiency improved by 9.91%. These changes seemed to be sustained at later time points. These findings provide evidence that the psychologic approach to chronic insomnia is safer and better tolerated than medication.

Lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain β-amyloid burden, brain glucose metabolism, or hippocampal volume, according to a study published online ahead of print June 10 in Neurology. Researchers evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with an average age of 74. The researchers analyzed the data with backward elimination general linear models. Greater cognitive activity was correlated with greater estimated IQ and education and better neuropsychologic testing performance. Evidence did not support an association of Pittsburgh compound B retention, ¹⁸F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, nor with current physical activity.

Among people who have had organ transplants, taking calcineurin daily to prevent organ rejection may protect against Alzheimer’s disease, according to a study published online ahead of print June 8 in Journal of Alzheimer’s Disease. Researchers analyzed data from the medical records of 2,644 patients who received organ transplants and must take calcineurin inhibitor-based medications for the rest of their lives. The participants were separated into groups by age at the time of last visit or death, gender, and ethnicity. Eight participants showed evidence of dementia. Two of these participants were younger than 65, five were between ages 65 and 74, and one person was between ages 75 and 84. The prevalence of dementia and Alzheimer’s disease in the study population was significantly lower than that in the general population.

Academic performance may decline after pediatric epilepsy surgery, according to a study published in the June issue of Epilepsy & Behavior. Investigators examined 136 children with a mean age of 14.3 who underwent resective epilepsy surgery. Academic functioning was assessed before and after surgery using standardized tests of reading, reading comprehension, arithmetic, and spelling. At baseline, 65% of the children displayed low achievement, and 28% had underachievement in at least one academic domain. Performance in reading, numeral operations, and spelling significantly declined after surgery among all patients. Seizure freedom at follow-up did not influence this relationship. Reading comprehension and IQ remained unchanged after surgery. The researchers found similar results when examining patients with a baseline IQ of 70 or greater and when controlling for IQ.

Incident stroke does not explain racial differences in cognitive decline or affect cognition differently by race, according to a study published online ahead of print May 21 in Stroke. Included in this study were 4,908 black and white participants who were age 65 or older and free of stroke and cognitive impairment. Researchers examined longitudinal changes in global cognition by race, before and after adjusting the data. In all, 7.5% of blacks and 6.7% of whites had incident stroke during a mean of 4.1 years of follow-up. Blacks had greater cognitive decline than whites, and the difference persisted after adjustments for cumulative incidence of stroke. Stroke was associated with a decrease in global cognition similar to that associated with approximately 7.9 years of cognitive aging.

Type 2 diabetes may protect against amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print June 1 in JAMA Neurology. The population-based, nested case–control study included 3,650 Danish residents who received a diagnosis of ALS between January 1, 1982, and December 31, 2009, and 365,000 age- and sex-matched controls. The estimated odds ratio for ALS among individuals with diabetes was 0.61. Researchers found a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association with diabetes was stronger with increasing age at ALS diagnosis, and the odds ratio for first mention of diabetes was 1.66 before age 40, but 0.52 for older ages.

The FDA has approved Qudexy XR (topiramate) extended-release capsules for use as initial monotherapy in patients age two and older with partial-onset seizures or primary generalized tonic–clonic seizures. The capsules are engineered to deliver a consistent pharmacokinetic profile. Qudexy XR is approved for administration by sprinkling the contents onto soft food, which may aid the treatment of young children who have difficulty swallowing whole capsules or tablets. Qudexy XR previously was approved for use as initial monotherapy in patients age 10 and older with partial-onset seizures or primary generalized tonic–clonic seizures. The drug is also approved as an adjunctive therapy in patients age two or older with partial-onset seizures, primary generalized tonic–clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

—Kimberly Williams

Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment for adults with chronic insomnia, according to a review published online ahead of print June 9 in Annals of Internal Medicine. Researchers analyzed 20 randomized controlled trials that included 1,162 participants, of whom 64% were female, with a mean age of 56. Approaches to CBT-I incorporated techniques such as cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. At the post-treatment time point, sleep onset latency improved by an average of 19.03 minutes, wake after sleep onset improved by 26.00 minutes, total sleep time improved by 7.61 minutes, and sleep efficiency improved by 9.91%. These changes seemed to be sustained at later time points. These findings provide evidence that the psychologic approach to chronic insomnia is safer and better tolerated than medication.

Lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain β-amyloid burden, brain glucose metabolism, or hippocampal volume, according to a study published online ahead of print June 10 in Neurology. Researchers evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with an average age of 74. The researchers analyzed the data with backward elimination general linear models. Greater cognitive activity was correlated with greater estimated IQ and education and better neuropsychologic testing performance. Evidence did not support an association of Pittsburgh compound B retention, ¹⁸F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, nor with current physical activity.

Among people who have had organ transplants, taking calcineurin daily to prevent organ rejection may protect against Alzheimer’s disease, according to a study published online ahead of print June 8 in Journal of Alzheimer’s Disease. Researchers analyzed data from the medical records of 2,644 patients who received organ transplants and must take calcineurin inhibitor-based medications for the rest of their lives. The participants were separated into groups by age at the time of last visit or death, gender, and ethnicity. Eight participants showed evidence of dementia. Two of these participants were younger than 65, five were between ages 65 and 74, and one person was between ages 75 and 84. The prevalence of dementia and Alzheimer’s disease in the study population was significantly lower than that in the general population.

Academic performance may decline after pediatric epilepsy surgery, according to a study published in the June issue of Epilepsy & Behavior. Investigators examined 136 children with a mean age of 14.3 who underwent resective epilepsy surgery. Academic functioning was assessed before and after surgery using standardized tests of reading, reading comprehension, arithmetic, and spelling. At baseline, 65% of the children displayed low achievement, and 28% had underachievement in at least one academic domain. Performance in reading, numeral operations, and spelling significantly declined after surgery among all patients. Seizure freedom at follow-up did not influence this relationship. Reading comprehension and IQ remained unchanged after surgery. The researchers found similar results when examining patients with a baseline IQ of 70 or greater and when controlling for IQ.

Incident stroke does not explain racial differences in cognitive decline or affect cognition differently by race, according to a study published online ahead of print May 21 in Stroke. Included in this study were 4,908 black and white participants who were age 65 or older and free of stroke and cognitive impairment. Researchers examined longitudinal changes in global cognition by race, before and after adjusting the data. In all, 7.5% of blacks and 6.7% of whites had incident stroke during a mean of 4.1 years of follow-up. Blacks had greater cognitive decline than whites, and the difference persisted after adjustments for cumulative incidence of stroke. Stroke was associated with a decrease in global cognition similar to that associated with approximately 7.9 years of cognitive aging.

Type 2 diabetes may protect against amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print June 1 in JAMA Neurology. The population-based, nested case–control study included 3,650 Danish residents who received a diagnosis of ALS between January 1, 1982, and December 31, 2009, and 365,000 age- and sex-matched controls. The estimated odds ratio for ALS among individuals with diabetes was 0.61. Researchers found a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association with diabetes was stronger with increasing age at ALS diagnosis, and the odds ratio for first mention of diabetes was 1.66 before age 40, but 0.52 for older ages.

The FDA has approved Qudexy XR (topiramate) extended-release capsules for use as initial monotherapy in patients age two and older with partial-onset seizures or primary generalized tonic–clonic seizures. The capsules are engineered to deliver a consistent pharmacokinetic profile. Qudexy XR is approved for administration by sprinkling the contents onto soft food, which may aid the treatment of young children who have difficulty swallowing whole capsules or tablets. Qudexy XR previously was approved for use as initial monotherapy in patients age 10 and older with partial-onset seizures or primary generalized tonic–clonic seizures. The drug is also approved as an adjunctive therapy in patients age two or older with partial-onset seizures, primary generalized tonic–clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

—Kimberly Williams

Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment for adults with chronic insomnia, according to a review published online ahead of print June 9 in Annals of Internal Medicine. Researchers analyzed 20 randomized controlled trials that included 1,162 participants, of whom 64% were female, with a mean age of 56. Approaches to CBT-I incorporated techniques such as cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. At the post-treatment time point, sleep onset latency improved by an average of 19.03 minutes, wake after sleep onset improved by 26.00 minutes, total sleep time improved by 7.61 minutes, and sleep efficiency improved by 9.91%. These changes seemed to be sustained at later time points. These findings provide evidence that the psychologic approach to chronic insomnia is safer and better tolerated than medication.

Lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain β-amyloid burden, brain glucose metabolism, or hippocampal volume, according to a study published online ahead of print June 10 in Neurology. Researchers evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with an average age of 74. The researchers analyzed the data with backward elimination general linear models. Greater cognitive activity was correlated with greater estimated IQ and education and better neuropsychologic testing performance. Evidence did not support an association of Pittsburgh compound B retention, ¹⁸F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, nor with current physical activity.

Among people who have had organ transplants, taking calcineurin daily to prevent organ rejection may protect against Alzheimer’s disease, according to a study published online ahead of print June 8 in Journal of Alzheimer’s Disease. Researchers analyzed data from the medical records of 2,644 patients who received organ transplants and must take calcineurin inhibitor-based medications for the rest of their lives. The participants were separated into groups by age at the time of last visit or death, gender, and ethnicity. Eight participants showed evidence of dementia. Two of these participants were younger than 65, five were between ages 65 and 74, and one person was between ages 75 and 84. The prevalence of dementia and Alzheimer’s disease in the study population was significantly lower than that in the general population.

Academic performance may decline after pediatric epilepsy surgery, according to a study published in the June issue of Epilepsy & Behavior. Investigators examined 136 children with a mean age of 14.3 who underwent resective epilepsy surgery. Academic functioning was assessed before and after surgery using standardized tests of reading, reading comprehension, arithmetic, and spelling. At baseline, 65% of the children displayed low achievement, and 28% had underachievement in at least one academic domain. Performance in reading, numeral operations, and spelling significantly declined after surgery among all patients. Seizure freedom at follow-up did not influence this relationship. Reading comprehension and IQ remained unchanged after surgery. The researchers found similar results when examining patients with a baseline IQ of 70 or greater and when controlling for IQ.

Incident stroke does not explain racial differences in cognitive decline or affect cognition differently by race, according to a study published online ahead of print May 21 in Stroke. Included in this study were 4,908 black and white participants who were age 65 or older and free of stroke and cognitive impairment. Researchers examined longitudinal changes in global cognition by race, before and after adjusting the data. In all, 7.5% of blacks and 6.7% of whites had incident stroke during a mean of 4.1 years of follow-up. Blacks had greater cognitive decline than whites, and the difference persisted after adjustments for cumulative incidence of stroke. Stroke was associated with a decrease in global cognition similar to that associated with approximately 7.9 years of cognitive aging.

Type 2 diabetes may protect against amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print June 1 in JAMA Neurology. The population-based, nested case–control study included 3,650 Danish residents who received a diagnosis of ALS between January 1, 1982, and December 31, 2009, and 365,000 age- and sex-matched controls. The estimated odds ratio for ALS among individuals with diabetes was 0.61. Researchers found a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association with diabetes was stronger with increasing age at ALS diagnosis, and the odds ratio for first mention of diabetes was 1.66 before age 40, but 0.52 for older ages.

The FDA has approved Qudexy XR (topiramate) extended-release capsules for use as initial monotherapy in patients age two and older with partial-onset seizures or primary generalized tonic–clonic seizures. The capsules are engineered to deliver a consistent pharmacokinetic profile. Qudexy XR is approved for administration by sprinkling the contents onto soft food, which may aid the treatment of young children who have difficulty swallowing whole capsules or tablets. Qudexy XR previously was approved for use as initial monotherapy in patients age 10 and older with partial-onset seizures or primary generalized tonic–clonic seizures. The drug is also approved as an adjunctive therapy in patients age two or older with partial-onset seizures, primary generalized tonic–clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

—Kimberly Williams

A study published in JAMA Internal Medicine in December 2014 looked at decision fatigue in primary care providers. The researchers focused on antibiotic prescriptions for acute respiratory infections (including those for which antibiotics are never indicated) over a 16-month period covering 21,867 visits to 204 clinicians. They compared the rate of antibiotic prescription at the first, second, third, and fourth hour of clinic, with the premise being that over a period of repeated decision making the quality of the decisions declines (JAMA Intern. Med. 2014;174:2029-31).

