Outcomes Research in Review

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of an intervention targeting both patients and clinicians intended to increase goals-of-care conversations.

Design. Multicenter cluster-randomized controlled trial.

Setting and participants. Clinicians (physicians or nurse practitioners) were recruited between February 2014 and November 2015 from 2 large health centers in the Pacific Northwest and were eligible if they provided primary or specialty care and had at least 5 eligible patients in their panels. Using the electronic health record (EHR) and clinic schedules, study staff identified and contacted (via mail or telephone) consecutive patients cared for by participating clinicians between March 2014 and May 2016 with the following eligibility criteria: age 18 years or older, 2 or more visits with the clinician in the last 18 months, and 1 or more qualifying conditions. Qualifying conditions included (1) metastatic cancer or inoperable lung cancer; (2) COPD with FEV₁ values below 35% of that predicted or oxygen dependence, restrictive lung disease with a total lung capacity below 50% of that predicted, or cystic fibrosis with FEV₁ below 30% of that predicted; (3) New York Heart Association class III or IV heart failure, pulmonary arterial hypertension, or left ventricular assist device or implantable cardioverter defibrillator implant; 4) cirrhosis or end-stage liver disease; (5) dialysis-dependent renal failure and diabetes; (6) age 75 or older with one or more life-limiting chronic illness; (7) age 90 or older; (8) hospitalization in the last 18 months with a life-limiting illness; (9) Charlson comorbidity index of 6 or higher. The qualifying criteria were selected to identify a median survival of approximately 2 years, suggesting relevance of goals-of-care discussions.

Intervention. The intervention was the patient-specific Jumpstart-Tips intervention, intended to prime clinicians and patients for a brief discussion of goals of care during a routine clinic visit. Patients in the intervention group received a survey to assess their preferences, barriers and facilitators for communication about end-of-life care. Survey responses were used to (1) generate an abstracted version of the patient’s preferences, (2) identify the most important communication barrier or facilitator, and (3) provide communication tips based on curricular materials from VitalTalk (http://vitaltalk.org) tailored to patient responses. The 1-page communication guide, called Jumpstart-Tips, was sent to clinicians 1 or 2 days prior to the target clinic visit date. Patients also received 1-page patient-specific Jumpstart-Tips forms, which summarized their survey responses and provided suggestions for having a goals-of-care conversation with the clinician. Patients in the control group completed the same surveys, but no information was provided to the patients or clinicians. Clinicians were randomly assigned in a 1:1 ratio to intervention or enhanced usual care.

Main outcome measures. The primary outcome was patient-reported occurrence of goals-of-care communication, which was evaluated using a validated dichotomous survey item. Other outcomes included clinician documentation of a goals-of-care conversation in the medical record, patient-reported quality of communication (measured using Quality of Communication questionnaire) at 2 weeks, patient reports of goal-concordant care at 3 months, and patient-reported symptoms of depression and anxiety at 3 and 6 months. All analyses included covariate adjustment for the baseline measure of the outcome and adjustment for other variables found to confound the association between randomization group and outcome.

Main results. Of 485 potentially eligible clinicians, 65 clinicians were randomized to the intervention group and 69 were randomized to the control group. Of these 132 clinicians, 124 had patients participating in the study: 537 out of 917 eligible patients enrolled, with 249 allocated to intervention and 288 to usual care.

Patients in the intervention group were more likely to report a goals-of-care conversation with their provider among all patients (74%, n = 137 vs 31%, n = 66; P n = 112 vs 28%, n = 44; P n = 140 vs 17%, n = 45; P n = 114 vs 17%, n = 34; P
Patients in the intervention group also reported higher quality ratings of goals-of-care conversations at the target visit (mean values, 4.6 v 2.1, P = 0.01, on the 4-indicator construct). Additionally, intervention members reported statistically significant higher ratings on 3 of the 7 individual quality-of-communication survey items.

Patient-assessed goal concordant care did not increase significantly overall (70% vs 57%; P = 0.08) but did increase for patients with stable goals between 3-month follow-up and last prior assessment (73% vs 57%; P = 0.03). Symptoms of depression or anxiety were not different between groups at 3 or 6 months.

Conclusion. The Jumpstart-Tips intervention was associated with an increase in patient reports and clinician documentation of goals-of-care communication. Increased patient-reported goal-concordant care among patients with stable goals was also associated with the intervention. Statistical significance was not detected for changes in depression or anxiety as a result of the intervention. The impact on goals-of-care discussion between patients and caregivers is suggestive of enhanced patient-centered care; however, further studies are needed to evaluate whether this communication is associated with changes in health care delivery.

