Outcomes Research in Review

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective. To evaluate the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab compared with sunitinib alone for the treatment of newly diagnosed advanced clear cell renal cell carcinoma (ccRCC).

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 1:1:1 ratio to receive treatment with 1 of 3 regimens: lenvatinib 20 mg daily plus pembrolizumab 200 mg on day 1 of each 21-day cycle; lenvatinib 18 mg daily plus everolimus 5 mg once daily for each 21-day cycle; or sunitinib 50 mg daily for 4 weeks followed by 2 weeks off. Patients were stratified according to geographic region and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk group.

Setting and participants. A total of 1417 patients were screened, and 1069 patients underwent randomization between October 2016 and July 2019: 355 patients were randomized to the lenvatinib plus pembrolizumab group, 357 were randomized to the lenvatinib plus everolimus group, and 357 were randomized to the sunitinib alone group. The patients must have had a diagnosis of previously untreated advanced renal cell carcinoma with a clear-cell component. All the patients need to have a Karnofsky performance status of at least 70, adequate renal function, and controlled blood pressure with or without antihypertensive medications.

Main outcome measures. The primary endpoint assessed the progression-free survival (PFS) as evaluated by independent review committee using RECIST, version 1.1. Imaging was performed at the time of screening and every 8 weeks thereafter. Secondary endpoints were safety, overall survival (OS), and objective response rate as well as investigator-assessed PFS. Also, they assessed the duration of response. During the treatment period, the safety and adverse events were assessed up to 30 days from the last dose of the trial drug.

Main results. The baseline characteristics were well balanced between the treatment groups. More than 70% of enrolled participants were male. Approximately 60% of participants were MSKCC intermediate risk, 27% were favorable risk, and 9% were poor risk. Patients with a PD-L1 combined positive score of 1% or more represented 30% of the population. The remainder had a PD-L1 combined positive score of <1% (30%) or such data were not available (38%). Liver metastases were present in 17% of patients at baseline in each group, and 70% of patients had a prior nephrectomy. The data cutoff occurred in August 2020 for PFS and the median follow-up for OS was 26.6 months. Around 40% of the participants in the lenvatinib plus pembrolizumab group, 18.8% in the sunitinib group, and 31% in the lenvatinib plus everolimus group were still receiving trial treatment at data cutoff. The leading cause for discontinuing therapy was disease progression. Approximately 50% of patients in the lenvatinib/everolimus group and sunitinib group received subsequent checkpoint inhibitor therapy after progression.

The median PFS in the lenvatinib plus pembrolizumab group was significantly longer than in the sunitinib group, 23.9 months vs 9.2 months (hazard ratio [HR], 0.39; 95% CI, 0.32-0.49; P < 0.001). The median PFS was also significantly longer in the lenvatinib plus everolimus group compared with sunitinib, 14.7 vs 9.2 months (HR 0.65; 95% CI 0.53-0.80; P < 0.001). The PFS benefit favored the lenvatinib combination groups over sunitinib in all subgroups, including the MSKCC prognostic risk groups. The median OS was not reached with any treatment, with 79% of patients in the lenvatinib plus pembrolizumab group, 66% of patients in the lenvatinib plus everolimus group, and 70% in the sunitinib group still alive at 24 months. Survival was significantly longer in the lenvatinib plus pembrolizumab group compared with sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = 0.005). The OS favored lenvatinib/pembrolizumab over sunitinib in the PD-L1 positive or negative groups. The median duration of response in the lenvatinib plus pembrolizumab group was 25.8 months compared to 16.6 months and 14.6 months in the lenvatinib plus everolimus and sunitinib groups, respectively. Complete response rates were higher in the lenvatinib plus pembrolizumab group (16%) compared with lenvatinib/everolimus (9.8%) or sunitinib (4.2%). The median time to response was around 1.9 months in all 3 groups.

The most frequent adverse events seen in all groups were diarrhea, hypertension, fatigue, and nausea. Hypothyroidism was seen more frequently in the lenvatinib plus pembrolizumab group (47%). Grade 3 adverse events were seen in approximately 80% of patients in all groups. The most common grade 3 or higher adverse event was hypertension in all 3 groups. The median time for discontinuing treatment due to side effects was 8.97 months in the lenvatinib plus pembrolizumab arm, 5.49 months in the lenvatinib plus everolimus group, and 4.57 months in the sunitinib group. In the lenvatinib plus pembrolizumab group, 15 patients had grade 5 adverse events; 11 participants had fatal events not related to disease progression. In the lenvatinib plus everolimus group, there were 22 patients with grade 5 events, with 10 fatal events not related to disease progression. In the sunitinib group, 11 patients had grade 5 events, and only 2 fatal events were not linked to disease progression.

Conclusion. The combination of lenvatinib plus pembrolizumab significantly prolongs PFS and OS compared with sunitinib in patients with previously untreated and advanced ccRCC. The median OS has not yet been reached.

Commentary

The results of the current phase 3 CLEAR trial highlight the efficacy and safety of lenvatinib plus pembrolizumab as a first-line treatment in advanced ccRCC. This trial adds to the rapidly growing body of literature supporting the notion that the combination of anti-PD-1 based therapy with either CTLA-4 antibodies or VEGF receptor tyrosine kinase inhibitors (TKI) improves outcomes in previously untreated patients with advanced ccRCC. Previously presented data from Keynote-426 (pembrolizumab plus axitinib), Checkmate-214 (nivolumab plus ipilimumab), and Javelin Renal 101 (Avelumab plus axitinib) have also shown improved outcomes with combination therapy in the frontline setting.^1-4 While the landscape of therapeutic options in the frontline setting continues to grow, there remains lack of clarity as to how to tailor our therapeutic decisions for specific patient populations. The exception would be nivolumab and ipilimumab, which are currently indicated for IMDC intermediate- or poor-risk patients.

The combination of VEGFR TKI therapy and PD-1 antibodies provides rapid disease control, with a median time to response in the current study of 1.9 months, and, generally speaking, a low risk of progression in the first 6 months of therapy. While cross-trial comparisons are always problematic, the PFS reported in this study and others with VEGFR TKI and PD-1 antibody combinations is quite impressive and surpasses that noted in Checkmate 214.³ While the median OS survival has not yet been reached, the long duration of PFS and complete response rate of 16% in this study certainly make this an attractive frontline option for newly diagnosed patients with advanced ccRCC. Longer follow-up is needed to confirm the survival benefit noted.

Applications for Clinical Practice

The current data support the use VEGFR TKI and anti-PD1 therapy in the frontline setting. How to choose between such combination regimens or combination immunotherapy remains unclear, and further biomarker-based assessments are needed to help guide therapeutic decisions for our patients.

Study Overview

Objective. To evaluate the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab compared with sunitinib alone for the treatment of newly diagnosed advanced clear cell renal cell carcinoma (ccRCC).

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 1:1:1 ratio to receive treatment with 1 of 3 regimens: lenvatinib 20 mg daily plus pembrolizumab 200 mg on day 1 of each 21-day cycle; lenvatinib 18 mg daily plus everolimus 5 mg once daily for each 21-day cycle; or sunitinib 50 mg daily for 4 weeks followed by 2 weeks off. Patients were stratified according to geographic region and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk group.

Setting and participants. A total of 1417 patients were screened, and 1069 patients underwent randomization between October 2016 and July 2019: 355 patients were randomized to the lenvatinib plus pembrolizumab group, 357 were randomized to the lenvatinib plus everolimus group, and 357 were randomized to the sunitinib alone group. The patients must have had a diagnosis of previously untreated advanced renal cell carcinoma with a clear-cell component. All the patients need to have a Karnofsky performance status of at least 70, adequate renal function, and controlled blood pressure with or without antihypertensive medications.

Main outcome measures. The primary endpoint assessed the progression-free survival (PFS) as evaluated by independent review committee using RECIST, version 1.1. Imaging was performed at the time of screening and every 8 weeks thereafter. Secondary endpoints were safety, overall survival (OS), and objective response rate as well as investigator-assessed PFS. Also, they assessed the duration of response. During the treatment period, the safety and adverse events were assessed up to 30 days from the last dose of the trial drug.

Main results. The baseline characteristics were well balanced between the treatment groups. More than 70% of enrolled participants were male. Approximately 60% of participants were MSKCC intermediate risk, 27% were favorable risk, and 9% were poor risk. Patients with a PD-L1 combined positive score of 1% or more represented 30% of the population. The remainder had a PD-L1 combined positive score of <1% (30%) or such data were not available (38%). Liver metastases were present in 17% of patients at baseline in each group, and 70% of patients had a prior nephrectomy. The data cutoff occurred in August 2020 for PFS and the median follow-up for OS was 26.6 months. Around 40% of the participants in the lenvatinib plus pembrolizumab group, 18.8% in the sunitinib group, and 31% in the lenvatinib plus everolimus group were still receiving trial treatment at data cutoff. The leading cause for discontinuing therapy was disease progression. Approximately 50% of patients in the lenvatinib/everolimus group and sunitinib group received subsequent checkpoint inhibitor therapy after progression.

The median PFS in the lenvatinib plus pembrolizumab group was significantly longer than in the sunitinib group, 23.9 months vs 9.2 months (hazard ratio [HR], 0.39; 95% CI, 0.32-0.49; P < 0.001). The median PFS was also significantly longer in the lenvatinib plus everolimus group compared with sunitinib, 14.7 vs 9.2 months (HR 0.65; 95% CI 0.53-0.80; P < 0.001). The PFS benefit favored the lenvatinib combination groups over sunitinib in all subgroups, including the MSKCC prognostic risk groups. The median OS was not reached with any treatment, with 79% of patients in the lenvatinib plus pembrolizumab group, 66% of patients in the lenvatinib plus everolimus group, and 70% in the sunitinib group still alive at 24 months. Survival was significantly longer in the lenvatinib plus pembrolizumab group compared with sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = 0.005). The OS favored lenvatinib/pembrolizumab over sunitinib in the PD-L1 positive or negative groups. The median duration of response in the lenvatinib plus pembrolizumab group was 25.8 months compared to 16.6 months and 14.6 months in the lenvatinib plus everolimus and sunitinib groups, respectively. Complete response rates were higher in the lenvatinib plus pembrolizumab group (16%) compared with lenvatinib/everolimus (9.8%) or sunitinib (4.2%). The median time to response was around 1.9 months in all 3 groups.

The most frequent adverse events seen in all groups were diarrhea, hypertension, fatigue, and nausea. Hypothyroidism was seen more frequently in the lenvatinib plus pembrolizumab group (47%). Grade 3 adverse events were seen in approximately 80% of patients in all groups. The most common grade 3 or higher adverse event was hypertension in all 3 groups. The median time for discontinuing treatment due to side effects was 8.97 months in the lenvatinib plus pembrolizumab arm, 5.49 months in the lenvatinib plus everolimus group, and 4.57 months in the sunitinib group. In the lenvatinib plus pembrolizumab group, 15 patients had grade 5 adverse events; 11 participants had fatal events not related to disease progression. In the lenvatinib plus everolimus group, there were 22 patients with grade 5 events, with 10 fatal events not related to disease progression. In the sunitinib group, 11 patients had grade 5 events, and only 2 fatal events were not linked to disease progression.

Conclusion. The combination of lenvatinib plus pembrolizumab significantly prolongs PFS and OS compared with sunitinib in patients with previously untreated and advanced ccRCC. The median OS has not yet been reached.

Commentary

The results of the current phase 3 CLEAR trial highlight the efficacy and safety of lenvatinib plus pembrolizumab as a first-line treatment in advanced ccRCC. This trial adds to the rapidly growing body of literature supporting the notion that the combination of anti-PD-1 based therapy with either CTLA-4 antibodies or VEGF receptor tyrosine kinase inhibitors (TKI) improves outcomes in previously untreated patients with advanced ccRCC. Previously presented data from Keynote-426 (pembrolizumab plus axitinib), Checkmate-214 (nivolumab plus ipilimumab), and Javelin Renal 101 (Avelumab plus axitinib) have also shown improved outcomes with combination therapy in the frontline setting.^1-4 While the landscape of therapeutic options in the frontline setting continues to grow, there remains lack of clarity as to how to tailor our therapeutic decisions for specific patient populations. The exception would be nivolumab and ipilimumab, which are currently indicated for IMDC intermediate- or poor-risk patients.

The combination of VEGFR TKI therapy and PD-1 antibodies provides rapid disease control, with a median time to response in the current study of 1.9 months, and, generally speaking, a low risk of progression in the first 6 months of therapy. While cross-trial comparisons are always problematic, the PFS reported in this study and others with VEGFR TKI and PD-1 antibody combinations is quite impressive and surpasses that noted in Checkmate 214.³ While the median OS survival has not yet been reached, the long duration of PFS and complete response rate of 16% in this study certainly make this an attractive frontline option for newly diagnosed patients with advanced ccRCC. Longer follow-up is needed to confirm the survival benefit noted.

Applications for Clinical Practice

The current data support the use VEGFR TKI and anti-PD1 therapy in the frontline setting. How to choose between such combination regimens or combination immunotherapy remains unclear, and further biomarker-based assessments are needed to help guide therapeutic decisions for our patients.

Study Overview

Objective. To evaluate the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab compared with sunitinib alone for the treatment of newly diagnosed advanced clear cell renal cell carcinoma (ccRCC).

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 1:1:1 ratio to receive treatment with 1 of 3 regimens: lenvatinib 20 mg daily plus pembrolizumab 200 mg on day 1 of each 21-day cycle; lenvatinib 18 mg daily plus everolimus 5 mg once daily for each 21-day cycle; or sunitinib 50 mg daily for 4 weeks followed by 2 weeks off. Patients were stratified according to geographic region and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk group.

Setting and participants. A total of 1417 patients were screened, and 1069 patients underwent randomization between October 2016 and July 2019: 355 patients were randomized to the lenvatinib plus pembrolizumab group, 357 were randomized to the lenvatinib plus everolimus group, and 357 were randomized to the sunitinib alone group. The patients must have had a diagnosis of previously untreated advanced renal cell carcinoma with a clear-cell component. All the patients need to have a Karnofsky performance status of at least 70, adequate renal function, and controlled blood pressure with or without antihypertensive medications.