If, like me, you think you have unrealistic expectations about physicians being unimpeachable, you might be disappointed to learn that antibiotic prescriptions were significantly higher for the third and fourth hour of clinic. It seems that as the clinic session wore on, physicians opted for the “safer,” “easier” option.

Another paper involving similarly weighty consequences was published in 2011 in Proceedings of the National Academy of Sciences (and cited as one of only six references in the JAMA paper). The researchers looked at parole decisions made by judges in four Israeli prisons. Data from 1,112 judicial rulings involving eight judges showed that “the percentage of favorable rulings drops gradually from ~65% to nearly zero within each decision session and returns abruptly to ~65% after a break” (Proc. Natl. Acad. Sci. U.S.A. 2011;108:6889-92). (Breaks lasted about 30 minutes and involved a meal.) That’s a pretty dramatic rate of change. It is sobering to think of lives being hugely affected by such seemingly irrelevant details. Talk about fate being fickle.

Decision fatigue suggests that when we make repeated decisions over a brief period of time there is an erosion of self-control and we are more likely to choose the “affectively pleasing” option. It has been written about in psychology journals for the past 2 decades, but for practical and ethical reasons, most studies on the subject involve minor decisions, such as what to choose at the grocery store or which items to add to one’s wedding registry. The concept has become quite popular in the fields of behavioral economic and advertising. It is the reason groceries display candy at the cash register.

Decision fatigue is part of a larger theory on our executive functions, proposed by Dr. Roy Baumeister, professor of social psychology at the University of Florida. His central idea is that self-control, volitional acts, responsibility, and self-regulatory efforts “draw upon a common resource and deplete it.” He calls it ego depletion. In one simple but powerful experiment, researchers conducted a study where students were asked to commit either two digits or seven digits to memory. When offered a choice of fruit salad or chocolate cake as compensation for participation in the study, those who had to remember seven digits were far more likely to choose the chocolate cake – certainly the more “affectively pleasing” option. So ego depletion is to blame for my constant kitchen-grazing behavior at the end of a trying clinic day. Apart from affecting my waistline, I’m sure it affects me in ways that I am unaware of, ways that may have an impact not just on patients but on society, too.

The JAMA Internal Medicine article seems to be the first of its kind in the medical literature. To me, it is hugely important because it reminds us of two major truths: that there are often bigger things at stake, and that doctors, being mere mortals, are not exempt from human frailty.

Dr. Chan practices rheumatology in Pawtucket, R.I.

A study published in JAMA Internal Medicine in December 2014 looked at decision fatigue in primary care providers. The researchers focused on antibiotic prescriptions for acute respiratory infections (including those for which antibiotics are never indicated) over a 16-month period covering 21,867 visits to 204 clinicians. They compared the rate of antibiotic prescription at the first, second, third, and fourth hour of clinic, with the premise being that over a period of repeated decision making the quality of the decisions declines (JAMA Intern. Med. 2014;174:2029-31).

If, like me, you think you have unrealistic expectations about physicians being unimpeachable, you might be disappointed to learn that antibiotic prescriptions were significantly higher for the third and fourth hour of clinic. It seems that as the clinic session wore on, physicians opted for the “safer,” “easier” option.

Another paper involving similarly weighty consequences was published in 2011 in Proceedings of the National Academy of Sciences (and cited as one of only six references in the JAMA paper). The researchers looked at parole decisions made by judges in four Israeli prisons. Data from 1,112 judicial rulings involving eight judges showed that “the percentage of favorable rulings drops gradually from ~65% to nearly zero within each decision session and returns abruptly to ~65% after a break” (Proc. Natl. Acad. Sci. U.S.A. 2011;108:6889-92). (Breaks lasted about 30 minutes and involved a meal.) That’s a pretty dramatic rate of change. It is sobering to think of lives being hugely affected by such seemingly irrelevant details. Talk about fate being fickle.