Commentary

Previous research has shown that patients with serious illness who discuss their goals-of-care fare better in terms of quality of life and reducing intensity of care at the end-of-life [1]. However, providers often fail to or inadequately discuss goals of care with seriously ill patients [2,3]. This contributes to the lack of concordance between patient wishes, particularly related to end-of-life care, and clinical plans of care [4,5]. Addressing this gap between care provided and care desired, as well as providing high-quality, patient-centered care is needed.

Access to palliative care providers (who are trained to address these priorities) in the outpatient setting lags, despite an increase in specialists [6,7]. Thus, primary and specialty care providers in the outpatient setting are best positioned to align their care strategy with the goals of their patients. However, there have been limited results in showing that goals-of-care communication can be improved within the practice setting [8,9]. A randomized clinical trial among hospitalized seniors at the end-of-life showed an association where those who received advanced care planning with had improved quality of life, reduced care at dying, and reduced psychological distress among family [10]. However, in another randomized trial, simulation-based communication training compared with usual education among internal medicine and nurse practitioner trainees did not improve quality of communication about end-of-life care or quality of end-of-life care but was associated with a small increase in patients’ depressive symptoms [11]. A recent 2018 literature review of strategies used to facilitate the discussion of advance care planning with older adults in primary care settings identified effective interventions, including delivering education using various delivery methods, computer-generated triggers for primary care physicians (PCPs), inclusion of multidisciplinary professionals for content delivery, and patient preparation for PCP visit [12].

This article adds to the literature by demonstrating the feasibility and impact of implementing an intervention to increase communication about goals of care and end-of-life care. Further, this study highlights how communication that is bilateral, predetermined, and structured can be integrated into primary care. Strengths of the study include the use of randomization; deployment of validated survey tools; and confirmatory factor analysis to assess whether the survey variables are consistent with the hypothesized constructs. In addition, study staff were blinded when extracting data from the EHR record around discussions and documentation of goals-of-care conversations during patient visits. However, several limitations are present. There may be limited generalizability as the study was performed at low-scale, across one region as well as selection bias among clinicians participating in the study. Clinicians were not blinded of their assignment, which may have influenced their behaviors to discuss and document goals-of-care conversations.

Applications for Clinical Practice

Increasing quality communication around the end of life and understanding of a patient’s goals is important. Good communication can facilitate the development of a comprehensive treatment plan that is medically sound and concordant with the patient’s wishes and values. Clinicians and practices should consider adopting approaches to communication priming and accurate documentation, including: (1) incorporating/automating Jumpstart-Tips forms into practice (and tailoring as needed); (2) identifying similar education material that can serve as a primer for patients; (3) creating a pre-visit form for patients/caregivers to document and inform the clinician of their goals prior to the visit; (4) incorporating a standard EHR note to document and update goals-of-care discussion at each visit; and (5) more broadly encouraging (or providing training for) clinicians to practice bilateral communications with patients during visits.

—Ronald Sanchez, MPH, and Katrina F. Mateo, MPH

Study Overview

Objective. To evaluate the efficacy of an intervention targeting both patients and clinicians intended to increase goals-of-care conversations.

Design. Multicenter cluster-randomized controlled trial.

Setting and participants. Clinicians (physicians or nurse practitioners) were recruited between February 2014 and November 2015 from 2 large health centers in the Pacific Northwest and were eligible if they provided primary or specialty care and had at least 5 eligible patients in their panels. Using the electronic health record (EHR) and clinic schedules, study staff identified and contacted (via mail or telephone) consecutive patients cared for by participating clinicians between March 2014 and May 2016 with the following eligibility criteria: age 18 years or older, 2 or more visits with the clinician in the last 18 months, and 1 or more qualifying conditions. Qualifying conditions included (1) metastatic cancer or inoperable lung cancer; (2) COPD with FEV₁ values below 35% of that predicted or oxygen dependence, restrictive lung disease with a total lung capacity below 50% of that predicted, or cystic fibrosis with FEV₁ below 30% of that predicted; (3) New York Heart Association class III or IV heart failure, pulmonary arterial hypertension, or left ventricular assist device or implantable cardioverter defibrillator implant; 4) cirrhosis or end-stage liver disease; (5) dialysis-dependent renal failure and diabetes; (6) age 75 or older with one or more life-limiting chronic illness; (7) age 90 or older; (8) hospitalization in the last 18 months with a life-limiting illness; (9) Charlson comorbidity index of 6 or higher. The qualifying criteria were selected to identify a median survival of approximately 2 years, suggesting relevance of goals-of-care discussions.