Main outcome measures. The primary endpoint assessed the progression-free survival (PFS) as evaluated by independent review committee using RECIST, version 1.1. Imaging was performed at the time of screening and every 8 weeks thereafter. Secondary endpoints were safety, overall survival (OS), and objective response rate as well as investigator-assessed PFS. Also, they assessed the duration of response. During the treatment period, the safety and adverse events were assessed up to 30 days from the last dose of the trial drug.

Main results. The baseline characteristics were well balanced between the treatment groups. More than 70% of enrolled participants were male. Approximately 60% of participants were MSKCC intermediate risk, 27% were favorable risk, and 9% were poor risk. Patients with a PD-L1 combined positive score of 1% or more represented 30% of the population. The remainder had a PD-L1 combined positive score of <1% (30%) or such data were not available (38%). Liver metastases were present in 17% of patients at baseline in each group, and 70% of patients had a prior nephrectomy. The data cutoff occurred in August 2020 for PFS and the median follow-up for OS was 26.6 months. Around 40% of the participants in the lenvatinib plus pembrolizumab group, 18.8% in the sunitinib group, and 31% in the lenvatinib plus everolimus group were still receiving trial treatment at data cutoff. The leading cause for discontinuing therapy was disease progression. Approximately 50% of patients in the lenvatinib/everolimus group and sunitinib group received subsequent checkpoint inhibitor therapy after progression.

The median PFS in the lenvatinib plus pembrolizumab group was significantly longer than in the sunitinib group, 23.9 months vs 9.2 months (hazard ratio [HR], 0.39; 95% CI, 0.32-0.49; P < 0.001). The median PFS was also significantly longer in the lenvatinib plus everolimus group compared with sunitinib, 14.7 vs 9.2 months (HR 0.65; 95% CI 0.53-0.80; P < 0.001). The PFS benefit favored the lenvatinib combination groups over sunitinib in all subgroups, including the MSKCC prognostic risk groups. The median OS was not reached with any treatment, with 79% of patients in the lenvatinib plus pembrolizumab group, 66% of patients in the lenvatinib plus everolimus group, and 70% in the sunitinib group still alive at 24 months. Survival was significantly longer in the lenvatinib plus pembrolizumab group compared with sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = 0.005). The OS favored lenvatinib/pembrolizumab over sunitinib in the PD-L1 positive or negative groups. The median duration of response in the lenvatinib plus pembrolizumab group was 25.8 months compared to 16.6 months and 14.6 months in the lenvatinib plus everolimus and sunitinib groups, respectively. Complete response rates were higher in the lenvatinib plus pembrolizumab group (16%) compared with lenvatinib/everolimus (9.8%) or sunitinib (4.2%). The median time to response was around 1.9 months in all 3 groups.

The most frequent adverse events seen in all groups were diarrhea, hypertension, fatigue, and nausea. Hypothyroidism was seen more frequently in the lenvatinib plus pembrolizumab group (47%). Grade 3 adverse events were seen in approximately 80% of patients in all groups. The most common grade 3 or higher adverse event was hypertension in all 3 groups. The median time for discontinuing treatment due to side effects was 8.97 months in the lenvatinib plus pembrolizumab arm, 5.49 months in the lenvatinib plus everolimus group, and 4.57 months in the sunitinib group. In the lenvatinib plus pembrolizumab group, 15 patients had grade 5 adverse events; 11 participants had fatal events not related to disease progression. In the lenvatinib plus everolimus group, there were 22 patients with grade 5 events, with 10 fatal events not related to disease progression. In the sunitinib group, 11 patients had grade 5 events, and only 2 fatal events were not linked to disease progression.

Conclusion. The combination of lenvatinib plus pembrolizumab significantly prolongs PFS and OS compared with sunitinib in patients with previously untreated and advanced ccRCC. The median OS has not yet been reached.

Commentary

The results of the current phase 3 CLEAR trial highlight the efficacy and safety of lenvatinib plus pembrolizumab as a first-line treatment in advanced ccRCC. This trial adds to the rapidly growing body of literature supporting the notion that the combination of anti-PD-1 based therapy with either CTLA-4 antibodies or VEGF receptor tyrosine kinase inhibitors (TKI) improves outcomes in previously untreated patients with advanced ccRCC. Previously presented data from Keynote-426 (pembrolizumab plus axitinib), Checkmate-214 (nivolumab plus ipilimumab), and Javelin Renal 101 (Avelumab plus axitinib) have also shown improved outcomes with combination therapy in the frontline setting.^1-4 While the landscape of therapeutic options in the frontline setting continues to grow, there remains lack of clarity as to how to tailor our therapeutic decisions for specific patient populations. The exception would be nivolumab and ipilimumab, which are currently indicated for IMDC intermediate- or poor-risk patients.

The combination of VEGFR TKI therapy and PD-1 antibodies provides rapid disease control, with a median time to response in the current study of 1.9 months, and, generally speaking, a low risk of progression in the first 6 months of therapy. While cross-trial comparisons are always problematic, the PFS reported in this study and others with VEGFR TKI and PD-1 antibody combinations is quite impressive and surpasses that noted in Checkmate 214.³ While the median OS survival has not yet been reached, the long duration of PFS and complete response rate of 16% in this study certainly make this an attractive frontline option for newly diagnosed patients with advanced ccRCC. Longer follow-up is needed to confirm the survival benefit noted.

Applications for Clinical Practice

The current data support the use VEGFR TKI and anti-PD1 therapy in the frontline setting. How to choose between such combination regimens or combination immunotherapy remains unclear, and further biomarker-based assessments are needed to help guide therapeutic decisions for our patients.

Study Overview

Objective. To determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the Theory of Planned Behavior (TPB), a widely accepted theory used to help predict human lifestyle-related behaviors.

Design. Pragmatic, cluster, randomized controlled trial.

Settings and participants. This study took place at the East Elgin Family Health Team, a primary care clinic in Aylmer, Ontario, Canada. Recruitment occurred between April 2017 and September 2018, with staggered intervention cohorts occurring from May 2017 to September 2019. Participants enrolled in a weight management program at the clinic were invited to participate in the study if they met the following inclusion criteria: body mass index (BMI) ≥25 kg/m², >18 years of age, English-speaking, willing to undergo genetic testing, having access to a computer with internet at least 1 day per week, and not seeing another health care provider for weight loss advice outside of the study. Exclusion criteria included pregnancy and lactation. All participants provided written informed consent.

Interventions. At baseline, weight management program cohorts (average cohort size was 14 participants) were randomized (1:1) to receive either the standard population-based intervention (Group Lifestyle Balance, or GLB) or a modified GLB intervention, which included the provision of lifestyle genomics (LGx) information and advice (GLB+LGx). Both interventions aimed to assist participants with weight management and healthy lifestyle change, with particular focus on nutrition and physical activity (PA). Interventions were 12 months long, consisting of 23 group-based sessions and 3 one-on-one sessions with a registered dietitian after 3, 6, and 12 months (all sessions were face-to-face). To improve intervention adherence, participants were given reminder calls for their one-on-one appointments and for the start of their program. A sample size was calculated based on the primary outcome indicating that a total of 74 participants were needed (n = 37 per group) for this trial. By September 2019, this sample size was exceeded with 10 randomized groups (n = 140).

The 5 randomized standard GLB groups followed the established GLB program curriculum comprising population-based information and advice while focusing on following a calorie-controlled, moderate-fat (25% of calories) nutrition plan with at least 150 minutes of weekly moderate-intensity PA. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting outlining population-based targets, including acceptable macronutrient distribution ranges for protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

The 5 randomized modified GLB+LGx groups followed a modified GLB program curriculum in which participants were given genetic-based information and advice, which differed from the advice given to the standard GLB group, while focusing on following a calorie-controlled nutrition plan. The nutrition and PA targets were personalized based on their individual genetic variation. For example, participants with the AA variant of FTO (rs9939609) were advised to engage in at least 30 to 60 minutes of PA daily 6 days per week, with muscle-strengthening activities at least 2 days per week, rather than receiving the standard population-based advice to aim for 150 minutes weekly of PA with at least 2 days per week of muscle-strengthening activity. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting, which outlined genetic-based information and advice related to protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

Measures and analysis. Change in the TPB components (attitudes, subjective norms and perceived behavioral control) were measured via a TPB questionnaire at 5 time points: baseline (2-week run-in period), immediately after the first group session (where participants received a summary report of either population-based or genetic-based recommendations depending on group assignment), and after 3-, 6- and 12-month follow-ups. Attitudes, subjective norms, and perceived behavioral control were measured on a Likert scale from 1 through 7. Self-reported measures of actual behavioral control (including annual household income, perceptions about events arising in one’s day-to-day life that suddenly take up one’s free time, perceptions about the frequency of feeling ill or tired, and highest achieved level of education) were collected via survey questions and assessed on a Likert scale of 1 through 7. Stage of change was also measured, based on the Transtheoretical Model, using a Likert scale of 1 through 6.

Linear mixed models were used to conduct within- and between-group analyses using SPSS version 26.0, while controlling for measures of actual behavioral control. All analyses were intention-to-treat by originally assigned groups, with mean value imputation conducted for missing data. A Bonferroni correction for multiple testing was used. For all statistical analyses, the level of significance was set at P < 0.05 and trending towards significance at P = 0.05–0.06.

Main results. Participants consisted of primarily middle-age, middle-income, Caucasian females. Baseline attitudes towards the effectiveness of nutrition and PA for weight management were generally positive, and participants perceived that undergoing genetic testing would assist with weight management. Participants had overall neutral subjective norms related to friends and family consuming a healthy diet and engaging in PA, but perceived that their friends, family, and health care team (HCT) believed it was important for them to achieve their nutrition and PA recommendations. Participants overall also perceived that their HCT believed genetic testing could assist with weight management. Baseline measures of perceived behavioral control were overall neutral, with baseline stage of change between “motivation” and “action” (short-term; <3 months).

In within-group analyses, significant improvements (P < 0.05) in attitudes towards the effectiveness of nutrition and PA recommendations for weight management, subjective norms related to both friends and family consuming a healthy diet, and perceived behavioral control in changing PA/dietary intake and managing weight tended to be short-term in the GLB group and long-term for the GLB+LGx group. In all cases of between-group differences for changes in TPB components, the GLB group exhibited reductions in scores, whereas the GLB+LGx group exhibited increases or improvements. Between-group differences (short-term and long-term) in several measures of subjective norms were observed. For example, after 3 months, significant between-group differences were observed in changes in perception that friends believed LGx would help with weight management (P = 0.024). After 12 months, between-group differences trending towards significance were also observed in changes in perception that family members believed genetic testing would help with weight management (P = 0.05). Significant between-group differences and differences trending towards significance were also observed at 12 months for changes in perception that family believed it was important for the participant to achieve the PA recommendations (P = 0.049) and nutrition recommendations (P = 0.05). Between-group differences trending towards significance were also observed at 3 months in attitudes towards the effectiveness of LGx for weight management (P = 0.06). There were no significant between-group differences observed in changes in perceived behavioral control.

Conclusion. Results from this study support the hypothesis that the TPB can help provide a theoretical explanation for why genetically tailored lifestyle information and advice can lead to improvements in lifestyle behavior change.

Commentary

Because health behaviors are critical in areas such as prevention, treatment, and rehabilitation, it is important to describe and understand what drives these behaviors.¹ Theories are important tools in this effort as they aim to explain and predict health behavior and are used in the design and evaluation of interventions.¹ The TPB is one of the most widely accepted behavior change theories and posits that attitudes, subjective norms (or social pressures and behaviors), and perceived behavioral control are significant predictors of an individual’s intention to engage in behaviors.² TPB has been highlighted in the literature as a validated theory for predicting nutrition and PA intentions and resulting behaviors.^3,4

Motivating lifestyle behavior change in clinical practice can be challenging, but some studies have demonstrated how providing genetic information and advice (or lifestyle genomics) can help motivate changes in nutrition and PA among patients.^5-7 Because this has yet to be explained using the TPB, this study is an important contribution to the literature as it aimed to determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the TPB. Briefly, results from within-group analyses in this study demonstrated that the provision of genetically tailored lifestyle information and advice (via the GLB+LGx intervention) tended to impact antecedents of behavior change, more so over the long-term, while population-based advice (via the standard GLB intervention) tended to impact antecedents of behavior change over the short-term (eg, attitudes towards dietary fat intake, perceptions that friends and family consume a healthy diet, and perceptions about the impact of genetic-based advice for weight management). In addition, between-group differences in subjective norms observed at 12 months suggested that social pressures and norms may be influencing long-term changes in lifestyle habits.

While key strengths of this study include its pragmatic cluster randomized controlled trial design, 12-month intervention duration, and intent-to-treat analyses, there are some study limitations, which are acknowledged by the authors. Generalizability is limited to the demographic characteristics of the study population (ie, middle-aged, middle-income, Caucasian females enrolled in a lifestyle change weight management program). Thus, replication of the study is needed in more diverse study populations and with health-related outcomes beyond weight management. In addition, as the authors indicate, future research should ensure the inclusion of theory-based questionnaires in genetic-based intervention studies assessing lifestyle behavior change to elucidate theory-based mechanisms of change.

Applications for Clinical Practice

Population-based research has consistently indicated that nutrition interventions typically impact short-term dietary changes. Confronting the challenge of long-term adherence to nutrition and PA recommendations requires an understanding of factors impacting long-term motivation and behavior change. With increased attention on and research into genetically tailored lifestyle advice (or lifestyle genomics), it is important for clinical practitioners to be familiar with the evidence supporting these approaches. In addition, this research highlights the need to consider individual factors (attitudes, subjective norms, and perceived behavioral control) that may predict successful change in lifestyle habits when providing nutrition and PA recommendations, whether population-based or genetically tailored.

—Katrina F. Mateo, PhD, MPH

Study Overview

Objective. To determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the Theory of Planned Behavior (TPB), a widely accepted theory used to help predict human lifestyle-related behaviors.

Design. Pragmatic, cluster, randomized controlled trial.

Settings and participants. This study took place at the East Elgin Family Health Team, a primary care clinic in Aylmer, Ontario, Canada. Recruitment occurred between April 2017 and September 2018, with staggered intervention cohorts occurring from May 2017 to September 2019. Participants enrolled in a weight management program at the clinic were invited to participate in the study if they met the following inclusion criteria: body mass index (BMI) ≥25 kg/m², >18 years of age, English-speaking, willing to undergo genetic testing, having access to a computer with internet at least 1 day per week, and not seeing another health care provider for weight loss advice outside of the study. Exclusion criteria included pregnancy and lactation. All participants provided written informed consent.