Decision fatigue suggests that when we make repeated decisions over a brief period of time there is an erosion of self-control and we are more likely to choose the “affectively pleasing” option. It has been written about in psychology journals for the past 2 decades, but for practical and ethical reasons, most studies on the subject involve minor decisions, such as what to choose at the grocery store or which items to add to one’s wedding registry. The concept has become quite popular in the fields of behavioral economic and advertising. It is the reason groceries display candy at the cash register.

Decision fatigue is part of a larger theory on our executive functions, proposed by Dr. Roy Baumeister, professor of social psychology at the University of Florida. His central idea is that self-control, volitional acts, responsibility, and self-regulatory efforts “draw upon a common resource and deplete it.” He calls it ego depletion. In one simple but powerful experiment, researchers conducted a study where students were asked to commit either two digits or seven digits to memory. When offered a choice of fruit salad or chocolate cake as compensation for participation in the study, those who had to remember seven digits were far more likely to choose the chocolate cake – certainly the more “affectively pleasing” option. So ego depletion is to blame for my constant kitchen-grazing behavior at the end of a trying clinic day. Apart from affecting my waistline, I’m sure it affects me in ways that I am unaware of, ways that may have an impact not just on patients but on society, too.

The JAMA Internal Medicine article seems to be the first of its kind in the medical literature. To me, it is hugely important because it reminds us of two major truths: that there are often bigger things at stake, and that doctors, being mere mortals, are not exempt from human frailty.

Dr. Chan practices rheumatology in Pawtucket, R.I.

A study published in JAMA Internal Medicine in December 2014 looked at decision fatigue in primary care providers. The researchers focused on antibiotic prescriptions for acute respiratory infections (including those for which antibiotics are never indicated) over a 16-month period covering 21,867 visits to 204 clinicians. They compared the rate of antibiotic prescription at the first, second, third, and fourth hour of clinic, with the premise being that over a period of repeated decision making the quality of the decisions declines (JAMA Intern. Med. 2014;174:2029-31).

If, like me, you think you have unrealistic expectations about physicians being unimpeachable, you might be disappointed to learn that antibiotic prescriptions were significantly higher for the third and fourth hour of clinic. It seems that as the clinic session wore on, physicians opted for the “safer,” “easier” option.

Another paper involving similarly weighty consequences was published in 2011 in Proceedings of the National Academy of Sciences (and cited as one of only six references in the JAMA paper). The researchers looked at parole decisions made by judges in four Israeli prisons. Data from 1,112 judicial rulings involving eight judges showed that “the percentage of favorable rulings drops gradually from ~65% to nearly zero within each decision session and returns abruptly to ~65% after a break” (Proc. Natl. Acad. Sci. U.S.A. 2011;108:6889-92). (Breaks lasted about 30 minutes and involved a meal.) That’s a pretty dramatic rate of change. It is sobering to think of lives being hugely affected by such seemingly irrelevant details. Talk about fate being fickle.

Decision fatigue suggests that when we make repeated decisions over a brief period of time there is an erosion of self-control and we are more likely to choose the “affectively pleasing” option. It has been written about in psychology journals for the past 2 decades, but for practical and ethical reasons, most studies on the subject involve minor decisions, such as what to choose at the grocery store or which items to add to one’s wedding registry. The concept has become quite popular in the fields of behavioral economic and advertising. It is the reason groceries display candy at the cash register.

Decision fatigue is part of a larger theory on our executive functions, proposed by Dr. Roy Baumeister, professor of social psychology at the University of Florida. His central idea is that self-control, volitional acts, responsibility, and self-regulatory efforts “draw upon a common resource and deplete it.” He calls it ego depletion. In one simple but powerful experiment, researchers conducted a study where students were asked to commit either two digits or seven digits to memory. When offered a choice of fruit salad or chocolate cake as compensation for participation in the study, those who had to remember seven digits were far more likely to choose the chocolate cake – certainly the more “affectively pleasing” option. So ego depletion is to blame for my constant kitchen-grazing behavior at the end of a trying clinic day. Apart from affecting my waistline, I’m sure it affects me in ways that I am unaware of, ways that may have an impact not just on patients but on society, too.