Intervention. The intervention was the patient-specific Jumpstart-Tips intervention, intended to prime clinicians and patients for a brief discussion of goals of care during a routine clinic visit. Patients in the intervention group received a survey to assess their preferences, barriers and facilitators for communication about end-of-life care. Survey responses were used to (1) generate an abstracted version of the patient’s preferences, (2) identify the most important communication barrier or facilitator, and (3) provide communication tips based on curricular materials from VitalTalk (http://vitaltalk.org) tailored to patient responses. The 1-page communication guide, called Jumpstart-Tips, was sent to clinicians 1 or 2 days prior to the target clinic visit date. Patients also received 1-page patient-specific Jumpstart-Tips forms, which summarized their survey responses and provided suggestions for having a goals-of-care conversation with the clinician. Patients in the control group completed the same surveys, but no information was provided to the patients or clinicians. Clinicians were randomly assigned in a 1:1 ratio to intervention or enhanced usual care.

Main outcome measures. The primary outcome was patient-reported occurrence of goals-of-care communication, which was evaluated using a validated dichotomous survey item. Other outcomes included clinician documentation of a goals-of-care conversation in the medical record, patient-reported quality of communication (measured using Quality of Communication questionnaire) at 2 weeks, patient reports of goal-concordant care at 3 months, and patient-reported symptoms of depression and anxiety at 3 and 6 months. All analyses included covariate adjustment for the baseline measure of the outcome and adjustment for other variables found to confound the association between randomization group and outcome.

Main results. Of 485 potentially eligible clinicians, 65 clinicians were randomized to the intervention group and 69 were randomized to the control group. Of these 132 clinicians, 124 had patients participating in the study: 537 out of 917 eligible patients enrolled, with 249 allocated to intervention and 288 to usual care.

Patients in the intervention group were more likely to report a goals-of-care conversation with their provider among all patients (74%, n = 137 vs 31%, n = 66; P n = 112 vs 28%, n = 44; P n = 140 vs 17%, n = 45; P n = 114 vs 17%, n = 34; P
Patients in the intervention group also reported higher quality ratings of goals-of-care conversations at the target visit (mean values, 4.6 v 2.1, P = 0.01, on the 4-indicator construct). Additionally, intervention members reported statistically significant higher ratings on 3 of the 7 individual quality-of-communication survey items.

Patient-assessed goal concordant care did not increase significantly overall (70% vs 57%; P = 0.08) but did increase for patients with stable goals between 3-month follow-up and last prior assessment (73% vs 57%; P = 0.03). Symptoms of depression or anxiety were not different between groups at 3 or 6 months.

Conclusion. The Jumpstart-Tips intervention was associated with an increase in patient reports and clinician documentation of goals-of-care communication. Increased patient-reported goal-concordant care among patients with stable goals was also associated with the intervention. Statistical significance was not detected for changes in depression or anxiety as a result of the intervention. The impact on goals-of-care discussion between patients and caregivers is suggestive of enhanced patient-centered care; however, further studies are needed to evaluate whether this communication is associated with changes in health care delivery.

Commentary

Previous research has shown that patients with serious illness who discuss their goals-of-care fare better in terms of quality of life and reducing intensity of care at the end-of-life [1]. However, providers often fail to or inadequately discuss goals of care with seriously ill patients [2,3]. This contributes to the lack of concordance between patient wishes, particularly related to end-of-life care, and clinical plans of care [4,5]. Addressing this gap between care provided and care desired, as well as providing high-quality, patient-centered care is needed.

Access to palliative care providers (who are trained to address these priorities) in the outpatient setting lags, despite an increase in specialists [6,7]. Thus, primary and specialty care providers in the outpatient setting are best positioned to align their care strategy with the goals of their patients. However, there have been limited results in showing that goals-of-care communication can be improved within the practice setting [8,9]. A randomized clinical trial among hospitalized seniors at the end-of-life showed an association where those who received advanced care planning with had improved quality of life, reduced care at dying, and reduced psychological distress among family [10]. However, in another randomized trial, simulation-based communication training compared with usual education among internal medicine and nurse practitioner trainees did not improve quality of communication about end-of-life care or quality of end-of-life care but was associated with a small increase in patients’ depressive symptoms [11]. A recent 2018 literature review of strategies used to facilitate the discussion of advance care planning with older adults in primary care settings identified effective interventions, including delivering education using various delivery methods, computer-generated triggers for primary care physicians (PCPs), inclusion of multidisciplinary professionals for content delivery, and patient preparation for PCP visit [12].