Interventions. At baseline, weight management program cohorts (average cohort size was 14 participants) were randomized (1:1) to receive either the standard population-based intervention (Group Lifestyle Balance, or GLB) or a modified GLB intervention, which included the provision of lifestyle genomics (LGx) information and advice (GLB+LGx). Both interventions aimed to assist participants with weight management and healthy lifestyle change, with particular focus on nutrition and physical activity (PA). Interventions were 12 months long, consisting of 23 group-based sessions and 3 one-on-one sessions with a registered dietitian after 3, 6, and 12 months (all sessions were face-to-face). To improve intervention adherence, participants were given reminder calls for their one-on-one appointments and for the start of their program. A sample size was calculated based on the primary outcome indicating that a total of 74 participants were needed (n = 37 per group) for this trial. By September 2019, this sample size was exceeded with 10 randomized groups (n = 140).

The 5 randomized standard GLB groups followed the established GLB program curriculum comprising population-based information and advice while focusing on following a calorie-controlled, moderate-fat (25% of calories) nutrition plan with at least 150 minutes of weekly moderate-intensity PA. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting outlining population-based targets, including acceptable macronutrient distribution ranges for protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

The 5 randomized modified GLB+LGx groups followed a modified GLB program curriculum in which participants were given genetic-based information and advice, which differed from the advice given to the standard GLB group, while focusing on following a calorie-controlled nutrition plan. The nutrition and PA targets were personalized based on their individual genetic variation. For example, participants with the AA variant of FTO (rs9939609) were advised to engage in at least 30 to 60 minutes of PA daily 6 days per week, with muscle-strengthening activities at least 2 days per week, rather than receiving the standard population-based advice to aim for 150 minutes weekly of PA with at least 2 days per week of muscle-strengthening activity. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting, which outlined genetic-based information and advice related to protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

Measures and analysis. Change in the TPB components (attitudes, subjective norms and perceived behavioral control) were measured via a TPB questionnaire at 5 time points: baseline (2-week run-in period), immediately after the first group session (where participants received a summary report of either population-based or genetic-based recommendations depending on group assignment), and after 3-, 6- and 12-month follow-ups. Attitudes, subjective norms, and perceived behavioral control were measured on a Likert scale from 1 through 7. Self-reported measures of actual behavioral control (including annual household income, perceptions about events arising in one’s day-to-day life that suddenly take up one’s free time, perceptions about the frequency of feeling ill or tired, and highest achieved level of education) were collected via survey questions and assessed on a Likert scale of 1 through 7. Stage of change was also measured, based on the Transtheoretical Model, using a Likert scale of 1 through 6.

Linear mixed models were used to conduct within- and between-group analyses using SPSS version 26.0, while controlling for measures of actual behavioral control. All analyses were intention-to-treat by originally assigned groups, with mean value imputation conducted for missing data. A Bonferroni correction for multiple testing was used. For all statistical analyses, the level of significance was set at P < 0.05 and trending towards significance at P = 0.05–0.06.

Main results. Participants consisted of primarily middle-age, middle-income, Caucasian females. Baseline attitudes towards the effectiveness of nutrition and PA for weight management were generally positive, and participants perceived that undergoing genetic testing would assist with weight management. Participants had overall neutral subjective norms related to friends and family consuming a healthy diet and engaging in PA, but perceived that their friends, family, and health care team (HCT) believed it was important for them to achieve their nutrition and PA recommendations. Participants overall also perceived that their HCT believed genetic testing could assist with weight management. Baseline measures of perceived behavioral control were overall neutral, with baseline stage of change between “motivation” and “action” (short-term; <3 months).

In within-group analyses, significant improvements (P < 0.05) in attitudes towards the effectiveness of nutrition and PA recommendations for weight management, subjective norms related to both friends and family consuming a healthy diet, and perceived behavioral control in changing PA/dietary intake and managing weight tended to be short-term in the GLB group and long-term for the GLB+LGx group. In all cases of between-group differences for changes in TPB components, the GLB group exhibited reductions in scores, whereas the GLB+LGx group exhibited increases or improvements. Between-group differences (short-term and long-term) in several measures of subjective norms were observed. For example, after 3 months, significant between-group differences were observed in changes in perception that friends believed LGx would help with weight management (P = 0.024). After 12 months, between-group differences trending towards significance were also observed in changes in perception that family members believed genetic testing would help with weight management (P = 0.05). Significant between-group differences and differences trending towards significance were also observed at 12 months for changes in perception that family believed it was important for the participant to achieve the PA recommendations (P = 0.049) and nutrition recommendations (P = 0.05). Between-group differences trending towards significance were also observed at 3 months in attitudes towards the effectiveness of LGx for weight management (P = 0.06). There were no significant between-group differences observed in changes in perceived behavioral control.

Conclusion. Results from this study support the hypothesis that the TPB can help provide a theoretical explanation for why genetically tailored lifestyle information and advice can lead to improvements in lifestyle behavior change.

Commentary

Because health behaviors are critical in areas such as prevention, treatment, and rehabilitation, it is important to describe and understand what drives these behaviors.¹ Theories are important tools in this effort as they aim to explain and predict health behavior and are used in the design and evaluation of interventions.¹ The TPB is one of the most widely accepted behavior change theories and posits that attitudes, subjective norms (or social pressures and behaviors), and perceived behavioral control are significant predictors of an individual’s intention to engage in behaviors.² TPB has been highlighted in the literature as a validated theory for predicting nutrition and PA intentions and resulting behaviors.^3,4

Motivating lifestyle behavior change in clinical practice can be challenging, but some studies have demonstrated how providing genetic information and advice (or lifestyle genomics) can help motivate changes in nutrition and PA among patients.^5-7 Because this has yet to be explained using the TPB, this study is an important contribution to the literature as it aimed to determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the TPB. Briefly, results from within-group analyses in this study demonstrated that the provision of genetically tailored lifestyle information and advice (via the GLB+LGx intervention) tended to impact antecedents of behavior change, more so over the long-term, while population-based advice (via the standard GLB intervention) tended to impact antecedents of behavior change over the short-term (eg, attitudes towards dietary fat intake, perceptions that friends and family consume a healthy diet, and perceptions about the impact of genetic-based advice for weight management). In addition, between-group differences in subjective norms observed at 12 months suggested that social pressures and norms may be influencing long-term changes in lifestyle habits.

While key strengths of this study include its pragmatic cluster randomized controlled trial design, 12-month intervention duration, and intent-to-treat analyses, there are some study limitations, which are acknowledged by the authors. Generalizability is limited to the demographic characteristics of the study population (ie, middle-aged, middle-income, Caucasian females enrolled in a lifestyle change weight management program). Thus, replication of the study is needed in more diverse study populations and with health-related outcomes beyond weight management. In addition, as the authors indicate, future research should ensure the inclusion of theory-based questionnaires in genetic-based intervention studies assessing lifestyle behavior change to elucidate theory-based mechanisms of change.

Applications for Clinical Practice

Population-based research has consistently indicated that nutrition interventions typically impact short-term dietary changes. Confronting the challenge of long-term adherence to nutrition and PA recommendations requires an understanding of factors impacting long-term motivation and behavior change. With increased attention on and research into genetically tailored lifestyle advice (or lifestyle genomics), it is important for clinical practitioners to be familiar with the evidence supporting these approaches. In addition, this research highlights the need to consider individual factors (attitudes, subjective norms, and perceived behavioral control) that may predict successful change in lifestyle habits when providing nutrition and PA recommendations, whether population-based or genetically tailored.

—Katrina F. Mateo, PhD, MPH

Study Overview

Objective. To determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the Theory of Planned Behavior (TPB), a widely accepted theory used to help predict human lifestyle-related behaviors.

Design. Pragmatic, cluster, randomized controlled trial.

Settings and participants. This study took place at the East Elgin Family Health Team, a primary care clinic in Aylmer, Ontario, Canada. Recruitment occurred between April 2017 and September 2018, with staggered intervention cohorts occurring from May 2017 to September 2019. Participants enrolled in a weight management program at the clinic were invited to participate in the study if they met the following inclusion criteria: body mass index (BMI) ≥25 kg/m², >18 years of age, English-speaking, willing to undergo genetic testing, having access to a computer with internet at least 1 day per week, and not seeing another health care provider for weight loss advice outside of the study. Exclusion criteria included pregnancy and lactation. All participants provided written informed consent.

Interventions. At baseline, weight management program cohorts (average cohort size was 14 participants) were randomized (1:1) to receive either the standard population-based intervention (Group Lifestyle Balance, or GLB) or a modified GLB intervention, which included the provision of lifestyle genomics (LGx) information and advice (GLB+LGx). Both interventions aimed to assist participants with weight management and healthy lifestyle change, with particular focus on nutrition and physical activity (PA). Interventions were 12 months long, consisting of 23 group-based sessions and 3 one-on-one sessions with a registered dietitian after 3, 6, and 12 months (all sessions were face-to-face). To improve intervention adherence, participants were given reminder calls for their one-on-one appointments and for the start of their program. A sample size was calculated based on the primary outcome indicating that a total of 74 participants were needed (n = 37 per group) for this trial. By September 2019, this sample size was exceeded with 10 randomized groups (n = 140).

The 5 randomized standard GLB groups followed the established GLB program curriculum comprising population-based information and advice while focusing on following a calorie-controlled, moderate-fat (25% of calories) nutrition plan with at least 150 minutes of weekly moderate-intensity PA. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting outlining population-based targets, including acceptable macronutrient distribution ranges for protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

The 5 randomized modified GLB+LGx groups followed a modified GLB program curriculum in which participants were given genetic-based information and advice, which differed from the advice given to the standard GLB group, while focusing on following a calorie-controlled nutrition plan. The nutrition and PA targets were personalized based on their individual genetic variation. For example, participants with the AA variant of FTO (rs9939609) were advised to engage in at least 30 to 60 minutes of PA daily 6 days per week, with muscle-strengthening activities at least 2 days per week, rather than receiving the standard population-based advice to aim for 150 minutes weekly of PA with at least 2 days per week of muscle-strengthening activity. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting, which outlined genetic-based information and advice related to protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

Measures and analysis. Change in the TPB components (attitudes, subjective norms and perceived behavioral control) were measured via a TPB questionnaire at 5 time points: baseline (2-week run-in period), immediately after the first group session (where participants received a summary report of either population-based or genetic-based recommendations depending on group assignment), and after 3-, 6- and 12-month follow-ups. Attitudes, subjective norms, and perceived behavioral control were measured on a Likert scale from 1 through 7. Self-reported measures of actual behavioral control (including annual household income, perceptions about events arising in one’s day-to-day life that suddenly take up one’s free time, perceptions about the frequency of feeling ill or tired, and highest achieved level of education) were collected via survey questions and assessed on a Likert scale of 1 through 7. Stage of change was also measured, based on the Transtheoretical Model, using a Likert scale of 1 through 6.

Linear mixed models were used to conduct within- and between-group analyses using SPSS version 26.0, while controlling for measures of actual behavioral control. All analyses were intention-to-treat by originally assigned groups, with mean value imputation conducted for missing data. A Bonferroni correction for multiple testing was used. For all statistical analyses, the level of significance was set at P < 0.05 and trending towards significance at P = 0.05–0.06.

Main results. Participants consisted of primarily middle-age, middle-income, Caucasian females. Baseline attitudes towards the effectiveness of nutrition and PA for weight management were generally positive, and participants perceived that undergoing genetic testing would assist with weight management. Participants had overall neutral subjective norms related to friends and family consuming a healthy diet and engaging in PA, but perceived that their friends, family, and health care team (HCT) believed it was important for them to achieve their nutrition and PA recommendations. Participants overall also perceived that their HCT believed genetic testing could assist with weight management. Baseline measures of perceived behavioral control were overall neutral, with baseline stage of change between “motivation” and “action” (short-term; <3 months).

In within-group analyses, significant improvements (P < 0.05) in attitudes towards the effectiveness of nutrition and PA recommendations for weight management, subjective norms related to both friends and family consuming a healthy diet, and perceived behavioral control in changing PA/dietary intake and managing weight tended to be short-term in the GLB group and long-term for the GLB+LGx group. In all cases of between-group differences for changes in TPB components, the GLB group exhibited reductions in scores, whereas the GLB+LGx group exhibited increases or improvements. Between-group differences (short-term and long-term) in several measures of subjective norms were observed. For example, after 3 months, significant between-group differences were observed in changes in perception that friends believed LGx would help with weight management (P = 0.024). After 12 months, between-group differences trending towards significance were also observed in changes in perception that family members believed genetic testing would help with weight management (P = 0.05). Significant between-group differences and differences trending towards significance were also observed at 12 months for changes in perception that family believed it was important for the participant to achieve the PA recommendations (P = 0.049) and nutrition recommendations (P = 0.05). Between-group differences trending towards significance were also observed at 3 months in attitudes towards the effectiveness of LGx for weight management (P = 0.06). There were no significant between-group differences observed in changes in perceived behavioral control.

Conclusion. Results from this study support the hypothesis that the TPB can help provide a theoretical explanation for why genetically tailored lifestyle information and advice can lead to improvements in lifestyle behavior change.

Commentary

Because health behaviors are critical in areas such as prevention, treatment, and rehabilitation, it is important to describe and understand what drives these behaviors.¹ Theories are important tools in this effort as they aim to explain and predict health behavior and are used in the design and evaluation of interventions.¹ The TPB is one of the most widely accepted behavior change theories and posits that attitudes, subjective norms (or social pressures and behaviors), and perceived behavioral control are significant predictors of an individual’s intention to engage in behaviors.² TPB has been highlighted in the literature as a validated theory for predicting nutrition and PA intentions and resulting behaviors.^3,4

Motivating lifestyle behavior change in clinical practice can be challenging, but some studies have demonstrated how providing genetic information and advice (or lifestyle genomics) can help motivate changes in nutrition and PA among patients.^5-7 Because this has yet to be explained using the TPB, this study is an important contribution to the literature as it aimed to determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the TPB. Briefly, results from within-group analyses in this study demonstrated that the provision of genetically tailored lifestyle information and advice (via the GLB+LGx intervention) tended to impact antecedents of behavior change, more so over the long-term, while population-based advice (via the standard GLB intervention) tended to impact antecedents of behavior change over the short-term (eg, attitudes towards dietary fat intake, perceptions that friends and family consume a healthy diet, and perceptions about the impact of genetic-based advice for weight management). In addition, between-group differences in subjective norms observed at 12 months suggested that social pressures and norms may be influencing long-term changes in lifestyle habits.