The JAMA Internal Medicine article seems to be the first of its kind in the medical literature. To me, it is hugely important because it reminds us of two major truths: that there are often bigger things at stake, and that doctors, being mere mortals, are not exempt from human frailty.

Dr. Chan practices rheumatology in Pawtucket, R.I.

TORONTO—Interim results of a phase 3 study suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of

dabigatran in real-world situations.

In the RE-VERSE AD trial, idarucizumab normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.

In addition, researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.

These results have been published in NEJM and presented at the 2015 ISTH Congress (abstract LB005). The study was sponsored by Boehringer Ingelheim, the company developing idarucizumab and dabigatran.

“The interim analysis from RE-VERSE AD is important for healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations,” said study investigator Charles Pollack, MD, of the University of Pennsylvania in Philadelphia.

Because RE-VERSE AD was designed to evaluate how idarucizumab would perform in real-world situations, severely ill or injured patients were eligible for enrollment. The interim analysis included data from 90 patients in emergency settings who were taking dabigatran and required reversal.

The patients were divided into 2 groups: those with uncontrolled or life-threatening bleeding complications, such as intracranial hemorrhage or severe trauma (group A, n=51), and patients requiring emergency surgery or an invasive procedure (group B, n=39).

The primary endpoint of the study is the degree to which 5 g of idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

The researchers were able to evaluate the percentage of reversal by dTT in 68 patients (40 in group A and 28 in group B) and the percentage of reversal by ECT in 81 patients (47 in group A and 34 in group B).

The dTT was normalized in 98% of evaluable patients in group A and 93% in group B. The ECT was normalized in 89% of evaluable patients in group A and 88% in group B.

At 12 hours and 24 hours, the dTT was below the upper limit of the normal range in 90% of evaluable patients in group A and 81% in group B. The ECT was below the upper limit of the normal range in 72% of evaluable group A patients and 54% of evaluable group B patients.

Among the 35 evaluable patients in group A, hemostasis was restored at a median of 11.4 hours. Among the 36 patients in group B who underwent a procedure, 33 had normal intraoperative hemostasis. Two patients had mildly abnormal hemostasis, and 1 patient had moderately abnormal hemostasis.

“As observed in earlier research in volunteers, idarucizumab reversed the anticoagulant effect of dabigatran in patients completely within minutes, even in those rare critical care situations studied in RE-VERSE AD,” Dr Pollack said.

“These data demonstrate that use of idarucizumab can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients.”

Twenty-one patients (13 in group A and 8 in group B) experienced serious adverse events during the study.

This included 18 events that led to death, 5 thrombotic events, 2 cases of gastrointestinal hemorrhage, a postoperative wound infection, a case of delirium, a case of right ventricular failure, and a case of pulmonary edema. (Some patients had more than one serious adverse event.)

TORONTO—Interim results of a phase 3 study suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of

dabigatran in real-world situations.

In the RE-VERSE AD trial, idarucizumab normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.

In addition, researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.

These results have been published in NEJM and presented at the 2015 ISTH Congress (abstract LB005). The study was sponsored by Boehringer Ingelheim, the company developing idarucizumab and dabigatran.

“The interim analysis from RE-VERSE AD is important for healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations,” said study investigator Charles Pollack, MD, of the University of Pennsylvania in Philadelphia.

Because RE-VERSE AD was designed to evaluate how idarucizumab would perform in real-world situations, severely ill or injured patients were eligible for enrollment. The interim analysis included data from 90 patients in emergency settings who were taking dabigatran and required reversal.

The patients were divided into 2 groups: those with uncontrolled or life-threatening bleeding complications, such as intracranial hemorrhage or severe trauma (group A, n=51), and patients requiring emergency surgery or an invasive procedure (group B, n=39).