This article adds to the literature by demonstrating the feasibility and impact of implementing an intervention to increase communication about goals of care and end-of-life care. Further, this study highlights how communication that is bilateral, predetermined, and structured can be integrated into primary care. Strengths of the study include the use of randomization; deployment of validated survey tools; and confirmatory factor analysis to assess whether the survey variables are consistent with the hypothesized constructs. In addition, study staff were blinded when extracting data from the EHR record around discussions and documentation of goals-of-care conversations during patient visits. However, several limitations are present. There may be limited generalizability as the study was performed at low-scale, across one region as well as selection bias among clinicians participating in the study. Clinicians were not blinded of their assignment, which may have influenced their behaviors to discuss and document goals-of-care conversations.

Applications for Clinical Practice

Increasing quality communication around the end of life and understanding of a patient’s goals is important. Good communication can facilitate the development of a comprehensive treatment plan that is medically sound and concordant with the patient’s wishes and values. Clinicians and practices should consider adopting approaches to communication priming and accurate documentation, including: (1) incorporating/automating Jumpstart-Tips forms into practice (and tailoring as needed); (2) identifying similar education material that can serve as a primer for patients; (3) creating a pre-visit form for patients/caregivers to document and inform the clinician of their goals prior to the visit; (4) incorporating a standard EHR note to document and update goals-of-care discussion at each visit; and (5) more broadly encouraging (or providing training for) clinicians to practice bilateral communications with patients during visits.

—Ronald Sanchez, MPH, and Katrina F. Mateo, MPH

Study Overview

Objective. To evaluate the efficacy of an intervention targeting both patients and clinicians intended to increase goals-of-care conversations.

Design. Multicenter cluster-randomized controlled trial.

Setting and participants. Clinicians (physicians or nurse practitioners) were recruited between February 2014 and November 2015 from 2 large health centers in the Pacific Northwest and were eligible if they provided primary or specialty care and had at least 5 eligible patients in their panels. Using the electronic health record (EHR) and clinic schedules, study staff identified and contacted (via mail or telephone) consecutive patients cared for by participating clinicians between March 2014 and May 2016 with the following eligibility criteria: age 18 years or older, 2 or more visits with the clinician in the last 18 months, and 1 or more qualifying conditions. Qualifying conditions included (1) metastatic cancer or inoperable lung cancer; (2) COPD with FEV₁ values below 35% of that predicted or oxygen dependence, restrictive lung disease with a total lung capacity below 50% of that predicted, or cystic fibrosis with FEV₁ below 30% of that predicted; (3) New York Heart Association class III or IV heart failure, pulmonary arterial hypertension, or left ventricular assist device or implantable cardioverter defibrillator implant; 4) cirrhosis or end-stage liver disease; (5) dialysis-dependent renal failure and diabetes; (6) age 75 or older with one or more life-limiting chronic illness; (7) age 90 or older; (8) hospitalization in the last 18 months with a life-limiting illness; (9) Charlson comorbidity index of 6 or higher. The qualifying criteria were selected to identify a median survival of approximately 2 years, suggesting relevance of goals-of-care discussions.

Intervention. The intervention was the patient-specific Jumpstart-Tips intervention, intended to prime clinicians and patients for a brief discussion of goals of care during a routine clinic visit. Patients in the intervention group received a survey to assess their preferences, barriers and facilitators for communication about end-of-life care. Survey responses were used to (1) generate an abstracted version of the patient’s preferences, (2) identify the most important communication barrier or facilitator, and (3) provide communication tips based on curricular materials from VitalTalk (http://vitaltalk.org) tailored to patient responses. The 1-page communication guide, called Jumpstart-Tips, was sent to clinicians 1 or 2 days prior to the target clinic visit date. Patients also received 1-page patient-specific Jumpstart-Tips forms, which summarized their survey responses and provided suggestions for having a goals-of-care conversation with the clinician. Patients in the control group completed the same surveys, but no information was provided to the patients or clinicians. Clinicians were randomly assigned in a 1:1 ratio to intervention or enhanced usual care.

Main outcome measures. The primary outcome was patient-reported occurrence of goals-of-care communication, which was evaluated using a validated dichotomous survey item. Other outcomes included clinician documentation of a goals-of-care conversation in the medical record, patient-reported quality of communication (measured using Quality of Communication questionnaire) at 2 weeks, patient reports of goal-concordant care at 3 months, and patient-reported symptoms of depression and anxiety at 3 and 6 months. All analyses included covariate adjustment for the baseline measure of the outcome and adjustment for other variables found to confound the association between randomization group and outcome.

Main results. Of 485 potentially eligible clinicians, 65 clinicians were randomized to the intervention group and 69 were randomized to the control group. Of these 132 clinicians, 124 had patients participating in the study: 537 out of 917 eligible patients enrolled, with 249 allocated to intervention and 288 to usual care.