While key strengths of this study include its pragmatic cluster randomized controlled trial design, 12-month intervention duration, and intent-to-treat analyses, there are some study limitations, which are acknowledged by the authors. Generalizability is limited to the demographic characteristics of the study population (ie, middle-aged, middle-income, Caucasian females enrolled in a lifestyle change weight management program). Thus, replication of the study is needed in more diverse study populations and with health-related outcomes beyond weight management. In addition, as the authors indicate, future research should ensure the inclusion of theory-based questionnaires in genetic-based intervention studies assessing lifestyle behavior change to elucidate theory-based mechanisms of change.

Applications for Clinical Practice

Population-based research has consistently indicated that nutrition interventions typically impact short-term dietary changes. Confronting the challenge of long-term adherence to nutrition and PA recommendations requires an understanding of factors impacting long-term motivation and behavior change. With increased attention on and research into genetically tailored lifestyle advice (or lifestyle genomics), it is important for clinical practitioners to be familiar with the evidence supporting these approaches. In addition, this research highlights the need to consider individual factors (attitudes, subjective norms, and perceived behavioral control) that may predict successful change in lifestyle habits when providing nutrition and PA recommendations, whether population-based or genetically tailored.

—Katrina F. Mateo, PhD, MPH

Study Overview

Objective. To examine the trend of noninvasive and invasive mechanical ventilation at the end of life from 2000 to 2017.

Design. Observational population-based cohort study.

Setting and participants. The study was a population-based cohort study to examine the use of noninvasive and invasive mechanical ventilation among decedents. The study included a random 20% sample of Medicare beneficiaries older than 65 years who were hospitalized in the last 30 days of life and died between January 1, 2000, and December 31, 2017, except for the period October 1, 2015, to December 31, 2015, when the transition from International Classification of Diseases, Ninth Revision (ICD-9) to ICD-10 occurred. Beneficiaries with the primary admitting diagnosis of cardiac arrest or with preexisting tracheostomy were excluded because of expected requirements for ventilatory support. The sample included a total of 2,470,735 Medicare beneficiaries; mean age was 82.2 years, and 54.8% were female. Primary admitting diagnosis codes were used to identify 3 subcohorts: congestive heart failure, chronic obstructive pulmonary disease, and cancer; a fourth subcohort of dementia was identified using the primary admitting diagnosis code or the first 9 secondary diagnosis codes.

Main outcome measures. The study used procedure codes to identify the use of noninvasive ventilation, invasive mechanical ventilation, or none among decedents who were hospitalized in the last 30 days of life. Descriptive statistics to characterize variables by year of hospitalization and ventilatory support were calculated, and the rates of noninvasive and invasive mechanical ventilation use were tabulated. Other outcomes of interest include site of death (in-hospital death), hospice enrollment at death, and hospice enrollment in the last 3 days of life as measures of end-of- life care use. Multivariable logistic regressions were used to examine noninvasive and invasive mechanical ventilation use among decedents, and time trends were examined, with the pattern of use in year 2000 as reference. Subgroup analysis with the subcohort of patients with different diagnoses were conducted to examine trends.

Main results. From 2000 to 2017, 16.3% of decedents had invasive mechanical ventilation, 3.7% had noninvasive ventilation, and 1.0% had both noninvasive and invasive ventilation during their hospital stay. Compared to the reference year 2000, there was a 9-fold increase in noninvasive ventilation use, from 0.8% to 7.1% in 2017, and invasive mechanical ventilation use also increased slightly, from 15.0% to 18.5%. Compared to year 2000, decedents were 2.63 times and 1.04 times (adjusted odds ratio [OR]) more likely to receive noninvasive ventilation and invasive mechanical ventilation, respectively, in 2005, 7.87 times and 1.39 times more likely in 2011, and 11.84 times and 1.63 times more likely in 2017.

Subgroup analysis showed that for congestive heart failure and chronic obstructive pulmonary disease, the increase in noninvasive ventilation use mirrored the trend observed for the overall population, but the use of invasive mechanical ventilation did not increase from 2000 to 2017, with a rate of use of 11.1% versus 7.8% (adjusted OR, 1.07; 95% confidence interval [CI], 0.95-1.19) for congestive heart failure and 17.4% vs 13.2% (OR 1.03, 95% CI, 0.88-1.21) for chronic obstructive pulmonary disease. For the cancer and dementia subgroups, the increase in noninvasive ventilation use from 2000 to 2017 was accompanied by an increase in the use of invasive mechanical ventilation, with a rate of 6.2% versus 7.4% (OR, 1.40; 95% CI, 1.26-1.55) for decedents with cancer and a rate of 5.7% versus 6.2% (OR, 1.28; 95% CI, 1.17-1.41) for decedents with dementia. For other measures of end-of-life care, noninvasive ventilation use when compared to invasive mechanical ventilation use was associated with lower rates of in-hospital (acute care) deaths (50.3% vs 76.7%), hospice enrollment in the last 3 days of life (late hospice enrollment; 57.7% vs 63.0%), and higher rates of hospice enrollment at death (41.3% vs 20.0%).

Conclusion. There was an increase in the use of noninvasive ventilation from 2000 through 2017 among Medicare beneficiaries who died. The findings also suggest that the use of invasive mechanical ventilation did not increase among decedents with congestive heart failure and chronic obstructive pulmonary disease but increased among decedents with cancer and dementia.

Noninvasive ventilation offers an alternative to invasive mechanical ventilation for providing ventilatory support for respiratory failure, and may offer benefits as it could avert adverse effects associated with invasive mechanical ventilation, particularly in the management of respiratory failure due to congestive heart failure and chronic obstructive pulmonary disease.¹ There is evidence for potential benefits of use of noninvasive ventilation in other clinical scenarios, such as pneumonia in older adults with comorbidities, though its clinical utility is not as well established for other diseases.²

As noninvasive ventilation is introduced into clinical practice, it is not surprising that over the period of the study (2000 to 2017) that its use increased substantially. Advance directives that involve discussion of life-sustaining treatments, including in scenarios with respiratory failure, may also result in physician orders that specify whether an individual desires invasive mechanical ventilation versus other medical treatments, including noninvasive ventilation.^3,4 By examining the temporal trends of use of noninvasive and invasive ventilation, this study reveals that invasive mechanical ventilation use among decedents with dementia and cancer has increased, despite increases in the use of noninvasive ventilation. It is important to understand further what would explain these temporal trends and whether the use of noninvasive and also invasive mechanical ventilation at the end of life represents appropriate care with clear goals or whether it may represent overuse. It is also less clear in the end-of-life care scenario what the goals of treatment with noninvasive ventilation would be, especially if it does not avert the use of invasive mechanical ventilation.

The study includes decedents only, thus limiting the ability to draw conclusions about clinically appropriate care.⁵ Further studies should examine a cohort of patients who have serious and life-threatening illness to examine the trends and potential effects of noninvasive ventilation on outcomes and utilization, as individuals who have improved and survived would not be included in this present decedent cohort.

Applications for Clinical Practice

This study highlights changes in the use of noninvasive and invasive ventilation over time and the different trends seen among subgroups with different diagnoses. For older adults with serious comorbid illness such as dementia, it is especially important to have discussions on advance directives so that care at the end of life is concordant with the patient’s wishes and that unnecessary, burdensome care can be averted. Further studies to understand and define the appropriate use of noninvasive and invasive mechanical ventilation for older adults with significant comorbidities who have serious, life-threatening illness are needed to ensure appropriate clinical treatment at the end of life.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine the trend of noninvasive and invasive mechanical ventilation at the end of life from 2000 to 2017.

Design. Observational population-based cohort study.

Setting and participants. The study was a population-based cohort study to examine the use of noninvasive and invasive mechanical ventilation among decedents. The study included a random 20% sample of Medicare beneficiaries older than 65 years who were hospitalized in the last 30 days of life and died between January 1, 2000, and December 31, 2017, except for the period October 1, 2015, to December 31, 2015, when the transition from International Classification of Diseases, Ninth Revision (ICD-9) to ICD-10 occurred. Beneficiaries with the primary admitting diagnosis of cardiac arrest or with preexisting tracheostomy were excluded because of expected requirements for ventilatory support. The sample included a total of 2,470,735 Medicare beneficiaries; mean age was 82.2 years, and 54.8% were female. Primary admitting diagnosis codes were used to identify 3 subcohorts: congestive heart failure, chronic obstructive pulmonary disease, and cancer; a fourth subcohort of dementia was identified using the primary admitting diagnosis code or the first 9 secondary diagnosis codes.

Main outcome measures. The study used procedure codes to identify the use of noninvasive ventilation, invasive mechanical ventilation, or none among decedents who were hospitalized in the last 30 days of life. Descriptive statistics to characterize variables by year of hospitalization and ventilatory support were calculated, and the rates of noninvasive and invasive mechanical ventilation use were tabulated. Other outcomes of interest include site of death (in-hospital death), hospice enrollment at death, and hospice enrollment in the last 3 days of life as measures of end-of- life care use. Multivariable logistic regressions were used to examine noninvasive and invasive mechanical ventilation use among decedents, and time trends were examined, with the pattern of use in year 2000 as reference. Subgroup analysis with the subcohort of patients with different diagnoses were conducted to examine trends.

Main results. From 2000 to 2017, 16.3% of decedents had invasive mechanical ventilation, 3.7% had noninvasive ventilation, and 1.0% had both noninvasive and invasive ventilation during their hospital stay. Compared to the reference year 2000, there was a 9-fold increase in noninvasive ventilation use, from 0.8% to 7.1% in 2017, and invasive mechanical ventilation use also increased slightly, from 15.0% to 18.5%. Compared to year 2000, decedents were 2.63 times and 1.04 times (adjusted odds ratio [OR]) more likely to receive noninvasive ventilation and invasive mechanical ventilation, respectively, in 2005, 7.87 times and 1.39 times more likely in 2011, and 11.84 times and 1.63 times more likely in 2017.

Subgroup analysis showed that for congestive heart failure and chronic obstructive pulmonary disease, the increase in noninvasive ventilation use mirrored the trend observed for the overall population, but the use of invasive mechanical ventilation did not increase from 2000 to 2017, with a rate of use of 11.1% versus 7.8% (adjusted OR, 1.07; 95% confidence interval [CI], 0.95-1.19) for congestive heart failure and 17.4% vs 13.2% (OR 1.03, 95% CI, 0.88-1.21) for chronic obstructive pulmonary disease. For the cancer and dementia subgroups, the increase in noninvasive ventilation use from 2000 to 2017 was accompanied by an increase in the use of invasive mechanical ventilation, with a rate of 6.2% versus 7.4% (OR, 1.40; 95% CI, 1.26-1.55) for decedents with cancer and a rate of 5.7% versus 6.2% (OR, 1.28; 95% CI, 1.17-1.41) for decedents with dementia. For other measures of end-of-life care, noninvasive ventilation use when compared to invasive mechanical ventilation use was associated with lower rates of in-hospital (acute care) deaths (50.3% vs 76.7%), hospice enrollment in the last 3 days of life (late hospice enrollment; 57.7% vs 63.0%), and higher rates of hospice enrollment at death (41.3% vs 20.0%).

Conclusion. There was an increase in the use of noninvasive ventilation from 2000 through 2017 among Medicare beneficiaries who died. The findings also suggest that the use of invasive mechanical ventilation did not increase among decedents with congestive heart failure and chronic obstructive pulmonary disease but increased among decedents with cancer and dementia.

Noninvasive ventilation offers an alternative to invasive mechanical ventilation for providing ventilatory support for respiratory failure, and may offer benefits as it could avert adverse effects associated with invasive mechanical ventilation, particularly in the management of respiratory failure due to congestive heart failure and chronic obstructive pulmonary disease.¹ There is evidence for potential benefits of use of noninvasive ventilation in other clinical scenarios, such as pneumonia in older adults with comorbidities, though its clinical utility is not as well established for other diseases.²

As noninvasive ventilation is introduced into clinical practice, it is not surprising that over the period of the study (2000 to 2017) that its use increased substantially. Advance directives that involve discussion of life-sustaining treatments, including in scenarios with respiratory failure, may also result in physician orders that specify whether an individual desires invasive mechanical ventilation versus other medical treatments, including noninvasive ventilation.^3,4 By examining the temporal trends of use of noninvasive and invasive ventilation, this study reveals that invasive mechanical ventilation use among decedents with dementia and cancer has increased, despite increases in the use of noninvasive ventilation. It is important to understand further what would explain these temporal trends and whether the use of noninvasive and also invasive mechanical ventilation at the end of life represents appropriate care with clear goals or whether it may represent overuse. It is also less clear in the end-of-life care scenario what the goals of treatment with noninvasive ventilation would be, especially if it does not avert the use of invasive mechanical ventilation.

The study includes decedents only, thus limiting the ability to draw conclusions about clinically appropriate care.⁵ Further studies should examine a cohort of patients who have serious and life-threatening illness to examine the trends and potential effects of noninvasive ventilation on outcomes and utilization, as individuals who have improved and survived would not be included in this present decedent cohort.

Applications for Clinical Practice

This study highlights changes in the use of noninvasive and invasive ventilation over time and the different trends seen among subgroups with different diagnoses. For older adults with serious comorbid illness such as dementia, it is especially important to have discussions on advance directives so that care at the end of life is concordant with the patient’s wishes and that unnecessary, burdensome care can be averted. Further studies to understand and define the appropriate use of noninvasive and invasive mechanical ventilation for older adults with significant comorbidities who have serious, life-threatening illness are needed to ensure appropriate clinical treatment at the end of life.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine the trend of noninvasive and invasive mechanical ventilation at the end of life from 2000 to 2017.

Design. Observational population-based cohort study.

Setting and participants. The study was a population-based cohort study to examine the use of noninvasive and invasive mechanical ventilation among decedents. The study included a random 20% sample of Medicare beneficiaries older than 65 years who were hospitalized in the last 30 days of life and died between January 1, 2000, and December 31, 2017, except for the period October 1, 2015, to December 31, 2015, when the transition from International Classification of Diseases, Ninth Revision (ICD-9) to ICD-10 occurred. Beneficiaries with the primary admitting diagnosis of cardiac arrest or with preexisting tracheostomy were excluded because of expected requirements for ventilatory support. The sample included a total of 2,470,735 Medicare beneficiaries; mean age was 82.2 years, and 54.8% were female. Primary admitting diagnosis codes were used to identify 3 subcohorts: congestive heart failure, chronic obstructive pulmonary disease, and cancer; a fourth subcohort of dementia was identified using the primary admitting diagnosis code or the first 9 secondary diagnosis codes.