The primary endpoint of the study is the degree to which 5 g of idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

The researchers were able to evaluate the percentage of reversal by dTT in 68 patients (40 in group A and 28 in group B) and the percentage of reversal by ECT in 81 patients (47 in group A and 34 in group B).

The dTT was normalized in 98% of evaluable patients in group A and 93% in group B. The ECT was normalized in 89% of evaluable patients in group A and 88% in group B.

At 12 hours and 24 hours, the dTT was below the upper limit of the normal range in 90% of evaluable patients in group A and 81% in group B. The ECT was below the upper limit of the normal range in 72% of evaluable group A patients and 54% of evaluable group B patients.

Among the 35 evaluable patients in group A, hemostasis was restored at a median of 11.4 hours. Among the 36 patients in group B who underwent a procedure, 33 had normal intraoperative hemostasis. Two patients had mildly abnormal hemostasis, and 1 patient had moderately abnormal hemostasis.

“As observed in earlier research in volunteers, idarucizumab reversed the anticoagulant effect of dabigatran in patients completely within minutes, even in those rare critical care situations studied in RE-VERSE AD,” Dr Pollack said.

“These data demonstrate that use of idarucizumab can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients.”

Twenty-one patients (13 in group A and 8 in group B) experienced serious adverse events during the study.

This included 18 events that led to death, 5 thrombotic events, 2 cases of gastrointestinal hemorrhage, a postoperative wound infection, a case of delirium, a case of right ventricular failure, and a case of pulmonary edema. (Some patients had more than one serious adverse event.)

TORONTO—Interim results of a phase 3 study suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of

dabigatran in real-world situations.

In the RE-VERSE AD trial, idarucizumab normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.

In addition, researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.

These results have been published in NEJM and presented at the 2015 ISTH Congress (abstract LB005). The study was sponsored by Boehringer Ingelheim, the company developing idarucizumab and dabigatran.

“The interim analysis from RE-VERSE AD is important for healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations,” said study investigator Charles Pollack, MD, of the University of Pennsylvania in Philadelphia.

Because RE-VERSE AD was designed to evaluate how idarucizumab would perform in real-world situations, severely ill or injured patients were eligible for enrollment. The interim analysis included data from 90 patients in emergency settings who were taking dabigatran and required reversal.

The patients were divided into 2 groups: those with uncontrolled or life-threatening bleeding complications, such as intracranial hemorrhage or severe trauma (group A, n=51), and patients requiring emergency surgery or an invasive procedure (group B, n=39).

The primary endpoint of the study is the degree to which 5 g of idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

The researchers were able to evaluate the percentage of reversal by dTT in 68 patients (40 in group A and 28 in group B) and the percentage of reversal by ECT in 81 patients (47 in group A and 34 in group B).

The dTT was normalized in 98% of evaluable patients in group A and 93% in group B. The ECT was normalized in 89% of evaluable patients in group A and 88% in group B.

At 12 hours and 24 hours, the dTT was below the upper limit of the normal range in 90% of evaluable patients in group A and 81% in group B. The ECT was below the upper limit of the normal range in 72% of evaluable group A patients and 54% of evaluable group B patients.

Among the 35 evaluable patients in group A, hemostasis was restored at a median of 11.4 hours. Among the 36 patients in group B who underwent a procedure, 33 had normal intraoperative hemostasis. Two patients had mildly abnormal hemostasis, and 1 patient had moderately abnormal hemostasis.

“As observed in earlier research in volunteers, idarucizumab reversed the anticoagulant effect of dabigatran in patients completely within minutes, even in those rare critical care situations studied in RE-VERSE AD,” Dr Pollack said.

“These data demonstrate that use of idarucizumab can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients.”

Twenty-one patients (13 in group A and 8 in group B) experienced serious adverse events during the study.

This included 18 events that led to death, 5 thrombotic events, 2 cases of gastrointestinal hemorrhage, a postoperative wound infection, a case of delirium, a case of right ventricular failure, and a case of pulmonary edema. (Some patients had more than one serious adverse event.)