Patients in the intervention group were more likely to report a goals-of-care conversation with their provider among all patients (74%, n = 137 vs 31%, n = 66; P n = 112 vs 28%, n = 44; P n = 140 vs 17%, n = 45; P n = 114 vs 17%, n = 34; P
Patients in the intervention group also reported higher quality ratings of goals-of-care conversations at the target visit (mean values, 4.6 v 2.1, P = 0.01, on the 4-indicator construct). Additionally, intervention members reported statistically significant higher ratings on 3 of the 7 individual quality-of-communication survey items.

Patient-assessed goal concordant care did not increase significantly overall (70% vs 57%; P = 0.08) but did increase for patients with stable goals between 3-month follow-up and last prior assessment (73% vs 57%; P = 0.03). Symptoms of depression or anxiety were not different between groups at 3 or 6 months.

Conclusion. The Jumpstart-Tips intervention was associated with an increase in patient reports and clinician documentation of goals-of-care communication. Increased patient-reported goal-concordant care among patients with stable goals was also associated with the intervention. Statistical significance was not detected for changes in depression or anxiety as a result of the intervention. The impact on goals-of-care discussion between patients and caregivers is suggestive of enhanced patient-centered care; however, further studies are needed to evaluate whether this communication is associated with changes in health care delivery.

Commentary

Previous research has shown that patients with serious illness who discuss their goals-of-care fare better in terms of quality of life and reducing intensity of care at the end-of-life [1]. However, providers often fail to or inadequately discuss goals of care with seriously ill patients [2,3]. This contributes to the lack of concordance between patient wishes, particularly related to end-of-life care, and clinical plans of care [4,5]. Addressing this gap between care provided and care desired, as well as providing high-quality, patient-centered care is needed.

Access to palliative care providers (who are trained to address these priorities) in the outpatient setting lags, despite an increase in specialists [6,7]. Thus, primary and specialty care providers in the outpatient setting are best positioned to align their care strategy with the goals of their patients. However, there have been limited results in showing that goals-of-care communication can be improved within the practice setting [8,9]. A randomized clinical trial among hospitalized seniors at the end-of-life showed an association where those who received advanced care planning with had improved quality of life, reduced care at dying, and reduced psychological distress among family [10]. However, in another randomized trial, simulation-based communication training compared with usual education among internal medicine and nurse practitioner trainees did not improve quality of communication about end-of-life care or quality of end-of-life care but was associated with a small increase in patients’ depressive symptoms [11]. A recent 2018 literature review of strategies used to facilitate the discussion of advance care planning with older adults in primary care settings identified effective interventions, including delivering education using various delivery methods, computer-generated triggers for primary care physicians (PCPs), inclusion of multidisciplinary professionals for content delivery, and patient preparation for PCP visit [12].

This article adds to the literature by demonstrating the feasibility and impact of implementing an intervention to increase communication about goals of care and end-of-life care. Further, this study highlights how communication that is bilateral, predetermined, and structured can be integrated into primary care. Strengths of the study include the use of randomization; deployment of validated survey tools; and confirmatory factor analysis to assess whether the survey variables are consistent with the hypothesized constructs. In addition, study staff were blinded when extracting data from the EHR record around discussions and documentation of goals-of-care conversations during patient visits. However, several limitations are present. There may be limited generalizability as the study was performed at low-scale, across one region as well as selection bias among clinicians participating in the study. Clinicians were not blinded of their assignment, which may have influenced their behaviors to discuss and document goals-of-care conversations.

Applications for Clinical Practice

Increasing quality communication around the end of life and understanding of a patient’s goals is important. Good communication can facilitate the development of a comprehensive treatment plan that is medically sound and concordant with the patient’s wishes and values. Clinicians and practices should consider adopting approaches to communication priming and accurate documentation, including: (1) incorporating/automating Jumpstart-Tips forms into practice (and tailoring as needed); (2) identifying similar education material that can serve as a primer for patients; (3) creating a pre-visit form for patients/caregivers to document and inform the clinician of their goals prior to the visit; (4) incorporating a standard EHR note to document and update goals-of-care discussion at each visit; and (5) more broadly encouraging (or providing training for) clinicians to practice bilateral communications with patients during visits.

—Ronald Sanchez, MPH, and Katrina F. Mateo, MPH

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To assess usability and patient perceptions of the sarilumab auto-injector device  (“sarilumab pen”) among patients with moderate-to-severe rheumatoid arthritis (RA).

Design. 12-week, randomized, parallel-group usability study.