Main outcome measures. The study used procedure codes to identify the use of noninvasive ventilation, invasive mechanical ventilation, or none among decedents who were hospitalized in the last 30 days of life. Descriptive statistics to characterize variables by year of hospitalization and ventilatory support were calculated, and the rates of noninvasive and invasive mechanical ventilation use were tabulated. Other outcomes of interest include site of death (in-hospital death), hospice enrollment at death, and hospice enrollment in the last 3 days of life as measures of end-of- life care use. Multivariable logistic regressions were used to examine noninvasive and invasive mechanical ventilation use among decedents, and time trends were examined, with the pattern of use in year 2000 as reference. Subgroup analysis with the subcohort of patients with different diagnoses were conducted to examine trends.

Main results. From 2000 to 2017, 16.3% of decedents had invasive mechanical ventilation, 3.7% had noninvasive ventilation, and 1.0% had both noninvasive and invasive ventilation during their hospital stay. Compared to the reference year 2000, there was a 9-fold increase in noninvasive ventilation use, from 0.8% to 7.1% in 2017, and invasive mechanical ventilation use also increased slightly, from 15.0% to 18.5%. Compared to year 2000, decedents were 2.63 times and 1.04 times (adjusted odds ratio [OR]) more likely to receive noninvasive ventilation and invasive mechanical ventilation, respectively, in 2005, 7.87 times and 1.39 times more likely in 2011, and 11.84 times and 1.63 times more likely in 2017.

Subgroup analysis showed that for congestive heart failure and chronic obstructive pulmonary disease, the increase in noninvasive ventilation use mirrored the trend observed for the overall population, but the use of invasive mechanical ventilation did not increase from 2000 to 2017, with a rate of use of 11.1% versus 7.8% (adjusted OR, 1.07; 95% confidence interval [CI], 0.95-1.19) for congestive heart failure and 17.4% vs 13.2% (OR 1.03, 95% CI, 0.88-1.21) for chronic obstructive pulmonary disease. For the cancer and dementia subgroups, the increase in noninvasive ventilation use from 2000 to 2017 was accompanied by an increase in the use of invasive mechanical ventilation, with a rate of 6.2% versus 7.4% (OR, 1.40; 95% CI, 1.26-1.55) for decedents with cancer and a rate of 5.7% versus 6.2% (OR, 1.28; 95% CI, 1.17-1.41) for decedents with dementia. For other measures of end-of-life care, noninvasive ventilation use when compared to invasive mechanical ventilation use was associated with lower rates of in-hospital (acute care) deaths (50.3% vs 76.7%), hospice enrollment in the last 3 days of life (late hospice enrollment; 57.7% vs 63.0%), and higher rates of hospice enrollment at death (41.3% vs 20.0%).

Conclusion. There was an increase in the use of noninvasive ventilation from 2000 through 2017 among Medicare beneficiaries who died. The findings also suggest that the use of invasive mechanical ventilation did not increase among decedents with congestive heart failure and chronic obstructive pulmonary disease but increased among decedents with cancer and dementia.

Noninvasive ventilation offers an alternative to invasive mechanical ventilation for providing ventilatory support for respiratory failure, and may offer benefits as it could avert adverse effects associated with invasive mechanical ventilation, particularly in the management of respiratory failure due to congestive heart failure and chronic obstructive pulmonary disease.¹ There is evidence for potential benefits of use of noninvasive ventilation in other clinical scenarios, such as pneumonia in older adults with comorbidities, though its clinical utility is not as well established for other diseases.²

As noninvasive ventilation is introduced into clinical practice, it is not surprising that over the period of the study (2000 to 2017) that its use increased substantially. Advance directives that involve discussion of life-sustaining treatments, including in scenarios with respiratory failure, may also result in physician orders that specify whether an individual desires invasive mechanical ventilation versus other medical treatments, including noninvasive ventilation.^3,4 By examining the temporal trends of use of noninvasive and invasive ventilation, this study reveals that invasive mechanical ventilation use among decedents with dementia and cancer has increased, despite increases in the use of noninvasive ventilation. It is important to understand further what would explain these temporal trends and whether the use of noninvasive and also invasive mechanical ventilation at the end of life represents appropriate care with clear goals or whether it may represent overuse. It is also less clear in the end-of-life care scenario what the goals of treatment with noninvasive ventilation would be, especially if it does not avert the use of invasive mechanical ventilation.

The study includes decedents only, thus limiting the ability to draw conclusions about clinically appropriate care.⁵ Further studies should examine a cohort of patients who have serious and life-threatening illness to examine the trends and potential effects of noninvasive ventilation on outcomes and utilization, as individuals who have improved and survived would not be included in this present decedent cohort.

Applications for Clinical Practice

This study highlights changes in the use of noninvasive and invasive ventilation over time and the different trends seen among subgroups with different diagnoses. For older adults with serious comorbid illness such as dementia, it is especially important to have discussions on advance directives so that care at the end of life is concordant with the patient’s wishes and that unnecessary, burdensome care can be averted. Further studies to understand and define the appropriate use of noninvasive and invasive mechanical ventilation for older adults with significant comorbidities who have serious, life-threatening illness are needed to ensure appropriate clinical treatment at the end of life.

–William W. Hung, MD, MPH

Study Overview

Objective. To determine the effect of the timing of nonculprit-lesion percutaneous coronary intervention (PCI) on outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Design. Planned substudy of an international, multicenter, randomized controlled trial blinded to outcome.

Setting and participants. Among 4041 patients with STEMI who had multivessel coronary disease, randomization to nonculprit PCI versus culprit-only PCI was stratified according to intended timing of nonculprit lesion PCI. A total of 2702 patients with intended timing of nonculprit PCI during the index hospitalization and 1339 patients with intended timing of nonculprit PCI after the index hospitalization within 45 days were included.

Main outcome measures. The first co-primary endpoint was a composite of cardiovascular (CV) death or myocardial infarction (MI).

Main results. In both groups, the composite endpoint of CV death or MI was reduced with complete revascularization compared to the culprit-only strategy (index hospitalization: hazard ratio [HR], 0.77, 95% confidence interval [CI], 0.59-1.00; after hospital discharge: HR, 0.69, 95% CI, 0.49-0.97; interaction, P = 0.62). Landmark analyses demonstrated a HR of 0.86 (95% CI, 0.59-1.24) during the first 45 days and 0.69 (95% CI,0.54-0.89) from 45 days to the end of follow-up for intended nonculprit lesion PCI versus culprit-lesion-only PCI.

Conclusion. Among patients with STEMI and multivessel disease, the benefit of complete revascularization over culprit-lesion-only PCI was consistent, irrespective of the investigator-determined timing of staged nonculprit lesion intervention.

Commentary

Patients presenting with STEMI often have multivessel disease^.1 Although the question of whether to revascularize the nonculprit vessel has been controversial, multiple contemporary studies have reported benefit of nonculprit-vessel revascularization compared to the culprit-only strategy.^2-5 Compared to these previous medium-sized randomized controlled trials that included ischemia-driven revascularization as a composite endpoint, the COMPETE trial was unique in that it enrolled a large number of patients and reported a benefit in hard outcomes of a composite of CV death or MI.⁶

As the previous studies point toward the benefit of complete revascularization in patients presenting with STEMI, another important question has been the optimal timing of nonculprit vessel revascularization. Operators have 3 possible options: during the index procedure as primary PCI, as a staged procedure during the index admission, or as a staged procedure as an outpatient following discharge. Timing of nonculprit PCI has been inconsistent in the previous studies. For example, in the PRAMI trial, nonculprit PCI was performed during the index procedure,² while in the CvPRIT and COMPARE ACUTE trials, the nonculprit PCI was performed during the index procedure or as a staged procedure during the same admission at the operator’s discretion.^3,5

In this context, the COMPLETE investigators report their findings of the prespecified substudy regarding the timing of staged nonculprit vessel PCI. In the COMPLETE trial, 4041 patients were stratified by intended timing of nonculprit lesion PCI (2702 patients during index hospitalization, 1339 after discharge), which was predetermined by the operator prior to the randomization. Among the patients with intended staged nonculprit PCI during index hospitalization, the incidence of the first co-primary outcome of CV death or MI was 2.7% per year in patients with complete revascularization, as compared to 3.5% per year in patients with culprit-lesion only PCI (HR, 0.77; 95% CI, 0.59-1.00). Similarly, in patients with intended nonculprit PCI after the index hospitalization, the incidence of the first co-primary outcome of CV death or MI was 2.7% per year in patients randomized to complete revascularization, as compared to 3.9% per year in patients with culprit-lesion-only PCI (HR, 0.69; 95% CI, 0.49-0.97). These findings were similar for the second co-primary outcome of CV death, MI, or ischemia-driven revascularization (3.0% vs 6.6% per year for intended timing of nonculprit PCI during index admission, and 3.1% vs 5.4% per year for intended timing of nonculprit PCI after discharge, both favoring complete revascularization).

The investigators also performed a landmark analysis before and after 45 days of randomization. Within the first 45 days, CV death or MI occurred in 2.5% of the complete revascularization group and 3.0% of the culprit-lesion-only PCI group (HR, 0.86; 95% CI, 0.59-1.24). On the other hand, during the interval from 45 days to the end of the study, CV death or MI occurred in 5.5% in the complete revascularization group and 7.8% in the culprit-lesion-only group (HR, 0.69; 95% CI, 0.54-0.89).

There were a number of strengths of the COMPLETE study, as we have previously described, such as multiple patients enrolled, contemporary therapy with high use of radial access, mandated use of fractional flow reserve for 50% to 69% stenosis lesions, and low cross-over rate.⁷ In addition, the current substudy is unique and important, as it was the first study to systematically evaluate the timing of the staged PCI. In addition to their finding of consistent benefit between staged procedure before or after discharge, the results from their landmark analysis suggest that the benefit of complete revascularization accumulates over the long term rather than the short term.

The main limitation of the COMPLETE study is that it was not adequately powered to find statistical differences in each subgroup studied. In addition, since all nonculprit PCIs were staged in this study, nonculprit PCI performed during the index procedure cannot be assessed.

Nevertheless, the finding of similar benefit of complete revascularization regardless of the timing of the staged PCI has clinical implication for practicing interventional cardiologists and patients presenting with STEMI. For example, if the patient presents with hemodynamically stable STEMI on a Friday, the patient can potentially be safely discharged over the weekend and return for a staged PCI as an outpatient instead of staying extra days for an inpatient staged PCI. Whether this approach may improve the patient satisfaction and hospital resource utilization will require further study.

Applications for Clinical Practice

In patients presenting with hemodynamically stable STEMI, staged complete revascularization can be performed during the admission or after discharge within 45 days.

—Taishi Hirai, MD

Study Overview

Objective. To determine the effect of the timing of nonculprit-lesion percutaneous coronary intervention (PCI) on outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Design. Planned substudy of an international, multicenter, randomized controlled trial blinded to outcome.

Setting and participants. Among 4041 patients with STEMI who had multivessel coronary disease, randomization to nonculprit PCI versus culprit-only PCI was stratified according to intended timing of nonculprit lesion PCI. A total of 2702 patients with intended timing of nonculprit PCI during the index hospitalization and 1339 patients with intended timing of nonculprit PCI after the index hospitalization within 45 days were included.

Main outcome measures. The first co-primary endpoint was a composite of cardiovascular (CV) death or myocardial infarction (MI).

Main results. In both groups, the composite endpoint of CV death or MI was reduced with complete revascularization compared to the culprit-only strategy (index hospitalization: hazard ratio [HR], 0.77, 95% confidence interval [CI], 0.59-1.00; after hospital discharge: HR, 0.69, 95% CI, 0.49-0.97; interaction, P = 0.62). Landmark analyses demonstrated a HR of 0.86 (95% CI, 0.59-1.24) during the first 45 days and 0.69 (95% CI,0.54-0.89) from 45 days to the end of follow-up for intended nonculprit lesion PCI versus culprit-lesion-only PCI.

Conclusion. Among patients with STEMI and multivessel disease, the benefit of complete revascularization over culprit-lesion-only PCI was consistent, irrespective of the investigator-determined timing of staged nonculprit lesion intervention.

Commentary

Patients presenting with STEMI often have multivessel disease^.1 Although the question of whether to revascularize the nonculprit vessel has been controversial, multiple contemporary studies have reported benefit of nonculprit-vessel revascularization compared to the culprit-only strategy.^2-5 Compared to these previous medium-sized randomized controlled trials that included ischemia-driven revascularization as a composite endpoint, the COMPETE trial was unique in that it enrolled a large number of patients and reported a benefit in hard outcomes of a composite of CV death or MI.⁶

As the previous studies point toward the benefit of complete revascularization in patients presenting with STEMI, another important question has been the optimal timing of nonculprit vessel revascularization. Operators have 3 possible options: during the index procedure as primary PCI, as a staged procedure during the index admission, or as a staged procedure as an outpatient following discharge. Timing of nonculprit PCI has been inconsistent in the previous studies. For example, in the PRAMI trial, nonculprit PCI was performed during the index procedure,² while in the CvPRIT and COMPARE ACUTE trials, the nonculprit PCI was performed during the index procedure or as a staged procedure during the same admission at the operator’s discretion.^3,5

In this context, the COMPLETE investigators report their findings of the prespecified substudy regarding the timing of staged nonculprit vessel PCI. In the COMPLETE trial, 4041 patients were stratified by intended timing of nonculprit lesion PCI (2702 patients during index hospitalization, 1339 after discharge), which was predetermined by the operator prior to the randomization. Among the patients with intended staged nonculprit PCI during index hospitalization, the incidence of the first co-primary outcome of CV death or MI was 2.7% per year in patients with complete revascularization, as compared to 3.5% per year in patients with culprit-lesion only PCI (HR, 0.77; 95% CI, 0.59-1.00). Similarly, in patients with intended nonculprit PCI after the index hospitalization, the incidence of the first co-primary outcome of CV death or MI was 2.7% per year in patients randomized to complete revascularization, as compared to 3.9% per year in patients with culprit-lesion-only PCI (HR, 0.69; 95% CI, 0.49-0.97). These findings were similar for the second co-primary outcome of CV death, MI, or ischemia-driven revascularization (3.0% vs 6.6% per year for intended timing of nonculprit PCI during index admission, and 3.1% vs 5.4% per year for intended timing of nonculprit PCI after discharge, both favoring complete revascularization).