Setting and participants. The study was conducted at 53 centers in 6 countries. Inclusion criteria were a diagnosis of RA (as defined by American College of Rheumatology/ European League Against Rheumatism 2010 Criteria) of ≥ 3-month disease duration, willing and able to self inject, continuous treatment with 1 or a combination of nonbiologic disease modifying antirheumatic drugs (except leflunomide in combination with methotrexate); and moderatly to severely active RA, defined as 4/66 swollen joint, 4/68 tender joints, and high-sensitivity C-reactive protein (hsCRP) measurement ≥ 4 mg/L. Exclusion criteria were age

Patients were randomized 1:1:1:1 to sarilumamb 150 or 200 mg every 2 weeks administered by single-use, disposable, prefilled pen or pre-filled syringe. Randomization method was not reported.

Main outcomes measures. The primary endpoint was number of “product technical failures” (PTFs). Patients randomized to the pen were given a diary that had questions related to their ability to remove the cap, start the injection, and complete the injection. Participants were asked to answer the questions each time they used the pen. If the response was “no” to any of the 3 questions, this was considered a “product technical complaint” (PTC). PTCs that had a validated technical cause based on pen evaluation and analysis were considered PTFs.

In addition, patient perceptions and satisfaction with the pen were assessed via questionnaire. At baseline, patients were asked about injections and prior experience with self-injection, and at 12 weeks they were asked about their experiences in using the pen. Other outcomes assessed included adverse events and pharmokinetic parameters.

Results. 217 participants were enrolled: 108 patients were in the pen group (56 randomized to 150 mg and 52 randomized to 200 mg) and 109 were in the syringe group (53 randomized to 150 mg and 56 randomized to 200 mg). Completion rates were similar among groups. Sixteen patients discontinued due to treatment-emergent adverse events. There were no PTFs. There was one PTC, in which the user accidently bumped the pen, which expelled the drug onto the floor.

At baseline, before the first injection, the majority of patients reported that they were not afraid of needles (58%), had past experience with self-injections (55%), and were either “very confident” or “extremely confident” regarding self-injections (55%). After the 12-week assessment phase, when asked about their overall level of satisfaction, 98% of patients reported they were “satisfied” or “very satisfied” with the sarilumab pen.

Treatment emergent adverse events occurred in 66% of patients, with no clinically meaningful differences leading to discontinuation in the pen and syringe groups. The most common adverse events were infections and neutropenia.

Conclusion. Patients successfully completed self-injections with the sarilumab pen and found it easy to use.

Commentary

Rheumatoid arthritis (RA) is a common immune-mediated disease characterized by chronically progressive inflammation and destruction of joints and associated structures, resulting in significant morbidity, mortality, and disability. Improved understanding of RA disease pathogenesis in recent years has led to the development of new biologic treatments designed to target specific elements of the RA inflammatory response.

Sarilumab is an interleukin-6 blocker that was approved in the US in 2017 for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. While a syringe form of this drug is currently available, at the time of this writing the pen has not yet been released.

In this real-world usability study sponsored by Sanofi, there were no technical difficulties with using the pen. Most patients thought the pen was easy or very easy to use, and safety and effeicacy appeared to be generally comparable between the pen and syringe. The pen also offers safety protection features that prevent needlestick injury.

The authors of the current study noted that results from previous studies have shown that patients with RA favor treatment devices that are easy to use, convenient, less painful, and take less time to use, and patients have demonstrated a preference for autoinjector devices over more conventional methods of treatment administration [1–3], such as syringes. Pens have been well accepted for the treatment of other chronic health conditions, including diabetes mellitus, migraine headaches, and growth hormone deficiency, and subcutaneous administration of a tumor necrosis factor (TNF) inhibitor via pen has also been accepted for the treatment of RA [1]. As RA requires lifelong treatment, the use of a pen that is ergonomically designed to take into account the manual dexterity issues relevant to this patient population could potentially enhance compliance.

Applications for Clinical Practice

A prefilled pen was well accepted and associated with favorable patient perceptions, indicating that this delivery system may be a viable option for RA patients who are prescribed sarilumab.

Study Overview

Objective. To assess usability and patient perceptions of the sarilumab auto-injector device  (“sarilumab pen”) among patients with moderate-to-severe rheumatoid arthritis (RA).

Design. 12-week, randomized, parallel-group usability study.

Setting and participants. The study was conducted at 53 centers in 6 countries. Inclusion criteria were a diagnosis of RA (as defined by American College of Rheumatology/ European League Against Rheumatism 2010 Criteria) of ≥ 3-month disease duration, willing and able to self inject, continuous treatment with 1 or a combination of nonbiologic disease modifying antirheumatic drugs (except leflunomide in combination with methotrexate); and moderatly to severely active RA, defined as 4/66 swollen joint, 4/68 tender joints, and high-sensitivity C-reactive protein (hsCRP) measurement ≥ 4 mg/L. Exclusion criteria were age

Patients were randomized 1:1:1:1 to sarilumamb 150 or 200 mg every 2 weeks administered by single-use, disposable, prefilled pen or pre-filled syringe. Randomization method was not reported.

Main outcomes measures. The primary endpoint was number of “product technical failures” (PTFs). Patients randomized to the pen were given a diary that had questions related to their ability to remove the cap, start the injection, and complete the injection. Participants were asked to answer the questions each time they used the pen. If the response was “no” to any of the 3 questions, this was considered a “product technical complaint” (PTC). PTCs that had a validated technical cause based on pen evaluation and analysis were considered PTFs.

In addition, patient perceptions and satisfaction with the pen were assessed via questionnaire. At baseline, patients were asked about injections and prior experience with self-injection, and at 12 weeks they were asked about their experiences in using the pen. Other outcomes assessed included adverse events and pharmokinetic parameters.

Results. 217 participants were enrolled: 108 patients were in the pen group (56 randomized to 150 mg and 52 randomized to 200 mg) and 109 were in the syringe group (53 randomized to 150 mg and 56 randomized to 200 mg). Completion rates were similar among groups. Sixteen patients discontinued due to treatment-emergent adverse events. There were no PTFs. There was one PTC, in which the user accidently bumped the pen, which expelled the drug onto the floor.

At baseline, before the first injection, the majority of patients reported that they were not afraid of needles (58%), had past experience with self-injections (55%), and were either “very confident” or “extremely confident” regarding self-injections (55%). After the 12-week assessment phase, when asked about their overall level of satisfaction, 98% of patients reported they were “satisfied” or “very satisfied” with the sarilumab pen.

Treatment emergent adverse events occurred in 66% of patients, with no clinically meaningful differences leading to discontinuation in the pen and syringe groups. The most common adverse events were infections and neutropenia.

Conclusion. Patients successfully completed self-injections with the sarilumab pen and found it easy to use.

Commentary

Rheumatoid arthritis (RA) is a common immune-mediated disease characterized by chronically progressive inflammation and destruction of joints and associated structures, resulting in significant morbidity, mortality, and disability. Improved understanding of RA disease pathogenesis in recent years has led to the development of new biologic treatments designed to target specific elements of the RA inflammatory response.

Sarilumab is an interleukin-6 blocker that was approved in the US in 2017 for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. While a syringe form of this drug is currently available, at the time of this writing the pen has not yet been released.

In this real-world usability study sponsored by Sanofi, there were no technical difficulties with using the pen. Most patients thought the pen was easy or very easy to use, and safety and effeicacy appeared to be generally comparable between the pen and syringe. The pen also offers safety protection features that prevent needlestick injury.

The authors of the current study noted that results from previous studies have shown that patients with RA favor treatment devices that are easy to use, convenient, less painful, and take less time to use, and patients have demonstrated a preference for autoinjector devices over more conventional methods of treatment administration [1–3], such as syringes. Pens have been well accepted for the treatment of other chronic health conditions, including diabetes mellitus, migraine headaches, and growth hormone deficiency, and subcutaneous administration of a tumor necrosis factor (TNF) inhibitor via pen has also been accepted for the treatment of RA [1]. As RA requires lifelong treatment, the use of a pen that is ergonomically designed to take into account the manual dexterity issues relevant to this patient population could potentially enhance compliance.

Applications for Clinical Practice

A prefilled pen was well accepted and associated with favorable patient perceptions, indicating that this delivery system may be a viable option for RA patients who are prescribed sarilumab.

Study Overview

Objective. To assess usability and patient perceptions of the sarilumab auto-injector device  (“sarilumab pen”) among patients with moderate-to-severe rheumatoid arthritis (RA).

Design. 12-week, randomized, parallel-group usability study.

Setting and participants. The study was conducted at 53 centers in 6 countries. Inclusion criteria were a diagnosis of RA (as defined by American College of Rheumatology/ European League Against Rheumatism 2010 Criteria) of ≥ 3-month disease duration, willing and able to self inject, continuous treatment with 1 or a combination of nonbiologic disease modifying antirheumatic drugs (except leflunomide in combination with methotrexate); and moderatly to severely active RA, defined as 4/66 swollen joint, 4/68 tender joints, and high-sensitivity C-reactive protein (hsCRP) measurement ≥ 4 mg/L. Exclusion criteria were age

Patients were randomized 1:1:1:1 to sarilumamb 150 or 200 mg every 2 weeks administered by single-use, disposable, prefilled pen or pre-filled syringe. Randomization method was not reported.