The investigators also performed a landmark analysis before and after 45 days of randomization. Within the first 45 days, CV death or MI occurred in 2.5% of the complete revascularization group and 3.0% of the culprit-lesion-only PCI group (HR, 0.86; 95% CI, 0.59-1.24). On the other hand, during the interval from 45 days to the end of the study, CV death or MI occurred in 5.5% in the complete revascularization group and 7.8% in the culprit-lesion-only group (HR, 0.69; 95% CI, 0.54-0.89).

There were a number of strengths of the COMPLETE study, as we have previously described, such as multiple patients enrolled, contemporary therapy with high use of radial access, mandated use of fractional flow reserve for 50% to 69% stenosis lesions, and low cross-over rate.⁷ In addition, the current substudy is unique and important, as it was the first study to systematically evaluate the timing of the staged PCI. In addition to their finding of consistent benefit between staged procedure before or after discharge, the results from their landmark analysis suggest that the benefit of complete revascularization accumulates over the long term rather than the short term.

The main limitation of the COMPLETE study is that it was not adequately powered to find statistical differences in each subgroup studied. In addition, since all nonculprit PCIs were staged in this study, nonculprit PCI performed during the index procedure cannot be assessed.

Nevertheless, the finding of similar benefit of complete revascularization regardless of the timing of the staged PCI has clinical implication for practicing interventional cardiologists and patients presenting with STEMI. For example, if the patient presents with hemodynamically stable STEMI on a Friday, the patient can potentially be safely discharged over the weekend and return for a staged PCI as an outpatient instead of staying extra days for an inpatient staged PCI. Whether this approach may improve the patient satisfaction and hospital resource utilization will require further study.

Applications for Clinical Practice

In patients presenting with hemodynamically stable STEMI, staged complete revascularization can be performed during the admission or after discharge within 45 days.

—Taishi Hirai, MD

Study Overview

Objective. To determine the effect of the timing of nonculprit-lesion percutaneous coronary intervention (PCI) on outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Design. Planned substudy of an international, multicenter, randomized controlled trial blinded to outcome.

Setting and participants. Among 4041 patients with STEMI who had multivessel coronary disease, randomization to nonculprit PCI versus culprit-only PCI was stratified according to intended timing of nonculprit lesion PCI. A total of 2702 patients with intended timing of nonculprit PCI during the index hospitalization and 1339 patients with intended timing of nonculprit PCI after the index hospitalization within 45 days were included.

Main outcome measures. The first co-primary endpoint was a composite of cardiovascular (CV) death or myocardial infarction (MI).

Main results. In both groups, the composite endpoint of CV death or MI was reduced with complete revascularization compared to the culprit-only strategy (index hospitalization: hazard ratio [HR], 0.77, 95% confidence interval [CI], 0.59-1.00; after hospital discharge: HR, 0.69, 95% CI, 0.49-0.97; interaction, P = 0.62). Landmark analyses demonstrated a HR of 0.86 (95% CI, 0.59-1.24) during the first 45 days and 0.69 (95% CI,0.54-0.89) from 45 days to the end of follow-up for intended nonculprit lesion PCI versus culprit-lesion-only PCI.

Conclusion. Among patients with STEMI and multivessel disease, the benefit of complete revascularization over culprit-lesion-only PCI was consistent, irrespective of the investigator-determined timing of staged nonculprit lesion intervention.

Commentary

Patients presenting with STEMI often have multivessel disease^.1 Although the question of whether to revascularize the nonculprit vessel has been controversial, multiple contemporary studies have reported benefit of nonculprit-vessel revascularization compared to the culprit-only strategy.^2-5 Compared to these previous medium-sized randomized controlled trials that included ischemia-driven revascularization as a composite endpoint, the COMPETE trial was unique in that it enrolled a large number of patients and reported a benefit in hard outcomes of a composite of CV death or MI.⁶

As the previous studies point toward the benefit of complete revascularization in patients presenting with STEMI, another important question has been the optimal timing of nonculprit vessel revascularization. Operators have 3 possible options: during the index procedure as primary PCI, as a staged procedure during the index admission, or as a staged procedure as an outpatient following discharge. Timing of nonculprit PCI has been inconsistent in the previous studies. For example, in the PRAMI trial, nonculprit PCI was performed during the index procedure,² while in the CvPRIT and COMPARE ACUTE trials, the nonculprit PCI was performed during the index procedure or as a staged procedure during the same admission at the operator’s discretion.^3,5

In this context, the COMPLETE investigators report their findings of the prespecified substudy regarding the timing of staged nonculprit vessel PCI. In the COMPLETE trial, 4041 patients were stratified by intended timing of nonculprit lesion PCI (2702 patients during index hospitalization, 1339 after discharge), which was predetermined by the operator prior to the randomization. Among the patients with intended staged nonculprit PCI during index hospitalization, the incidence of the first co-primary outcome of CV death or MI was 2.7% per year in patients with complete revascularization, as compared to 3.5% per year in patients with culprit-lesion only PCI (HR, 0.77; 95% CI, 0.59-1.00). Similarly, in patients with intended nonculprit PCI after the index hospitalization, the incidence of the first co-primary outcome of CV death or MI was 2.7% per year in patients randomized to complete revascularization, as compared to 3.9% per year in patients with culprit-lesion-only PCI (HR, 0.69; 95% CI, 0.49-0.97). These findings were similar for the second co-primary outcome of CV death, MI, or ischemia-driven revascularization (3.0% vs 6.6% per year for intended timing of nonculprit PCI during index admission, and 3.1% vs 5.4% per year for intended timing of nonculprit PCI after discharge, both favoring complete revascularization).

The investigators also performed a landmark analysis before and after 45 days of randomization. Within the first 45 days, CV death or MI occurred in 2.5% of the complete revascularization group and 3.0% of the culprit-lesion-only PCI group (HR, 0.86; 95% CI, 0.59-1.24). On the other hand, during the interval from 45 days to the end of the study, CV death or MI occurred in 5.5% in the complete revascularization group and 7.8% in the culprit-lesion-only group (HR, 0.69; 95% CI, 0.54-0.89).

There were a number of strengths of the COMPLETE study, as we have previously described, such as multiple patients enrolled, contemporary therapy with high use of radial access, mandated use of fractional flow reserve for 50% to 69% stenosis lesions, and low cross-over rate.⁷ In addition, the current substudy is unique and important, as it was the first study to systematically evaluate the timing of the staged PCI. In addition to their finding of consistent benefit between staged procedure before or after discharge, the results from their landmark analysis suggest that the benefit of complete revascularization accumulates over the long term rather than the short term.

The main limitation of the COMPLETE study is that it was not adequately powered to find statistical differences in each subgroup studied. In addition, since all nonculprit PCIs were staged in this study, nonculprit PCI performed during the index procedure cannot be assessed.

Nevertheless, the finding of similar benefit of complete revascularization regardless of the timing of the staged PCI has clinical implication for practicing interventional cardiologists and patients presenting with STEMI. For example, if the patient presents with hemodynamically stable STEMI on a Friday, the patient can potentially be safely discharged over the weekend and return for a staged PCI as an outpatient instead of staying extra days for an inpatient staged PCI. Whether this approach may improve the patient satisfaction and hospital resource utilization will require further study.

Applications for Clinical Practice

In patients presenting with hemodynamically stable STEMI, staged complete revascularization can be performed during the admission or after discharge within 45 days.

—Taishi Hirai, MD

Study Overview

Objective. To examine whether discontinuation of nonsteroidal anti-inflammatory drug (NSAID) therapy and initiation of telephone-based cognitive behavioral therapy (CBT) is not worse than continuation of NSAIDs in the management of arthritis pain.

Design. Randomized controlled trial with noninferiority design.

Setting and participants. This study was a multicenter trial conducted across 4 Veterans Affairs health care systems in Boston, Providence, Connecticut, and North Florida/South Georgia that started September 2013 and ended September 2018. Eligibility criteria included being age 20 years or older, radiographic evidence of knee osteoarthritis, and use of an NSAID for knee pain on most days of the month for at least the past 3 months. Exclusion criteria included significant hearing impairments that may impede the conduct of the trial, current opioid prescriptions excluding tramadol, contraindications to NSAID use, recent or scheduled intra-articular injections or surgery, comorbid conditions other than knee pain that limited walking, and bilateral knee replacements or pain only in the replaced knee. Concurrent use of tramadol and other non-NSAID analgesics was permitted.

A total of 490 participants took part in the 2-week run-in period where their NSAID regimen was discontinued and they were started on a standardized dose of the NSAID meloxicam 15 mg daily. During the run-in period, 126 participants were excluded for several reasons, including worsening pain and patient withdrawal, yielding 364 participants who were randomized to continue meloxicam treatment or placebo for 4 weeks with blinding.

Intervention. Subsequent to the 4-week phase 1 placebo controlled trial, participants in the placebo group were given CBT via telephone (unblinded) for 10 weeks, and the meloxicam group continued treatment with meloxicam for phase 2. The CBT group received 10 modules over 10 weeks in 30- to 45-minute telephone contacts with a psychologist using a treatment manual modified for knee osteoarthritis. These modules consisted of 1 introductory module, 8 pain coping skills modules (eg, deep breathing and visual imagery, progressive muscle relaxation, physical activity and bodily mechanics, identifying unhealthy thoughts, balancing unhealthy thoughts, managing stress, time-based pacing, and sleep hygiene), and a final module emphasizing skill consolidation and relapse prevention. Outcomes were assessed at the end of the phase 1 and phase 2 periods.

Main outcome measures. Main study outcome measures included pain as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 4 weeks. Secondary outcomes included the WOMAC pain score, disability score, and global impression of change after treatment at 14 weeks. The WOMAC pain scale ranges from 0 to 20, and consists of 5 questions regarding severity of pain during walking, stair use, lying in bed at night, sitting, and standing, with 0 indicating no pain; 1, mild pain; 2, moderate pain; 3, severe pain; and 4, very severe pain for each item. The WOMAC disability scale measures self-reported difficulty in performing tasks that reflect lower-extremity physical function, including climbing stairs, rising from a chair, walking, and other activities of daily living. The global impression of change after treatment was measured on a 5-point scale (where 1 indicates much better and 5 indicates much worse). The minimum clinically important difference of the WOMAC pain scale is 2, based on prior literature. With the noninferiority design, the margin was set as a score of 1.

Main results. The placebo group consisted of 180 participants, with an average age of 58.2 years (SD, 11.8 years); 89% of them were male. The meloxicam group consisted of 184 participants, with an average age of 58.6 years (SD, 10 years); 84% of them were male. The average body mass index was 33.9 and 33.4 in each group, respectively. For the primary outcome, the placebo group had a worse pain score than the meloxicam group at 4 weeks (difference of 1.4; 95% confidence interval, 0.8- 2.0). At 14 weeks, the placebo group (with CBT) had a worse pain score than the meloxicam group (difference of 0.8; 95% CI, 0.2-1.4). There was no statistically significant difference in the disability score or global impression of change after treatment score between the 2 groups. The observed difference in pain score did not, however, exceed the minimum clinically important difference.

Conclusion. Placebo treatment and CBT are inferior to NSAIDs in managing pain for patients with knee osteoarthritis. The difference in pain may not be clinically important, and there were no differences in function at 14 weeks.

Commentary

Osteoarthritis is a common chronic condition that causes pain and disability and is often treated with oral analgesics. NSAIDs, despite few high-quality trials demonstrating their efficacy, are among the most commonly used treatment for osteoarthritis pain.¹ NSAID therapy, however, does have potential side effects, such as gastric reflux and renal dysfunction.² This withdrawal trial with placebo control contributes further evidence of the effectiveness of NSAIDs on knee osteoarthritis, demonstrating that indeed NSAIDs improve pain scores to a greater degree than placebo treatment. Augmenting placebo treatment with nonpharmacologic CBT was inferior to NSAIDs in pain management. The authors pointed out that the difference in pain score may not be clinically important, and that lower-extremity function was not different between the groups, concluding that, despite the higher pain score, CBT could be a treatment option, particularly for those who may have difficulty tolerating NSAID treatment.

The study population had a number of chronic conditions in addition to having knee arthritis, and thus likely were taking multiple medications for chronic disease management. Use of multiple medications is associated with an increased risk of rug interactions and adverse effects of medications.³ Thus, this attempt to assess whether a nonpharmacologic alternative treatment is noninferior to a drug treatment is a step toward building the evidence base for deprescribing and enhancing medication safety.⁴ Previous studies have examined other nonpharmacologic treatments for knee arthritis, such as acupuncture,⁵ and it is worthwhile to consider combining nonpharmacological approaches as an alternative to oral analgesic medication use.

Applications for Clinical Practice

This study advances our understanding of the effect of NSAID use on knee osteoarthritis when compared to placebo with CBT. Although this is a negative study that failed to show that placebo combined with CBT is noninferior to NSAIDs, it did quantify the expected treatment effect of NSAIDs and showed that this effect likely is not clinically important and/or does not alter lower-extremity function. Further studies are needed to identify other nonpharmacologic approaches and test whether combinations of approaches are effective in the management of chronic pain from osteoarthritis.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine whether discontinuation of nonsteroidal anti-inflammatory drug (NSAID) therapy and initiation of telephone-based cognitive behavioral therapy (CBT) is not worse than continuation of NSAIDs in the management of arthritis pain.

Design. Randomized controlled trial with noninferiority design.

Setting and participants. This study was a multicenter trial conducted across 4 Veterans Affairs health care systems in Boston, Providence, Connecticut, and North Florida/South Georgia that started September 2013 and ended September 2018. Eligibility criteria included being age 20 years or older, radiographic evidence of knee osteoarthritis, and use of an NSAID for knee pain on most days of the month for at least the past 3 months. Exclusion criteria included significant hearing impairments that may impede the conduct of the trial, current opioid prescriptions excluding tramadol, contraindications to NSAID use, recent or scheduled intra-articular injections or surgery, comorbid conditions other than knee pain that limited walking, and bilateral knee replacements or pain only in the replaced knee. Concurrent use of tramadol and other non-NSAID analgesics was permitted.

A total of 490 participants took part in the 2-week run-in period where their NSAID regimen was discontinued and they were started on a standardized dose of the NSAID meloxicam 15 mg daily. During the run-in period, 126 participants were excluded for several reasons, including worsening pain and patient withdrawal, yielding 364 participants who were randomized to continue meloxicam treatment or placebo for 4 weeks with blinding.

Intervention. Subsequent to the 4-week phase 1 placebo controlled trial, participants in the placebo group were given CBT via telephone (unblinded) for 10 weeks, and the meloxicam group continued treatment with meloxicam for phase 2. The CBT group received 10 modules over 10 weeks in 30- to 45-minute telephone contacts with a psychologist using a treatment manual modified for knee osteoarthritis. These modules consisted of 1 introductory module, 8 pain coping skills modules (eg, deep breathing and visual imagery, progressive muscle relaxation, physical activity and bodily mechanics, identifying unhealthy thoughts, balancing unhealthy thoughts, managing stress, time-based pacing, and sleep hygiene), and a final module emphasizing skill consolidation and relapse prevention. Outcomes were assessed at the end of the phase 1 and phase 2 periods.

Main outcome measures. Main study outcome measures included pain as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 4 weeks. Secondary outcomes included the WOMAC pain score, disability score, and global impression of change after treatment at 14 weeks. The WOMAC pain scale ranges from 0 to 20, and consists of 5 questions regarding severity of pain during walking, stair use, lying in bed at night, sitting, and standing, with 0 indicating no pain; 1, mild pain; 2, moderate pain; 3, severe pain; and 4, very severe pain for each item. The WOMAC disability scale measures self-reported difficulty in performing tasks that reflect lower-extremity physical function, including climbing stairs, rising from a chair, walking, and other activities of daily living. The global impression of change after treatment was measured on a 5-point scale (where 1 indicates much better and 5 indicates much worse). The minimum clinically important difference of the WOMAC pain scale is 2, based on prior literature. With the noninferiority design, the margin was set as a score of 1.

Main results. The placebo group consisted of 180 participants, with an average age of 58.2 years (SD, 11.8 years); 89% of them were male. The meloxicam group consisted of 184 participants, with an average age of 58.6 years (SD, 10 years); 84% of them were male. The average body mass index was 33.9 and 33.4 in each group, respectively. For the primary outcome, the placebo group had a worse pain score than the meloxicam group at 4 weeks (difference of 1.4; 95% confidence interval, 0.8- 2.0). At 14 weeks, the placebo group (with CBT) had a worse pain score than the meloxicam group (difference of 0.8; 95% CI, 0.2-1.4). There was no statistically significant difference in the disability score or global impression of change after treatment score between the 2 groups. The observed difference in pain score did not, however, exceed the minimum clinically important difference.

Conclusion. Placebo treatment and CBT are inferior to NSAIDs in managing pain for patients with knee osteoarthritis. The difference in pain may not be clinically important, and there were no differences in function at 14 weeks.

Commentary

Osteoarthritis is a common chronic condition that causes pain and disability and is often treated with oral analgesics. NSAIDs, despite few high-quality trials demonstrating their efficacy, are among the most commonly used treatment for osteoarthritis pain.¹ NSAID therapy, however, does have potential side effects, such as gastric reflux and renal dysfunction.² This withdrawal trial with placebo control contributes further evidence of the effectiveness of NSAIDs on knee osteoarthritis, demonstrating that indeed NSAIDs improve pain scores to a greater degree than placebo treatment. Augmenting placebo treatment with nonpharmacologic CBT was inferior to NSAIDs in pain management. The authors pointed out that the difference in pain score may not be clinically important, and that lower-extremity function was not different between the groups, concluding that, despite the higher pain score, CBT could be a treatment option, particularly for those who may have difficulty tolerating NSAID treatment.

The study population had a number of chronic conditions in addition to having knee arthritis, and thus likely were taking multiple medications for chronic disease management. Use of multiple medications is associated with an increased risk of rug interactions and adverse effects of medications.³ Thus, this attempt to assess whether a nonpharmacologic alternative treatment is noninferior to a drug treatment is a step toward building the evidence base for deprescribing and enhancing medication safety.⁴ Previous studies have examined other nonpharmacologic treatments for knee arthritis, such as acupuncture,⁵ and it is worthwhile to consider combining nonpharmacological approaches as an alternative to oral analgesic medication use.

Applications for Clinical Practice

This study advances our understanding of the effect of NSAID use on knee osteoarthritis when compared to placebo with CBT. Although this is a negative study that failed to show that placebo combined with CBT is noninferior to NSAIDs, it did quantify the expected treatment effect of NSAIDs and showed that this effect likely is not clinically important and/or does not alter lower-extremity function. Further studies are needed to identify other nonpharmacologic approaches and test whether combinations of approaches are effective in the management of chronic pain from osteoarthritis.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine whether discontinuation of nonsteroidal anti-inflammatory drug (NSAID) therapy and initiation of telephone-based cognitive behavioral therapy (CBT) is not worse than continuation of NSAIDs in the management of arthritis pain.

Design. Randomized controlled trial with noninferiority design.

Setting and participants. This study was a multicenter trial conducted across 4 Veterans Affairs health care systems in Boston, Providence, Connecticut, and North Florida/South Georgia that started September 2013 and ended September 2018. Eligibility criteria included being age 20 years or older, radiographic evidence of knee osteoarthritis, and use of an NSAID for knee pain on most days of the month for at least the past 3 months. Exclusion criteria included significant hearing impairments that may impede the conduct of the trial, current opioid prescriptions excluding tramadol, contraindications to NSAID use, recent or scheduled intra-articular injections or surgery, comorbid conditions other than knee pain that limited walking, and bilateral knee replacements or pain only in the replaced knee. Concurrent use of tramadol and other non-NSAID analgesics was permitted.

A total of 490 participants took part in the 2-week run-in period where their NSAID regimen was discontinued and they were started on a standardized dose of the NSAID meloxicam 15 mg daily. During the run-in period, 126 participants were excluded for several reasons, including worsening pain and patient withdrawal, yielding 364 participants who were randomized to continue meloxicam treatment or placebo for 4 weeks with blinding.

Intervention. Subsequent to the 4-week phase 1 placebo controlled trial, participants in the placebo group were given CBT via telephone (unblinded) for 10 weeks, and the meloxicam group continued treatment with meloxicam for phase 2. The CBT group received 10 modules over 10 weeks in 30- to 45-minute telephone contacts with a psychologist using a treatment manual modified for knee osteoarthritis. These modules consisted of 1 introductory module, 8 pain coping skills modules (eg, deep breathing and visual imagery, progressive muscle relaxation, physical activity and bodily mechanics, identifying unhealthy thoughts, balancing unhealthy thoughts, managing stress, time-based pacing, and sleep hygiene), and a final module emphasizing skill consolidation and relapse prevention. Outcomes were assessed at the end of the phase 1 and phase 2 periods.

Main outcome measures. Main study outcome measures included pain as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 4 weeks. Secondary outcomes included the WOMAC pain score, disability score, and global impression of change after treatment at 14 weeks. The WOMAC pain scale ranges from 0 to 20, and consists of 5 questions regarding severity of pain during walking, stair use, lying in bed at night, sitting, and standing, with 0 indicating no pain; 1, mild pain; 2, moderate pain; 3, severe pain; and 4, very severe pain for each item. The WOMAC disability scale measures self-reported difficulty in performing tasks that reflect lower-extremity physical function, including climbing stairs, rising from a chair, walking, and other activities of daily living. The global impression of change after treatment was measured on a 5-point scale (where 1 indicates much better and 5 indicates much worse). The minimum clinically important difference of the WOMAC pain scale is 2, based on prior literature. With the noninferiority design, the margin was set as a score of 1.

Main results. The placebo group consisted of 180 participants, with an average age of 58.2 years (SD, 11.8 years); 89% of them were male. The meloxicam group consisted of 184 participants, with an average age of 58.6 years (SD, 10 years); 84% of them were male. The average body mass index was 33.9 and 33.4 in each group, respectively. For the primary outcome, the placebo group had a worse pain score than the meloxicam group at 4 weeks (difference of 1.4; 95% confidence interval, 0.8- 2.0). At 14 weeks, the placebo group (with CBT) had a worse pain score than the meloxicam group (difference of 0.8; 95% CI, 0.2-1.4). There was no statistically significant difference in the disability score or global impression of change after treatment score between the 2 groups. The observed difference in pain score did not, however, exceed the minimum clinically important difference.

Conclusion. Placebo treatment and CBT are inferior to NSAIDs in managing pain for patients with knee osteoarthritis. The difference in pain may not be clinically important, and there were no differences in function at 14 weeks.

Commentary

Osteoarthritis is a common chronic condition that causes pain and disability and is often treated with oral analgesics. NSAIDs, despite few high-quality trials demonstrating their efficacy, are among the most commonly used treatment for osteoarthritis pain.¹ NSAID therapy, however, does have potential side effects, such as gastric reflux and renal dysfunction.² This withdrawal trial with placebo control contributes further evidence of the effectiveness of NSAIDs on knee osteoarthritis, demonstrating that indeed NSAIDs improve pain scores to a greater degree than placebo treatment. Augmenting placebo treatment with nonpharmacologic CBT was inferior to NSAIDs in pain management. The authors pointed out that the difference in pain score may not be clinically important, and that lower-extremity function was not different between the groups, concluding that, despite the higher pain score, CBT could be a treatment option, particularly for those who may have difficulty tolerating NSAID treatment.

The study population had a number of chronic conditions in addition to having knee arthritis, and thus likely were taking multiple medications for chronic disease management. Use of multiple medications is associated with an increased risk of rug interactions and adverse effects of medications.³ Thus, this attempt to assess whether a nonpharmacologic alternative treatment is noninferior to a drug treatment is a step toward building the evidence base for deprescribing and enhancing medication safety.⁴ Previous studies have examined other nonpharmacologic treatments for knee arthritis, such as acupuncture,⁵ and it is worthwhile to consider combining nonpharmacological approaches as an alternative to oral analgesic medication use.

Applications for Clinical Practice

This study advances our understanding of the effect of NSAID use on knee osteoarthritis when compared to placebo with CBT. Although this is a negative study that failed to show that placebo combined with CBT is noninferior to NSAIDs, it did quantify the expected treatment effect of NSAIDs and showed that this effect likely is not clinically important and/or does not alter lower-extremity function. Further studies are needed to identify other nonpharmacologic approaches and test whether combinations of approaches are effective in the management of chronic pain from osteoarthritis.

–William W. Hung, MD, MPH

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS

Study Overview

Objective. To evaluate the efficacy of maintenance avelumab in patients with advanced urothelial carcinoma who had received first-line platinum-based chemotherapy.

Design. International, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 ratio to receive either maintenance therapy with avelumab 10 mg/kg plus best supportive care (BSC) or BSC alone, per local practice. Randomization was stratified according to best response to first-line chemotherapy and metastatic site (visceral vs nonvisceral). Treatment was continued until progression, unacceptable toxicities, or patient withdrawal occurred.

Setting and participants. A total of 700 patients were enrolled at 197 sites (350 in the avelumab group and 350 in the BSC group). All patients had histologically confirmed unresectable or metastatic urothelial carcinoma. Patients received 4 to 6 cycles of chemotherapy with either gemcitabine plus cisplatin or carboplatin and had no evidence of progression after completion. Patients had a treatment-free interval of 4 to 10 weeks prior to starting maintenance therapy. Patients who received neoadjuvant or adjuvant platinum-based therapy within the prior 12 months were excluded.

Main outcome measures. The primary endpoint was overall survival (OS) assessed in both the overall population and PD-L1–positive population. Secondary endpoints included progression-free survival (PFS), objective response, time to response, duration of response, and disease control. PD-L1 expression was determined via the Ventana PD-L1 assay (SP263), and patients were classified as PD-L1 positive if they met 1 of the following: (1) at least 25% of tumor cells were positive for PD-L1; (2) at least 25% of immune cells were positive for PD-L1 if more than 1% of the tumor area contained immune cells; and (3) 100% of immune cells stained for PD-L1 if no more than 1% of the tumor area contained immune cells.

Results. The baseline characteristics were well balanced between the groups. A total of 51.1% of patients had PD-L1–positive tumors (57.6% in the avelumab group and 56.3% in the control group). At the time of analysis, 24% of patients in the avelumab group were still receiving therapy compared with only 7% in the BSC group. The most common reason for discontinuation of therapy was disease progression; 43.7% of patients in the control group received anti-PD-1 or anti-PD-L1 therapy at progression. The median follow-up was 19 months. OS at 1 year was 71.3% in the avelumab group and 58.4% in the control group. The median OS was 21.4 months in the avelumab group compared with 14.3 months in the control group (hazard ratio [HR] for death, 0.69; confidence interval [CI], 0.56-0.86, P = 0.001). In the PD-L1–positive population, OS was also significantly longer in the avelumab group (NE vs 17.1 months, HR, 0.56; CI, 0.40-0.79; P < 0.001). In the PD-L1–negative population, median OS was 18.8 months in the avelumab group versus 13.7 months in the control group (HR, 0.85). PFS was longer in the avelumab group than in the control group, with a median PFS of 3.7 months versus 2 months, respectively. The median PFS was 5.7 months in the avelumab group and 2.1 months in the control group in the PD-L1–positive population.

Adverse events (AEs) of any grade occurred in 98% of patients in the avelumab group and 77% in the control group. Grade 3 or higher AEs occurred in 47.4% of patients in the avelumab group. AEs led to discontinuation in 11.9% of patients in the avelumab group. Two patients died in the avelumab group as a result of toxicity (urinary tract infection with sepsis and ischemic stroke). Immune-related adverse events occurred in 29.4% of patients in the avelumab group. Of those, 7% were grade 3 in nature, and there were no grade 4 or 5 immune-related AEs. The most commonly seen immune-related AEs were thyroid disorders.

Conclusion. Avelumab maintenance significantly improved OS compared with BSC in patients with advanced/metastatic urothelial carcinoma whose disease did not progress after first-line platinum-based chemotherapy.

Commentary

In summary, the JAVELIN Bladder 100 trial showed significantly longer OS with the use of maintenance avelumab following first-line platinum-based chemotherapy. This survival benefit was seen in all subgroups, including those who received cisplatin or carboplatin therapy, as well as those with stable disease, partial response, or complete response to initial chemotherapy. Furthermore, the survival benefit was seen in both the overall population as well as in the PD-L1–positive population. There did not appear to be any new safety concerns noted in this trial. Based on these findings, avelumab maintenance in those who do not progress on first-line platinum-based therapy certainly represents a potentially new standard of care in this patient population. While the results of this study are promising and potentially practice changing, whether this “switch maintenance” approach is superior to treatment at progression (ie, use of checkpoint inhibition in the second-line setting) remains debatable. Nevertheless, for most patients, this appears to be the preferred approach given the notable longer OS and improved PFS, which is meaningful, particularly if the progression event is symptomatic. Furthermore, a portion of patients will not proceed to second-line therapy for a variety of reasons, and thus will not be exposed to checkpoint inhibitors if one takes a treatment break approach.

In the previous KEYNOTE-45 study evaluating pembrolizumab versus chemotherapy in the second-line setting after progression on previous platinum therapy, the median OS was just 10 months in the pembrolizumab arm.¹ This is markedly different from the 21.4-month median OS noted in the current study. While there are many limitations to this comparison, it does appear that switch maintenance leads to meaningful improvements in patient outcomes. It should be noted, however, that a portion of patients will have a durable response to platinum-based therapy, and thus there may be a portion of patients who would be “overtreated” with such an approach.

A similar approach has been explored in a randomized phase 2 trial looking at maintenance pembrolizumab after first-line chemotherapy (HCRN GU14-182).² This trial similarly showed improvement in PFS; however, OS was not yet mature at the time of data analysis. It should be noted that crossover was permitted in the HCRN study, while this was not allowed in the current Javelin 100 study. Certainly, this crossover effect influenced OS data in that trial. Thus, the current study is the first and only to show an OS benefit with such an approach in this population. Numerous ongoing studies are seeking to evaluate the efficacy of immune checkpoint inhibitors in the first-line setting for advanced urothelial carcinoma, and the results of these studies will help shed additional light regarding the efficacy of this approach.

Applications for Clinical Practice

First-line maintenance avelumab in patients who do not progress on platinum-based chemotherapy improves both progression-free and overall survival. This approach is certainly practice-changing and represents a new standard of care in this patient population. Careful discussion with each patient about the benefits and risks of a switch maintenance approach is warranted.

Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of maintenance avelumab in patients with advanced urothelial carcinoma who had received first-line platinum-based chemotherapy.

Design. International, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 ratio to receive either maintenance therapy with avelumab 10 mg/kg plus best supportive care (BSC) or BSC alone, per local practice. Randomization was stratified according to best response to first-line chemotherapy and metastatic site (visceral vs nonvisceral). Treatment was continued until progression, unacceptable toxicities, or patient withdrawal occurred.

Setting and participants. A total of 700 patients were enrolled at 197 sites (350 in the avelumab group and 350 in the BSC group). All patients had histologically confirmed unresectable or metastatic urothelial carcinoma. Patients received 4 to 6 cycles of chemotherapy with either gemcitabine plus cisplatin or carboplatin and had no evidence of progression after completion. Patients had a treatment-free interval of 4 to 10 weeks prior to starting maintenance therapy. Patients who received neoadjuvant or adjuvant platinum-based therapy within the prior 12 months were excluded.

Main outcome measures. The primary endpoint was overall survival (OS) assessed in both the overall population and PD-L1–positive population. Secondary endpoints included progression-free survival (PFS), objective response, time to response, duration of response, and disease control. PD-L1 expression was determined via the Ventana PD-L1 assay (SP263), and patients were classified as PD-L1 positive if they met 1 of the following: (1) at least 25% of tumor cells were positive for PD-L1; (2) at least 25% of immune cells were positive for PD-L1 if more than 1% of the tumor area contained immune cells; and (3) 100% of immune cells stained for PD-L1 if no more than 1% of the tumor area contained immune cells.

Results. The baseline characteristics were well balanced between the groups. A total of 51.1% of patients had PD-L1–positive tumors (57.6% in the avelumab group and 56.3% in the control group). At the time of analysis, 24% of patients in the avelumab group were still receiving therapy compared with only 7% in the BSC group. The most common reason for discontinuation of therapy was disease progression; 43.7% of patients in the control group received anti-PD-1 or anti-PD-L1 therapy at progression. The median follow-up was 19 months. OS at 1 year was 71.3% in the avelumab group and 58.4% in the control group. The median OS was 21.4 months in the avelumab group compared with 14.3 months in the control group (hazard ratio [HR] for death, 0.69; confidence interval [CI], 0.56-0.86, P = 0.001). In the PD-L1–positive population, OS was also significantly longer in the avelumab group (NE vs 17.1 months, HR, 0.56; CI, 0.40-0.79; P < 0.001). In the PD-L1–negative population, median OS was 18.8 months in the avelumab group versus 13.7 months in the control group (HR, 0.85). PFS was longer in the avelumab group than in the control group, with a median PFS of 3.7 months versus 2 months, respectively. The median PFS was 5.7 months in the avelumab group and 2.1 months in the control group in the PD-L1–positive population.

Adverse events (AEs) of any grade occurred in 98% of patients in the avelumab group and 77% in the control group. Grade 3 or higher AEs occurred in 47.4% of patients in the avelumab group. AEs led to discontinuation in 11.9% of patients in the avelumab group. Two patients died in the avelumab group as a result of toxicity (urinary tract infection with sepsis and ischemic stroke). Immune-related adverse events occurred in 29.4% of patients in the avelumab group. Of those, 7% were grade 3 in nature, and there were no grade 4 or 5 immune-related AEs. The most commonly seen immune-related AEs were thyroid disorders.

Conclusion. Avelumab maintenance significantly improved OS compared with BSC in patients with advanced/metastatic urothelial carcinoma whose disease did not progress after first-line platinum-based chemotherapy.

Commentary

In summary, the JAVELIN Bladder 100 trial showed significantly longer OS with the use of maintenance avelumab following first-line platinum-based chemotherapy. This survival benefit was seen in all subgroups, including those who received cisplatin or carboplatin therapy, as well as those with stable disease, partial response, or complete response to initial chemotherapy. Furthermore, the survival benefit was seen in both the overall population as well as in the PD-L1–positive population. There did not appear to be any new safety concerns noted in this trial. Based on these findings, avelumab maintenance in those who do not progress on first-line platinum-based therapy certainly represents a potentially new standard of care in this patient population. While the results of this study are promising and potentially practice changing, whether this “switch maintenance” approach is superior to treatment at progression (ie, use of checkpoint inhibition in the second-line setting) remains debatable. Nevertheless, for most patients, this appears to be the preferred approach given the notable longer OS and improved PFS, which is meaningful, particularly if the progression event is symptomatic. Furthermore, a portion of patients will not proceed to second-line therapy for a variety of reasons, and thus will not be exposed to checkpoint inhibitors if one takes a treatment break approach.

In the previous KEYNOTE-45 study evaluating pembrolizumab versus chemotherapy in the second-line setting after progression on previous platinum therapy, the median OS was just 10 months in the pembrolizumab arm.¹ This is markedly different from the 21.4-month median OS noted in the current study. While there are many limitations to this comparison, it does appear that switch maintenance leads to meaningful improvements in patient outcomes. It should be noted, however, that a portion of patients will have a durable response to platinum-based therapy, and thus there may be a portion of patients who would be “overtreated” with such an approach.

A similar approach has been explored in a randomized phase 2 trial looking at maintenance pembrolizumab after first-line chemotherapy (HCRN GU14-182).² This trial similarly showed improvement in PFS; however, OS was not yet mature at the time of data analysis. It should be noted that crossover was permitted in the HCRN study, while this was not allowed in the current Javelin 100 study. Certainly, this crossover effect influenced OS data in that trial. Thus, the current study is the first and only to show an OS benefit with such an approach in this population. Numerous ongoing studies are seeking to evaluate the efficacy of immune checkpoint inhibitors in the first-line setting for advanced urothelial carcinoma, and the results of these studies will help shed additional light regarding the efficacy of this approach.

Applications for Clinical Practice

First-line maintenance avelumab in patients who do not progress on platinum-based chemotherapy improves both progression-free and overall survival. This approach is certainly practice-changing and represents a new standard of care in this patient population. Careful discussion with each patient about the benefits and risks of a switch maintenance approach is warranted.

Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of maintenance avelumab in patients with advanced urothelial carcinoma who had received first-line platinum-based chemotherapy.

Design. International, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 ratio to receive either maintenance therapy with avelumab 10 mg/kg plus best supportive care (BSC) or BSC alone, per local practice. Randomization was stratified according to best response to first-line chemotherapy and metastatic site (visceral vs nonvisceral). Treatment was continued until progression, unacceptable toxicities, or patient withdrawal occurred.

Setting and participants. A total of 700 patients were enrolled at 197 sites (350 in the avelumab group and 350 in the BSC group). All patients had histologically confirmed unresectable or metastatic urothelial carcinoma. Patients received 4 to 6 cycles of chemotherapy with either gemcitabine plus cisplatin or carboplatin and had no evidence of progression after completion. Patients had a treatment-free interval of 4 to 10 weeks prior to starting maintenance therapy. Patients who received neoadjuvant or adjuvant platinum-based therapy within the prior 12 months were excluded.

Main outcome measures. The primary endpoint was overall survival (OS) assessed in both the overall population and PD-L1–positive population. Secondary endpoints included progression-free survival (PFS), objective response, time to response, duration of response, and disease control. PD-L1 expression was determined via the Ventana PD-L1 assay (SP263), and patients were classified as PD-L1 positive if they met 1 of the following: (1) at least 25% of tumor cells were positive for PD-L1; (2) at least 25% of immune cells were positive for PD-L1 if more than 1% of the tumor area contained immune cells; and (3) 100% of immune cells stained for PD-L1 if no more than 1% of the tumor area contained immune cells.

Results. The baseline characteristics were well balanced between the groups. A total of 51.1% of patients had PD-L1–positive tumors (57.6% in the avelumab group and 56.3% in the control group). At the time of analysis, 24% of patients in the avelumab group were still receiving therapy compared with only 7% in the BSC group. The most common reason for discontinuation of therapy was disease progression; 43.7% of patients in the control group received anti-PD-1 or anti-PD-L1 therapy at progression. The median follow-up was 19 months. OS at 1 year was 71.3% in the avelumab group and 58.4% in the control group. The median OS was 21.4 months in the avelumab group compared with 14.3 months in the control group (hazard ratio [HR] for death, 0.69; confidence interval [CI], 0.56-0.86, P = 0.001). In the PD-L1–positive population, OS was also significantly longer in the avelumab group (NE vs 17.1 months, HR, 0.56; CI, 0.40-0.79; P < 0.001). In the PD-L1–negative population, median OS was 18.8 months in the avelumab group versus 13.7 months in the control group (HR, 0.85). PFS was longer in the avelumab group than in the control group, with a median PFS of 3.7 months versus 2 months, respectively. The median PFS was 5.7 months in the avelumab group and 2.1 months in the control group in the PD-L1–positive population.

Adverse events (AEs) of any grade occurred in 98% of patients in the avelumab group and 77% in the control group. Grade 3 or higher AEs occurred in 47.4% of patients in the avelumab group. AEs led to discontinuation in 11.9% of patients in the avelumab group. Two patients died in the avelumab group as a result of toxicity (urinary tract infection with sepsis and ischemic stroke). Immune-related adverse events occurred in 29.4% of patients in the avelumab group. Of those, 7% were grade 3 in nature, and there were no grade 4 or 5 immune-related AEs. The most commonly seen immune-related AEs were thyroid disorders.

Conclusion. Avelumab maintenance significantly improved OS compared with BSC in patients with advanced/metastatic urothelial carcinoma whose disease did not progress after first-line platinum-based chemotherapy.

Commentary

In summary, the JAVELIN Bladder 100 trial showed significantly longer OS with the use of maintenance avelumab following first-line platinum-based chemotherapy. This survival benefit was seen in all subgroups, including those who received cisplatin or carboplatin therapy, as well as those with stable disease, partial response, or complete response to initial chemotherapy. Furthermore, the survival benefit was seen in both the overall population as well as in the PD-L1–positive population. There did not appear to be any new safety concerns noted in this trial. Based on these findings, avelumab maintenance in those who do not progress on first-line platinum-based therapy certainly represents a potentially new standard of care in this patient population. While the results of this study are promising and potentially practice changing, whether this “switch maintenance” approach is superior to treatment at progression (ie, use of checkpoint inhibition in the second-line setting) remains debatable. Nevertheless, for most patients, this appears to be the preferred approach given the notable longer OS and improved PFS, which is meaningful, particularly if the progression event is symptomatic. Furthermore, a portion of patients will not proceed to second-line therapy for a variety of reasons, and thus will not be exposed to checkpoint inhibitors if one takes a treatment break approach.

In the previous KEYNOTE-45 study evaluating pembrolizumab versus chemotherapy in the second-line setting after progression on previous platinum therapy, the median OS was just 10 months in the pembrolizumab arm.¹ This is markedly different from the 21.4-month median OS noted in the current study. While there are many limitations to this comparison, it does appear that switch maintenance leads to meaningful improvements in patient outcomes. It should be noted, however, that a portion of patients will have a durable response to platinum-based therapy, and thus there may be a portion of patients who would be “overtreated” with such an approach.

A similar approach has been explored in a randomized phase 2 trial looking at maintenance pembrolizumab after first-line chemotherapy (HCRN GU14-182).² This trial similarly showed improvement in PFS; however, OS was not yet mature at the time of data analysis. It should be noted that crossover was permitted in the HCRN study, while this was not allowed in the current Javelin 100 study. Certainly, this crossover effect influenced OS data in that trial. Thus, the current study is the first and only to show an OS benefit with such an approach in this population. Numerous ongoing studies are seeking to evaluate the efficacy of immune checkpoint inhibitors in the first-line setting for advanced urothelial carcinoma, and the results of these studies will help shed additional light regarding the efficacy of this approach.

Applications for Clinical Practice

First-line maintenance avelumab in patients who do not progress on platinum-based chemotherapy improves both progression-free and overall survival. This approach is certainly practice-changing and represents a new standard of care in this patient population. Careful discussion with each patient about the benefits and risks of a switch maintenance approach is warranted.

Daniel Isaac, DO, MS