Main outcomes measures. The primary endpoint was number of “product technical failures” (PTFs). Patients randomized to the pen were given a diary that had questions related to their ability to remove the cap, start the injection, and complete the injection. Participants were asked to answer the questions each time they used the pen. If the response was “no” to any of the 3 questions, this was considered a “product technical complaint” (PTC). PTCs that had a validated technical cause based on pen evaluation and analysis were considered PTFs.

In addition, patient perceptions and satisfaction with the pen were assessed via questionnaire. At baseline, patients were asked about injections and prior experience with self-injection, and at 12 weeks they were asked about their experiences in using the pen. Other outcomes assessed included adverse events and pharmokinetic parameters.

Results. 217 participants were enrolled: 108 patients were in the pen group (56 randomized to 150 mg and 52 randomized to 200 mg) and 109 were in the syringe group (53 randomized to 150 mg and 56 randomized to 200 mg). Completion rates were similar among groups. Sixteen patients discontinued due to treatment-emergent adverse events. There were no PTFs. There was one PTC, in which the user accidently bumped the pen, which expelled the drug onto the floor.

At baseline, before the first injection, the majority of patients reported that they were not afraid of needles (58%), had past experience with self-injections (55%), and were either “very confident” or “extremely confident” regarding self-injections (55%). After the 12-week assessment phase, when asked about their overall level of satisfaction, 98% of patients reported they were “satisfied” or “very satisfied” with the sarilumab pen.

Treatment emergent adverse events occurred in 66% of patients, with no clinically meaningful differences leading to discontinuation in the pen and syringe groups. The most common adverse events were infections and neutropenia.

Conclusion. Patients successfully completed self-injections with the sarilumab pen and found it easy to use.

Commentary

Rheumatoid arthritis (RA) is a common immune-mediated disease characterized by chronically progressive inflammation and destruction of joints and associated structures, resulting in significant morbidity, mortality, and disability. Improved understanding of RA disease pathogenesis in recent years has led to the development of new biologic treatments designed to target specific elements of the RA inflammatory response.

Sarilumab is an interleukin-6 blocker that was approved in the US in 2017 for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. While a syringe form of this drug is currently available, at the time of this writing the pen has not yet been released.

In this real-world usability study sponsored by Sanofi, there were no technical difficulties with using the pen. Most patients thought the pen was easy or very easy to use, and safety and effeicacy appeared to be generally comparable between the pen and syringe. The pen also offers safety protection features that prevent needlestick injury.

The authors of the current study noted that results from previous studies have shown that patients with RA favor treatment devices that are easy to use, convenient, less painful, and take less time to use, and patients have demonstrated a preference for autoinjector devices over more conventional methods of treatment administration [1–3], such as syringes. Pens have been well accepted for the treatment of other chronic health conditions, including diabetes mellitus, migraine headaches, and growth hormone deficiency, and subcutaneous administration of a tumor necrosis factor (TNF) inhibitor via pen has also been accepted for the treatment of RA [1]. As RA requires lifelong treatment, the use of a pen that is ergonomically designed to take into account the manual dexterity issues relevant to this patient population could potentially enhance compliance.

Applications for Clinical Practice

A prefilled pen was well accepted and associated with favorable patient perceptions, indicating that this delivery system may be a viable option for RA patients who are prescribed sarilumab.

Study Overview

Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).

Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).

Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.

Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).

Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.

Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).

With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).

Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.

Commentary

Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].

This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.

This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.

Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].

Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.

Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.

In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.

Application for Clinical Practice

This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.

— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC

Study Overview

Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).

Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).

Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.

Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).

Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.

Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).

With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).

Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.

Commentary

Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].

This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.

This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.

Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].

Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.

Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.

In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.

Application for Clinical Practice

This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.

— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC

Study Overview

Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).

Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).

Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.

Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).

Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.

Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).

With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).

Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.

Commentary

Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].

This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.

This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.

Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].

Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.

Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.

In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.

Application for Clinical Practice

This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.

— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC

Study Overview

Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.

Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).

Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.

Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.

Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.

Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.

Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).

With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.

Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.

Commentary

Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.

Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.

An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury.  Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].

In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].

In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].

Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.

In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.

While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.

The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.

Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.

Applications for Clinical Practice

Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.

—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL

Study Overview

Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.

Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).

Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.

Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.

Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.

Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.

Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).

With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.

Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.

Commentary

Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.

Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.

An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury.  Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].

In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].

In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].

Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.

In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.

While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.

The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.

Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.

Applications for Clinical Practice

Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.

—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL

Study Overview

Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.

Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).

Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.

Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.

Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.

Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.

Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).

With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.

Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.

Commentary

Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.

Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.

An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury.  Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].

In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].

In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].

Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.

In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.

While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.

The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.

Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.

Applications for Clinical Practice

Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.

—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL