BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.

BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.

BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – Treatment with novel agent DUR-928 may be able to reduce mortality rates among patients with severe alcoholic hepatitis, investigators predicted.

In an open-label, phase IIa trial, 89% of patients with alcoholic hepatitis responded to treatment with the new therapy, reported lead author Tarek Hassanein, MD, of Southern California Research Center in Coronado, Calif., and colleagues.

In an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases, the investigators explained the urgent need for an agent such as DUR-928: “The mortality of severe alcoholic hepatitis remains high in the absence of effective treatment,” they wrote, noting that corticosteroids are only suitable for select patients. According to the investigators, DUR-928 is an endogenous sulfated oxysterol that has been shown to control lipotoxicity and inflammation while increasing hepatic regeneration and cell survival.

The agent was tested among 19 patients with alcoholic hepatitis, many of whom had severe disease; at baseline, 15 had Maddrey’s discriminant function (DF) scores of 32 or less, 12 had Model for End-stage Liver Disease (MELD) scores between 12 and 30, and 11 had serum bilirubin levels higher than 8 mg/dL.

Via intravenous infusion, three dose levels were given: 30 mg, 90 mg, or 150 mg. All patients received at least one dose on day 1, and if still hospitalized, a second dose on day 4, with a total follow-up of 28 days. Treatment response was defined by a Lille score of less than 0.45.

DUR-928 was well tolerated; no serious drug-related adverse events occurred and all patients survived the 28-day follow-up period. Across the population, the response rate was 89%. This figure fell slightly to 87% when considering only patients with severe disease (DF scores of 32 or less), and marginally further still to 83% for those with MELD scores between 21 and 30. Among patients with severe disease, MELD scores decreased by a median of 17.5% (P = .01) over the 28-day period, and in cases with bilirubin starting higher than 8 mg/dL, levels dropped by a median of 25.1% (P = .02) within the first week.

A comparison of these results with historical data revealed that treatment with DUR-928 led to significantly better Lille scores than previously reported (P less than .0001).

“These initial findings are encouraging for further development of DUR-928 in patients with alcoholic hepatitis, including severe alcoholic hepatitis,” the investigators concluded.

The investigators disclosed relationships with DURECT Corporation, Assembly Biosciences, Gilead, and others.

SOURCE: Hassanein T et al. The Liver Meeting 2019, Abstract LO9.

BOSTON – Treatment with novel agent DUR-928 may be able to reduce mortality rates among patients with severe alcoholic hepatitis, investigators predicted.

In an open-label, phase IIa trial, 89% of patients with alcoholic hepatitis responded to treatment with the new therapy, reported lead author Tarek Hassanein, MD, of Southern California Research Center in Coronado, Calif., and colleagues.

In an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases, the investigators explained the urgent need for an agent such as DUR-928: “The mortality of severe alcoholic hepatitis remains high in the absence of effective treatment,” they wrote, noting that corticosteroids are only suitable for select patients. According to the investigators, DUR-928 is an endogenous sulfated oxysterol that has been shown to control lipotoxicity and inflammation while increasing hepatic regeneration and cell survival.

The agent was tested among 19 patients with alcoholic hepatitis, many of whom had severe disease; at baseline, 15 had Maddrey’s discriminant function (DF) scores of 32 or less, 12 had Model for End-stage Liver Disease (MELD) scores between 12 and 30, and 11 had serum bilirubin levels higher than 8 mg/dL.

Via intravenous infusion, three dose levels were given: 30 mg, 90 mg, or 150 mg. All patients received at least one dose on day 1, and if still hospitalized, a second dose on day 4, with a total follow-up of 28 days. Treatment response was defined by a Lille score of less than 0.45.

DUR-928 was well tolerated; no serious drug-related adverse events occurred and all patients survived the 28-day follow-up period. Across the population, the response rate was 89%. This figure fell slightly to 87% when considering only patients with severe disease (DF scores of 32 or less), and marginally further still to 83% for those with MELD scores between 21 and 30. Among patients with severe disease, MELD scores decreased by a median of 17.5% (P = .01) over the 28-day period, and in cases with bilirubin starting higher than 8 mg/dL, levels dropped by a median of 25.1% (P = .02) within the first week.

A comparison of these results with historical data revealed that treatment with DUR-928 led to significantly better Lille scores than previously reported (P less than .0001).

“These initial findings are encouraging for further development of DUR-928 in patients with alcoholic hepatitis, including severe alcoholic hepatitis,” the investigators concluded.

The investigators disclosed relationships with DURECT Corporation, Assembly Biosciences, Gilead, and others.

SOURCE: Hassanein T et al. The Liver Meeting 2019, Abstract LO9.

BOSTON – Treatment with novel agent DUR-928 may be able to reduce mortality rates among patients with severe alcoholic hepatitis, investigators predicted.

In an open-label, phase IIa trial, 89% of patients with alcoholic hepatitis responded to treatment with the new therapy, reported lead author Tarek Hassanein, MD, of Southern California Research Center in Coronado, Calif., and colleagues.

In an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases, the investigators explained the urgent need for an agent such as DUR-928: “The mortality of severe alcoholic hepatitis remains high in the absence of effective treatment,” they wrote, noting that corticosteroids are only suitable for select patients. According to the investigators, DUR-928 is an endogenous sulfated oxysterol that has been shown to control lipotoxicity and inflammation while increasing hepatic regeneration and cell survival.

The agent was tested among 19 patients with alcoholic hepatitis, many of whom had severe disease; at baseline, 15 had Maddrey’s discriminant function (DF) scores of 32 or less, 12 had Model for End-stage Liver Disease (MELD) scores between 12 and 30, and 11 had serum bilirubin levels higher than 8 mg/dL.

Via intravenous infusion, three dose levels were given: 30 mg, 90 mg, or 150 mg. All patients received at least one dose on day 1, and if still hospitalized, a second dose on day 4, with a total follow-up of 28 days. Treatment response was defined by a Lille score of less than 0.45.

DUR-928 was well tolerated; no serious drug-related adverse events occurred and all patients survived the 28-day follow-up period. Across the population, the response rate was 89%. This figure fell slightly to 87% when considering only patients with severe disease (DF scores of 32 or less), and marginally further still to 83% for those with MELD scores between 21 and 30. Among patients with severe disease, MELD scores decreased by a median of 17.5% (P = .01) over the 28-day period, and in cases with bilirubin starting higher than 8 mg/dL, levels dropped by a median of 25.1% (P = .02) within the first week.

A comparison of these results with historical data revealed that treatment with DUR-928 led to significantly better Lille scores than previously reported (P less than .0001).

“These initial findings are encouraging for further development of DUR-928 in patients with alcoholic hepatitis, including severe alcoholic hepatitis,” the investigators concluded.

The investigators disclosed relationships with DURECT Corporation, Assembly Biosciences, Gilead, and others.

SOURCE: Hassanein T et al. The Liver Meeting 2019, Abstract LO9.

BOSTON – Specifically in patients with hepatitis C virus (HCV) genotype 3 infection and compensated cirrhosis, glecaprevir/pibrentasvir (Mavyret) was safe and had high efficacy in a phase 3 clinical trial, echoing an earlier report describing clinical results for the fixed-dose combination in multiple other genotypes.

Treatment with glecaprevir/pibrentasvir was safe and produced high rates of sustained virologic response 12 weeks after treatment (SVR12) for the genotype 3 patients and compensated cirrhosis in the recent results from the EXPEDITION-8 study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

In a previous report from EXPEDITION-8, investigators said that the treatment was well tolerated and effective in patients with HCV genotypes 1, 2, 4, 5, and 6.

“The availability of an 8-week, pangenotypic regimen for all treatment-naive HCV-infected patients regardless of cirrhosis status may simplify the HCV care pathway, furthering progress towards HCV elimination,” said investigator Robert S. Brown Jr., MD, MPH, and coinvestigators in a late-breaking abstract of the latest study results.

The nonrandomized, multicenter, phase 3b study included 343 adults with HCV genotypes 1-6 who received glecaprevir 300 mg and pibrentasvir 120 mg once daily for 8 weeks. A total of 63% of patients were male, 83% were white; 18% had HCV genotype 3, while the majority (67%) had HCV genotype 1.

For the genotype 3 patients, SVR12 rates were 95.2% in the intention-to-treat population, and 98.4% in the per-protocol population, Dr. Brown and coauthors said in their report on the study. For genotype 1, 2, 4, 5, and 6 patients, the intention-to-treat and per-protocol SVR12 rates were 98.2% and 100%.

Taken together, the SVR12 rates for all genotypes were 97.7% and 99.7%, respectively, for the intention-to-treat and per-protocol populations, according to the investigators.

There were no virologic failures on treatment, and one patients with genotype 3 relapsed in week 4 posttreatment, while one genotype 1 patient discontinued treatment though not because of adverse events, they said.

Most adverse events were grade 1 in severity, and included fatigue, pruritus, headache, and nausea. There were no liver-related toxicities, and no serious adverse events that were related to the study treatment, according to the investigators.

Glecaprevir/pibrentasvir is indicated for patients aged 12 years and older with treatment-naive HCV genotype 1-6 infection without cirrhosis or with compensated cirrhosis, and in patients with HCV genotype 1 infection previously treated with an HCV NS5A inhibitor or an NS3/4A protease inhibitor.

Dr. Brown reported disclosures related to pharmaceutical companies including AbbVie, which markets Mavyret.

SOURCE: Brown RS et al. The Liver Meeting 2019. Abstract LP9.

BOSTON – Specifically in patients with hepatitis C virus (HCV) genotype 3 infection and compensated cirrhosis, glecaprevir/pibrentasvir (Mavyret) was safe and had high efficacy in a phase 3 clinical trial, echoing an earlier report describing clinical results for the fixed-dose combination in multiple other genotypes.

Treatment with glecaprevir/pibrentasvir was safe and produced high rates of sustained virologic response 12 weeks after treatment (SVR12) for the genotype 3 patients and compensated cirrhosis in the recent results from the EXPEDITION-8 study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

In a previous report from EXPEDITION-8, investigators said that the treatment was well tolerated and effective in patients with HCV genotypes 1, 2, 4, 5, and 6.

“The availability of an 8-week, pangenotypic regimen for all treatment-naive HCV-infected patients regardless of cirrhosis status may simplify the HCV care pathway, furthering progress towards HCV elimination,” said investigator Robert S. Brown Jr., MD, MPH, and coinvestigators in a late-breaking abstract of the latest study results.

The nonrandomized, multicenter, phase 3b study included 343 adults with HCV genotypes 1-6 who received glecaprevir 300 mg and pibrentasvir 120 mg once daily for 8 weeks. A total of 63% of patients were male, 83% were white; 18% had HCV genotype 3, while the majority (67%) had HCV genotype 1.

For the genotype 3 patients, SVR12 rates were 95.2% in the intention-to-treat population, and 98.4% in the per-protocol population, Dr. Brown and coauthors said in their report on the study. For genotype 1, 2, 4, 5, and 6 patients, the intention-to-treat and per-protocol SVR12 rates were 98.2% and 100%.

Taken together, the SVR12 rates for all genotypes were 97.7% and 99.7%, respectively, for the intention-to-treat and per-protocol populations, according to the investigators.

There were no virologic failures on treatment, and one patients with genotype 3 relapsed in week 4 posttreatment, while one genotype 1 patient discontinued treatment though not because of adverse events, they said.

Most adverse events were grade 1 in severity, and included fatigue, pruritus, headache, and nausea. There were no liver-related toxicities, and no serious adverse events that were related to the study treatment, according to the investigators.

Glecaprevir/pibrentasvir is indicated for patients aged 12 years and older with treatment-naive HCV genotype 1-6 infection without cirrhosis or with compensated cirrhosis, and in patients with HCV genotype 1 infection previously treated with an HCV NS5A inhibitor or an NS3/4A protease inhibitor.

Dr. Brown reported disclosures related to pharmaceutical companies including AbbVie, which markets Mavyret.

SOURCE: Brown RS et al. The Liver Meeting 2019. Abstract LP9.

BOSTON – Specifically in patients with hepatitis C virus (HCV) genotype 3 infection and compensated cirrhosis, glecaprevir/pibrentasvir (Mavyret) was safe and had high efficacy in a phase 3 clinical trial, echoing an earlier report describing clinical results for the fixed-dose combination in multiple other genotypes.

Treatment with glecaprevir/pibrentasvir was safe and produced high rates of sustained virologic response 12 weeks after treatment (SVR12) for the genotype 3 patients and compensated cirrhosis in the recent results from the EXPEDITION-8 study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

In a previous report from EXPEDITION-8, investigators said that the treatment was well tolerated and effective in patients with HCV genotypes 1, 2, 4, 5, and 6.

“The availability of an 8-week, pangenotypic regimen for all treatment-naive HCV-infected patients regardless of cirrhosis status may simplify the HCV care pathway, furthering progress towards HCV elimination,” said investigator Robert S. Brown Jr., MD, MPH, and coinvestigators in a late-breaking abstract of the latest study results.

The nonrandomized, multicenter, phase 3b study included 343 adults with HCV genotypes 1-6 who received glecaprevir 300 mg and pibrentasvir 120 mg once daily for 8 weeks. A total of 63% of patients were male, 83% were white; 18% had HCV genotype 3, while the majority (67%) had HCV genotype 1.

For the genotype 3 patients, SVR12 rates were 95.2% in the intention-to-treat population, and 98.4% in the per-protocol population, Dr. Brown and coauthors said in their report on the study. For genotype 1, 2, 4, 5, and 6 patients, the intention-to-treat and per-protocol SVR12 rates were 98.2% and 100%.

Taken together, the SVR12 rates for all genotypes were 97.7% and 99.7%, respectively, for the intention-to-treat and per-protocol populations, according to the investigators.

There were no virologic failures on treatment, and one patients with genotype 3 relapsed in week 4 posttreatment, while one genotype 1 patient discontinued treatment though not because of adverse events, they said.

Most adverse events were grade 1 in severity, and included fatigue, pruritus, headache, and nausea. There were no liver-related toxicities, and no serious adverse events that were related to the study treatment, according to the investigators.

Glecaprevir/pibrentasvir is indicated for patients aged 12 years and older with treatment-naive HCV genotype 1-6 infection without cirrhosis or with compensated cirrhosis, and in patients with HCV genotype 1 infection previously treated with an HCV NS5A inhibitor or an NS3/4A protease inhibitor.

Dr. Brown reported disclosures related to pharmaceutical companies including AbbVie, which markets Mavyret.

SOURCE: Brown RS et al. The Liver Meeting 2019. Abstract LP9.

BOSTON – A prime-boost hepatitis C virus (HCV) vaccine regimen did not protect against chronic infection, but it did evoke immune responses and differences in viral trajectory, according to investigators in what is believed to be the first randomized, placebo-controlled efficacy trial in this setting.

copyright wildpixel/Thinkstock

There were no apparent safety concerns with the vaccine according to investigators, led by Kimberly Page, PhD, MPH, of the University of New Mexico, Albuquerque.

“A safe and effective vaccine to prevent chronic hepatitis C virus infection is essential to reduce transmission,” Dr. Page and coauthors said in a late-breaking abstract of the study results, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

The phase 1/2 trial described by Dr. Page and colleagues included 455 adults at risk of HCV infection because of injection drug use. They were randomized to vaccine, which consisted of a recombinant chimpanzee adenovirus-3 vectored vaccine prime plus a recombinant Modified Vaccinia virus Ankara boost, or to two doses of placebo at days 0 and 56 of the study.

There was no difference in chronic HCV infection at 6 months, the primary endpoint of the study. There were 14 chronically infected participants in the vaccine group, as well as 14 in the placebo group, for an overall incidence of infection of 13.0/100 person-years, Dr. Page and coauthors reported in the abstract.

However, there were significant differences in HCV RNA geometric mean peak at 1 month, which was 193,795 IU/L in the vaccine group and 1,078,092 IU/L in the placebo group, according to investigators. Similarly, geometric mean fold rise after infection was 0.2 in the vaccine group and 13.5 in the placebo group.

A total of 78% of vaccinated individuals had T-cell responses to at least one vaccine antigen pool, investigators said, adding that the vaccine was safe, well tolerated, and not associated with any serious adverse events.

Dr. Page had no disclosures related to the abstract.

SOURCE: Page K et al. The Liver Meeting 2019. Abstract LP17.

BOSTON – A prime-boost hepatitis C virus (HCV) vaccine regimen did not protect against chronic infection, but it did evoke immune responses and differences in viral trajectory, according to investigators in what is believed to be the first randomized, placebo-controlled efficacy trial in this setting.

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There were no apparent safety concerns with the vaccine according to investigators, led by Kimberly Page, PhD, MPH, of the University of New Mexico, Albuquerque.

“A safe and effective vaccine to prevent chronic hepatitis C virus infection is essential to reduce transmission,” Dr. Page and coauthors said in a late-breaking abstract of the study results, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

The phase 1/2 trial described by Dr. Page and colleagues included 455 adults at risk of HCV infection because of injection drug use. They were randomized to vaccine, which consisted of a recombinant chimpanzee adenovirus-3 vectored vaccine prime plus a recombinant Modified Vaccinia virus Ankara boost, or to two doses of placebo at days 0 and 56 of the study.

There was no difference in chronic HCV infection at 6 months, the primary endpoint of the study. There were 14 chronically infected participants in the vaccine group, as well as 14 in the placebo group, for an overall incidence of infection of 13.0/100 person-years, Dr. Page and coauthors reported in the abstract.

However, there were significant differences in HCV RNA geometric mean peak at 1 month, which was 193,795 IU/L in the vaccine group and 1,078,092 IU/L in the placebo group, according to investigators. Similarly, geometric mean fold rise after infection was 0.2 in the vaccine group and 13.5 in the placebo group.

A total of 78% of vaccinated individuals had T-cell responses to at least one vaccine antigen pool, investigators said, adding that the vaccine was safe, well tolerated, and not associated with any serious adverse events.

Dr. Page had no disclosures related to the abstract.

SOURCE: Page K et al. The Liver Meeting 2019. Abstract LP17.

BOSTON – A prime-boost hepatitis C virus (HCV) vaccine regimen did not protect against chronic infection, but it did evoke immune responses and differences in viral trajectory, according to investigators in what is believed to be the first randomized, placebo-controlled efficacy trial in this setting.

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There were no apparent safety concerns with the vaccine according to investigators, led by Kimberly Page, PhD, MPH, of the University of New Mexico, Albuquerque.

“A safe and effective vaccine to prevent chronic hepatitis C virus infection is essential to reduce transmission,” Dr. Page and coauthors said in a late-breaking abstract of the study results, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

The phase 1/2 trial described by Dr. Page and colleagues included 455 adults at risk of HCV infection because of injection drug use. They were randomized to vaccine, which consisted of a recombinant chimpanzee adenovirus-3 vectored vaccine prime plus a recombinant Modified Vaccinia virus Ankara boost, or to two doses of placebo at days 0 and 56 of the study.

There was no difference in chronic HCV infection at 6 months, the primary endpoint of the study. There were 14 chronically infected participants in the vaccine group, as well as 14 in the placebo group, for an overall incidence of infection of 13.0/100 person-years, Dr. Page and coauthors reported in the abstract.

However, there were significant differences in HCV RNA geometric mean peak at 1 month, which was 193,795 IU/L in the vaccine group and 1,078,092 IU/L in the placebo group, according to investigators. Similarly, geometric mean fold rise after infection was 0.2 in the vaccine group and 13.5 in the placebo group.

A total of 78% of vaccinated individuals had T-cell responses to at least one vaccine antigen pool, investigators said, adding that the vaccine was safe, well tolerated, and not associated with any serious adverse events.

Dr. Page had no disclosures related to the abstract.

SOURCE: Page K et al. The Liver Meeting 2019. Abstract LP17.

BOSTON – Fenofibrate is safe and effective for limiting triglyceride increases in patients with nonalcoholic steatohepatitis and advanced fibrosis, based on data from 31 adults.

Treatment of NASH with acetyl-CoA carboxylase inhibitors has been shown to improve liver fat and other liver conditions but may be associated with hyperlipidemia, according to Eric J. Lawitz, MD, of the University of Texas Health, San Antonio, and colleagues. The researchers examined the safety and effectiveness of fenofibrate to mitigate serum triglyceride increases in a study be presented in a late-breaking session at the annual meeting of the American Association for the Study of Liver Diseases.

The researchers randomized 15 patients to treatment with 48 mg of fenofibrate or 145 mg of fenofibrate once daily for 2 weeks, followed by a combination of the fenofibrate doses plus 20 mg of ACC inhibitor firsocostat daily for 24 weeks.

The median fasting triglycerides (TG) in the 48-mg and 145-mg fenofibrate groups were 218 mg/dL and 202 mg/dL, respectively. After 2 weeks, the median change in TG was +2 mg/dL in the 48-mg group and –42 mg/dL in the 145-mg group. After 24 weeks of combination therapy, TG levels were not significantly different from baseline in either group (+19 mg/dL in 48-mg group and +6 mg/dL in the 145-mg group). Significant reductions in serum alanine aminotransferase from baseline to week 24 occurred in the combined groups (median of 39 U/L vs. 27 U/L, respectively). In addition, 43% of patients overall showed at least a 30% reduction in protein density fat fraction.

Both firsocostat and fenofibrate were well tolerated, the researchers said. One treatment-emergent grade 3 TG elevation (defined as greater than 500 mg/dL) occurred in the 48-mg group at week 24. No hepatotoxicity was noted, no patients discontinued therapy because of adverse events, and no other grade 3 or 4 adverse events were reported.

“The combination of firsocostat and fenofibrate led to improvements in hepatic fat, liver biochemistry, and markers of fibrosis,” the researchers concluded in their abstract.

Lead author Dr. Lawitz disclosed financial relationships with Allergan, Akcea Therapeutics, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Madrigal Pharmaceuticals, and Novartis.

The AGA GI Patient Center provides education to help your patients understand NASH at https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash.

SOURCE: Lawitz E et al. The Liver Meeting 2019. Presentation LP5.

BOSTON – Fenofibrate is safe and effective for limiting triglyceride increases in patients with nonalcoholic steatohepatitis and advanced fibrosis, based on data from 31 adults.

Treatment of NASH with acetyl-CoA carboxylase inhibitors has been shown to improve liver fat and other liver conditions but may be associated with hyperlipidemia, according to Eric J. Lawitz, MD, of the University of Texas Health, San Antonio, and colleagues. The researchers examined the safety and effectiveness of fenofibrate to mitigate serum triglyceride increases in a study be presented in a late-breaking session at the annual meeting of the American Association for the Study of Liver Diseases.

The researchers randomized 15 patients to treatment with 48 mg of fenofibrate or 145 mg of fenofibrate once daily for 2 weeks, followed by a combination of the fenofibrate doses plus 20 mg of ACC inhibitor firsocostat daily for 24 weeks.

The median fasting triglycerides (TG) in the 48-mg and 145-mg fenofibrate groups were 218 mg/dL and 202 mg/dL, respectively. After 2 weeks, the median change in TG was +2 mg/dL in the 48-mg group and –42 mg/dL in the 145-mg group. After 24 weeks of combination therapy, TG levels were not significantly different from baseline in either group (+19 mg/dL in 48-mg group and +6 mg/dL in the 145-mg group). Significant reductions in serum alanine aminotransferase from baseline to week 24 occurred in the combined groups (median of 39 U/L vs. 27 U/L, respectively). In addition, 43% of patients overall showed at least a 30% reduction in protein density fat fraction.

Both firsocostat and fenofibrate were well tolerated, the researchers said. One treatment-emergent grade 3 TG elevation (defined as greater than 500 mg/dL) occurred in the 48-mg group at week 24. No hepatotoxicity was noted, no patients discontinued therapy because of adverse events, and no other grade 3 or 4 adverse events were reported.

“The combination of firsocostat and fenofibrate led to improvements in hepatic fat, liver biochemistry, and markers of fibrosis,” the researchers concluded in their abstract.

Lead author Dr. Lawitz disclosed financial relationships with Allergan, Akcea Therapeutics, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Madrigal Pharmaceuticals, and Novartis.

The AGA GI Patient Center provides education to help your patients understand NASH at https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash.

SOURCE: Lawitz E et al. The Liver Meeting 2019. Presentation LP5.

BOSTON – Fenofibrate is safe and effective for limiting triglyceride increases in patients with nonalcoholic steatohepatitis and advanced fibrosis, based on data from 31 adults.

Treatment of NASH with acetyl-CoA carboxylase inhibitors has been shown to improve liver fat and other liver conditions but may be associated with hyperlipidemia, according to Eric J. Lawitz, MD, of the University of Texas Health, San Antonio, and colleagues. The researchers examined the safety and effectiveness of fenofibrate to mitigate serum triglyceride increases in a study be presented in a late-breaking session at the annual meeting of the American Association for the Study of Liver Diseases.

The researchers randomized 15 patients to treatment with 48 mg of fenofibrate or 145 mg of fenofibrate once daily for 2 weeks, followed by a combination of the fenofibrate doses plus 20 mg of ACC inhibitor firsocostat daily for 24 weeks.

The median fasting triglycerides (TG) in the 48-mg and 145-mg fenofibrate groups were 218 mg/dL and 202 mg/dL, respectively. After 2 weeks, the median change in TG was +2 mg/dL in the 48-mg group and –42 mg/dL in the 145-mg group. After 24 weeks of combination therapy, TG levels were not significantly different from baseline in either group (+19 mg/dL in 48-mg group and +6 mg/dL in the 145-mg group). Significant reductions in serum alanine aminotransferase from baseline to week 24 occurred in the combined groups (median of 39 U/L vs. 27 U/L, respectively). In addition, 43% of patients overall showed at least a 30% reduction in protein density fat fraction.

Both firsocostat and fenofibrate were well tolerated, the researchers said. One treatment-emergent grade 3 TG elevation (defined as greater than 500 mg/dL) occurred in the 48-mg group at week 24. No hepatotoxicity was noted, no patients discontinued therapy because of adverse events, and no other grade 3 or 4 adverse events were reported.

“The combination of firsocostat and fenofibrate led to improvements in hepatic fat, liver biochemistry, and markers of fibrosis,” the researchers concluded in their abstract.

Lead author Dr. Lawitz disclosed financial relationships with Allergan, Akcea Therapeutics, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Madrigal Pharmaceuticals, and Novartis.

The AGA GI Patient Center provides education to help your patients understand NASH at https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash.

SOURCE: Lawitz E et al. The Liver Meeting 2019. Presentation LP5.

BOSTON – Alanine aminotransferase, hepatic fat, and body weight all decreased in patients with nonalcoholic steatohepatitis (NASH) treated for 12 weeks with higher doses of tropifexor, an investigational farnesoid X receptor agonist, according to interim results of a randomized trial.

Mild pruritus and minor decreases in LDL cholesterol were seen with tropifexor, similar to what has been seen with other farnesoid X receptor agonists, according to investigators, including senior study author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virgina Commonwealth University in Richmond.

“Changes in liver histology resulting from this trial, along with trials of tropifexor in combination with drugs with other mechanisms of action, will define future therapeutic options in fibrotic NASH,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

That randomized, double-blind, placebo-controlled, phase 2 study, called FLIGHT-FXR, is designed to evaluate tropifexor (LJN452) in patients with NASH at several different doses, according to Dr. Sanyal and coinvestigators.

Previous reports on the trial demonstrated that lower doses of tropifexor (60 and 90 mcg) had favorable safety with anti-inflammatory and antisteatotic efficacy based on biomarker analysis, according to investigators.

This latest report from FLIGHT-FXR includes 152 patients randomly allocated to receive placebo or tropifexor at one of two higher doses (140 or 200 mcg).

At the highest tropifexor dose of 200 mcg, decreases in alanine aminotransferase (ALT), hepatic fat fraction (HFF), gamma-glutamyl transferase (GGT), and body weight were all significant, compared with the decreases in the placebo arm, according to reported data, while in the 140-mcg arm, the findings were significant versus placebo for GGT and body weight.

Relative HFF reduction by at least 30% was seen in 64% of patients in the tropifexor 200-mcg arm, 32% in the tropifexor 140-mcg arm, and 20% in the placebo arm, the investigators reported.

Pruritus was mild among tropifexor-treated patients in more than 60% of cases, investigators said, and pruritus-related discontinuation rates were low, at 2% (1 patient) for the 140-mcg dose and 6% (3 patients) for 200 mcg.

Investigators noted a dose-related increase in LDL cholesterol with tropifexor treatment, but those lipid changes didn’t lead to reduced doses or stopped treatment, they said.

Serious adverse events were infrequent, with a comparable incidence across treatment and placebo groups, investigators added.

Dr. Sanyal provided disclosures related to Sanyal Bio, Exhalenz, Akarna, Fractyl Laboratories, Genfit, Durect, Tiziana, Novartis, Merck, Galectin, and Janssen, among others.

BOSTON – Alanine aminotransferase, hepatic fat, and body weight all decreased in patients with nonalcoholic steatohepatitis (NASH) treated for 12 weeks with higher doses of tropifexor, an investigational farnesoid X receptor agonist, according to interim results of a randomized trial.

Mild pruritus and minor decreases in LDL cholesterol were seen with tropifexor, similar to what has been seen with other farnesoid X receptor agonists, according to investigators, including senior study author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virgina Commonwealth University in Richmond.

“Changes in liver histology resulting from this trial, along with trials of tropifexor in combination with drugs with other mechanisms of action, will define future therapeutic options in fibrotic NASH,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

That randomized, double-blind, placebo-controlled, phase 2 study, called FLIGHT-FXR, is designed to evaluate tropifexor (LJN452) in patients with NASH at several different doses, according to Dr. Sanyal and coinvestigators.

Previous reports on the trial demonstrated that lower doses of tropifexor (60 and 90 mcg) had favorable safety with anti-inflammatory and antisteatotic efficacy based on biomarker analysis, according to investigators.

This latest report from FLIGHT-FXR includes 152 patients randomly allocated to receive placebo or tropifexor at one of two higher doses (140 or 200 mcg).

At the highest tropifexor dose of 200 mcg, decreases in alanine aminotransferase (ALT), hepatic fat fraction (HFF), gamma-glutamyl transferase (GGT), and body weight were all significant, compared with the decreases in the placebo arm, according to reported data, while in the 140-mcg arm, the findings were significant versus placebo for GGT and body weight.

Relative HFF reduction by at least 30% was seen in 64% of patients in the tropifexor 200-mcg arm, 32% in the tropifexor 140-mcg arm, and 20% in the placebo arm, the investigators reported.

Pruritus was mild among tropifexor-treated patients in more than 60% of cases, investigators said, and pruritus-related discontinuation rates were low, at 2% (1 patient) for the 140-mcg dose and 6% (3 patients) for 200 mcg.

Investigators noted a dose-related increase in LDL cholesterol with tropifexor treatment, but those lipid changes didn’t lead to reduced doses or stopped treatment, they said.

Serious adverse events were infrequent, with a comparable incidence across treatment and placebo groups, investigators added.

Dr. Sanyal provided disclosures related to Sanyal Bio, Exhalenz, Akarna, Fractyl Laboratories, Genfit, Durect, Tiziana, Novartis, Merck, Galectin, and Janssen, among others.

BOSTON – Alanine aminotransferase, hepatic fat, and body weight all decreased in patients with nonalcoholic steatohepatitis (NASH) treated for 12 weeks with higher doses of tropifexor, an investigational farnesoid X receptor agonist, according to interim results of a randomized trial.

Mild pruritus and minor decreases in LDL cholesterol were seen with tropifexor, similar to what has been seen with other farnesoid X receptor agonists, according to investigators, including senior study author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virgina Commonwealth University in Richmond.

“Changes in liver histology resulting from this trial, along with trials of tropifexor in combination with drugs with other mechanisms of action, will define future therapeutic options in fibrotic NASH,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

That randomized, double-blind, placebo-controlled, phase 2 study, called FLIGHT-FXR, is designed to evaluate tropifexor (LJN452) in patients with NASH at several different doses, according to Dr. Sanyal and coinvestigators.

Previous reports on the trial demonstrated that lower doses of tropifexor (60 and 90 mcg) had favorable safety with anti-inflammatory and antisteatotic efficacy based on biomarker analysis, according to investigators.

This latest report from FLIGHT-FXR includes 152 patients randomly allocated to receive placebo or tropifexor at one of two higher doses (140 or 200 mcg).

At the highest tropifexor dose of 200 mcg, decreases in alanine aminotransferase (ALT), hepatic fat fraction (HFF), gamma-glutamyl transferase (GGT), and body weight were all significant, compared with the decreases in the placebo arm, according to reported data, while in the 140-mcg arm, the findings were significant versus placebo for GGT and body weight.

Relative HFF reduction by at least 30% was seen in 64% of patients in the tropifexor 200-mcg arm, 32% in the tropifexor 140-mcg arm, and 20% in the placebo arm, the investigators reported.

Pruritus was mild among tropifexor-treated patients in more than 60% of cases, investigators said, and pruritus-related discontinuation rates were low, at 2% (1 patient) for the 140-mcg dose and 6% (3 patients) for 200 mcg.

Investigators noted a dose-related increase in LDL cholesterol with tropifexor treatment, but those lipid changes didn’t lead to reduced doses or stopped treatment, they said.

Serious adverse events were infrequent, with a comparable incidence across treatment and placebo groups, investigators added.

Dr. Sanyal provided disclosures related to Sanyal Bio, Exhalenz, Akarna, Fractyl Laboratories, Genfit, Durect, Tiziana, Novartis, Merck, Galectin, and Janssen, among others.

BOSTON – An ablative procedure intended to promote regrowth of duodenal mucosa was safe and had disease-modifying metabolic effects in a randomized study including patients with type 2 diabetes, according to investigators.

A single duodenal mucosal resurfacing (DMR) procedure improved glycemic, hepatic, and body-weight measures at 24 weeks in the multicenter study, investigators will report at the annual meeting of the American Association for the Study of Liver Diseases.

The novel and minimally invasive endoscopic procedure treats the duodenum, which is increasingly recognized as a key metabolic signaling center, according to the study authors, including senior author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virginia Commonwealth University, Richmond.

“Duodenal mucosal hyperplasia is a potential therapeutic target for insulin-resistance–related metabolic diseases,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study published in the AASLD meeting proceedings.

In a previous international open-label, prospective, multicenter study, published in July in Gut, DMR was feasible and safe, producing durable glycemic improvement in patients with type 2 diabetes with suboptimal control on oral glucose-lowering mediation, according to investigators.

The present study, conducted at nine sites in the European Union and two in Brazil, is the first sham-controlled, double-blind, prospective study of the modality in patients with suboptimally controlled type 2 diabetes, according to Dr. Sanyal and coauthors.

A total of 39 patients in the study underwent DMR, while 36 underwent a sham procedure, according to the published abstract. The mean hemoglobin A_1c for those patients was 8.3, the mean body mass index was 31.1 kg/m², and most (77%) were male.

Median change in hemoglobin A^1c from baseline to 24 weeks, one of two primary endpoints in the study, was –0.6% for DMR and –0.3% for the sham procedure (P less than 0.05), according to the study abstract.

Likewise, the primary efficacy endpoint of change in a nonalcoholic steatohepatitis biomarker favored the DMR arm. The median change in liver MRI–proton density fat fraction (MRI-PDFF) from baseline to 12 weeks was –5.4% for DMR and –2.4% for the sham procedure (P less than 0.05), according to the reported data.

Hypoglycemia rates were similar in the DMR and sham arms, and over 24 weeks of study, there were no unanticipated adverse effects attributable to the device and no serious adverse events, Dr. Sanyal and colleagues reported.

Dr. Sanyal reported disclosures related to Fractyl Laboratories, Sanyal Biotechnology, Exalenz Bioscience, Akarna Therapeutics, Genfit, Durect, Indalo, Tiziana, Novartis, Merck, Galectin Therapeutics, Janssen, and others.

BOSTON – An ablative procedure intended to promote regrowth of duodenal mucosa was safe and had disease-modifying metabolic effects in a randomized study including patients with type 2 diabetes, according to investigators.

A single duodenal mucosal resurfacing (DMR) procedure improved glycemic, hepatic, and body-weight measures at 24 weeks in the multicenter study, investigators will report at the annual meeting of the American Association for the Study of Liver Diseases.

The novel and minimally invasive endoscopic procedure treats the duodenum, which is increasingly recognized as a key metabolic signaling center, according to the study authors, including senior author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virginia Commonwealth University, Richmond.

“Duodenal mucosal hyperplasia is a potential therapeutic target for insulin-resistance–related metabolic diseases,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study published in the AASLD meeting proceedings.

In a previous international open-label, prospective, multicenter study, published in July in Gut, DMR was feasible and safe, producing durable glycemic improvement in patients with type 2 diabetes with suboptimal control on oral glucose-lowering mediation, according to investigators.

The present study, conducted at nine sites in the European Union and two in Brazil, is the first sham-controlled, double-blind, prospective study of the modality in patients with suboptimally controlled type 2 diabetes, according to Dr. Sanyal and coauthors.

A total of 39 patients in the study underwent DMR, while 36 underwent a sham procedure, according to the published abstract. The mean hemoglobin A_1c for those patients was 8.3, the mean body mass index was 31.1 kg/m², and most (77%) were male.

Median change in hemoglobin A^1c from baseline to 24 weeks, one of two primary endpoints in the study, was –0.6% for DMR and –0.3% for the sham procedure (P less than 0.05), according to the study abstract.

Likewise, the primary efficacy endpoint of change in a nonalcoholic steatohepatitis biomarker favored the DMR arm. The median change in liver MRI–proton density fat fraction (MRI-PDFF) from baseline to 12 weeks was –5.4% for DMR and –2.4% for the sham procedure (P less than 0.05), according to the reported data.

Hypoglycemia rates were similar in the DMR and sham arms, and over 24 weeks of study, there were no unanticipated adverse effects attributable to the device and no serious adverse events, Dr. Sanyal and colleagues reported.

Dr. Sanyal reported disclosures related to Fractyl Laboratories, Sanyal Biotechnology, Exalenz Bioscience, Akarna Therapeutics, Genfit, Durect, Indalo, Tiziana, Novartis, Merck, Galectin Therapeutics, Janssen, and others.

BOSTON – An ablative procedure intended to promote regrowth of duodenal mucosa was safe and had disease-modifying metabolic effects in a randomized study including patients with type 2 diabetes, according to investigators.

A single duodenal mucosal resurfacing (DMR) procedure improved glycemic, hepatic, and body-weight measures at 24 weeks in the multicenter study, investigators will report at the annual meeting of the American Association for the Study of Liver Diseases.

The novel and minimally invasive endoscopic procedure treats the duodenum, which is increasingly recognized as a key metabolic signaling center, according to the study authors, including senior author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virginia Commonwealth University, Richmond.

“Duodenal mucosal hyperplasia is a potential therapeutic target for insulin-resistance–related metabolic diseases,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study published in the AASLD meeting proceedings.

In a previous international open-label, prospective, multicenter study, published in July in Gut, DMR was feasible and safe, producing durable glycemic improvement in patients with type 2 diabetes with suboptimal control on oral glucose-lowering mediation, according to investigators.

The present study, conducted at nine sites in the European Union and two in Brazil, is the first sham-controlled, double-blind, prospective study of the modality in patients with suboptimally controlled type 2 diabetes, according to Dr. Sanyal and coauthors.

A total of 39 patients in the study underwent DMR, while 36 underwent a sham procedure, according to the published abstract. The mean hemoglobin A_1c for those patients was 8.3, the mean body mass index was 31.1 kg/m², and most (77%) were male.

Median change in hemoglobin A^1c from baseline to 24 weeks, one of two primary endpoints in the study, was –0.6% for DMR and –0.3% for the sham procedure (P less than 0.05), according to the study abstract.

Likewise, the primary efficacy endpoint of change in a nonalcoholic steatohepatitis biomarker favored the DMR arm. The median change in liver MRI–proton density fat fraction (MRI-PDFF) from baseline to 12 weeks was –5.4% for DMR and –2.4% for the sham procedure (P less than 0.05), according to the reported data.

Hypoglycemia rates were similar in the DMR and sham arms, and over 24 weeks of study, there were no unanticipated adverse effects attributable to the device and no serious adverse events, Dr. Sanyal and colleagues reported.

Dr. Sanyal reported disclosures related to Fractyl Laboratories, Sanyal Biotechnology, Exalenz Bioscience, Akarna Therapeutics, Genfit, Durect, Indalo, Tiziana, Novartis, Merck, Galectin Therapeutics, Janssen, and others.

BOSTON – Terlipressin, an investigational vasopressin analogue, improved renal function and reversed hepatorenal syndrome type 1 (HRS-1) among patients with progressive advanced liver disease in a randomized trial, according to investigators.

Compared with albumin alone, terlipressin plus albumin significantly reversed worsening of renal function in cirrhotic patients, including those meeting systemic inflammatory response syndrome (SIRS) criteria, said investigators, led by Florence Wong, MD, from the University of Toronto.

“This response was durable and associated with less need for early renal replacement therapy,” said Dr. Wong and coauthors of an abstract describing the study, which will be presented in a late-breaking study session here at the annual meeting of the American Association for the Study of Liver Diseases.

The North American randomized, controlled trial, known as CONFIRM, was designed to confirm the safety and efficacy of terlipressin/albumin as a treatment for HRS-1, a serious but potentially reversible type of acute kidney injury seen in patients with cirrhosis and ascites, investigators said in their communication.

Patients in CONFIRM had “well-defined” HRS-1, based on diagnostic criteria as outlined by the International Club of Ascites, investigators said.

A total of 300 participants were randomized, 199 to terlipressin 1 mg IV every 6 hours and 101 to placebo, with both groups also receiving albumin, for up to 14 days of treatment. According to the report, 132 subjects (44%) met SIRS criteria.

Verified HRS reversal was documented in 29.1% of terlipressin-treated patients versus just 15.8% of the placebo group (P less than .012), investigators reported in their abstract. Among the SIRS patients, verified HRS reversal was seen in 33.3% and 6.3% of the terlipressin- and placebo-treated groups, respectively (P less than .001).

As the primary endpoint of the study, verified HRS reversal is an outcome that combines improvement in renal function, short-term survival following improvement, and avoidance of renal replacement therapy, investigators explained in their report.

Liver transplantation occurred in 23.1% of the terlipressin group and 28.7% of the placebo group, investigators also reported in their abstract.

Ischemia-associated adverse events were seen in 4.5% of the terlipressin arm and 0% for placebo, though in general the rate of adverse events were similar for the treatment and control arms, Dr. Wong and colleagues noted in their report.

The CONFIRM study is supported by Mallinckrodt. Dr. Wong provided disclosures related to Mallinckrodt, Ferring, and Sequana.

BOSTON – Terlipressin, an investigational vasopressin analogue, improved renal function and reversed hepatorenal syndrome type 1 (HRS-1) among patients with progressive advanced liver disease in a randomized trial, according to investigators.

Compared with albumin alone, terlipressin plus albumin significantly reversed worsening of renal function in cirrhotic patients, including those meeting systemic inflammatory response syndrome (SIRS) criteria, said investigators, led by Florence Wong, MD, from the University of Toronto.

“This response was durable and associated with less need for early renal replacement therapy,” said Dr. Wong and coauthors of an abstract describing the study, which will be presented in a late-breaking study session here at the annual meeting of the American Association for the Study of Liver Diseases.

The North American randomized, controlled trial, known as CONFIRM, was designed to confirm the safety and efficacy of terlipressin/albumin as a treatment for HRS-1, a serious but potentially reversible type of acute kidney injury seen in patients with cirrhosis and ascites, investigators said in their communication.

Patients in CONFIRM had “well-defined” HRS-1, based on diagnostic criteria as outlined by the International Club of Ascites, investigators said.

A total of 300 participants were randomized, 199 to terlipressin 1 mg IV every 6 hours and 101 to placebo, with both groups also receiving albumin, for up to 14 days of treatment. According to the report, 132 subjects (44%) met SIRS criteria.

Verified HRS reversal was documented in 29.1% of terlipressin-treated patients versus just 15.8% of the placebo group (P less than .012), investigators reported in their abstract. Among the SIRS patients, verified HRS reversal was seen in 33.3% and 6.3% of the terlipressin- and placebo-treated groups, respectively (P less than .001).

As the primary endpoint of the study, verified HRS reversal is an outcome that combines improvement in renal function, short-term survival following improvement, and avoidance of renal replacement therapy, investigators explained in their report.

Liver transplantation occurred in 23.1% of the terlipressin group and 28.7% of the placebo group, investigators also reported in their abstract.

Ischemia-associated adverse events were seen in 4.5% of the terlipressin arm and 0% for placebo, though in general the rate of adverse events were similar for the treatment and control arms, Dr. Wong and colleagues noted in their report.

The CONFIRM study is supported by Mallinckrodt. Dr. Wong provided disclosures related to Mallinckrodt, Ferring, and Sequana.

BOSTON – Terlipressin, an investigational vasopressin analogue, improved renal function and reversed hepatorenal syndrome type 1 (HRS-1) among patients with progressive advanced liver disease in a randomized trial, according to investigators.

Compared with albumin alone, terlipressin plus albumin significantly reversed worsening of renal function in cirrhotic patients, including those meeting systemic inflammatory response syndrome (SIRS) criteria, said investigators, led by Florence Wong, MD, from the University of Toronto.

“This response was durable and associated with less need for early renal replacement therapy,” said Dr. Wong and coauthors of an abstract describing the study, which will be presented in a late-breaking study session here at the annual meeting of the American Association for the Study of Liver Diseases.

The North American randomized, controlled trial, known as CONFIRM, was designed to confirm the safety and efficacy of terlipressin/albumin as a treatment for HRS-1, a serious but potentially reversible type of acute kidney injury seen in patients with cirrhosis and ascites, investigators said in their communication.

Patients in CONFIRM had “well-defined” HRS-1, based on diagnostic criteria as outlined by the International Club of Ascites, investigators said.

A total of 300 participants were randomized, 199 to terlipressin 1 mg IV every 6 hours and 101 to placebo, with both groups also receiving albumin, for up to 14 days of treatment. According to the report, 132 subjects (44%) met SIRS criteria.

Verified HRS reversal was documented in 29.1% of terlipressin-treated patients versus just 15.8% of the placebo group (P less than .012), investigators reported in their abstract. Among the SIRS patients, verified HRS reversal was seen in 33.3% and 6.3% of the terlipressin- and placebo-treated groups, respectively (P less than .001).

As the primary endpoint of the study, verified HRS reversal is an outcome that combines improvement in renal function, short-term survival following improvement, and avoidance of renal replacement therapy, investigators explained in their report.

Liver transplantation occurred in 23.1% of the terlipressin group and 28.7% of the placebo group, investigators also reported in their abstract.

Ischemia-associated adverse events were seen in 4.5% of the terlipressin arm and 0% for placebo, though in general the rate of adverse events were similar for the treatment and control arms, Dr. Wong and colleagues noted in their report.

The CONFIRM study is supported by Mallinckrodt. Dr. Wong provided disclosures related to Mallinckrodt, Ferring, and Sequana.

In 2050, persons aged ≥ 85 years, also known as the oldest old, are projected to reach 18 million, accounting for 4.5% of the US population, up from 2.5% in 2030.¹ These patients are the fastest growing segment of the US population.

Advances in treating cardiovascular (CV) disease over the past 2 decades have led to an increased incidence of heart failure (HF) and hospitalizations among older patients.² Total costs of care for persons with HF have exceeded $30 billion annually and are expected to rise to more than $70 billion by 2030 due to growth of the aging population.^3,4 Moreover, the Framingham Study reported mortality increases with advancing age (HR 1.27 and 1.61 per decade in men and women, respectively).⁵

The prevalence of HF is also high and increasing over time. The National Health and Nutrition Examination Survey reported that about 5.7 million Americans have HF.⁶ The prevalence of HF is expected to reach 8 million by 2030.⁶ The higher numbers of HF among patients with advanced age is associated with age-related changes in CV structure and function, including reduced responsiveness to β-adrenergic stimulation, impaired left ventricular diastolic filling, and increased vascular stiffness. In addition, age-related changes in other systems might contribute to a HF diagnosis or worsening of the condition.⁷

Older adults experience physiologic changes in pharmacokinetics and pharmacodynamics, including decreased volume of distribution and creatinine clearance, which lead to significant changes in drug concentration and effectiveness.⁸

Geriatric patients aged > 65 years who have comorbidities and those who reside in long-term care settings are underrepresented in clinical trials, leading clinicians to make treatment decisions based on data from younger, community-dwelling individuals. Researchers have questioned whether to include elderly patients and those with comorbidities in clinical trials, given that their diminished response may produce less conclusive results with smaller treatment effects. Exclusion criteria based on comorbid conditions or functional status disqualify many older adults from clinical trials.

This article reviews evidence from major randomized controlled trials over the past 2 decades and explores their applicability to support HF treatment guidelines in patients with advanced age (Table). 

Pharmacotherapy for Heart Failure

Angiotensin-Converting Enzyme Inhibitors

Several randomized clinical trials have found that angiotensin-converting enzyme (ACE) inhibitors improve symptoms in patients with HF. The CooperativeNorth Scandinavian Enalapril Survival Study (CONSENSUS), demonstrated that enalapril improves survival in patients with New York Heart Association (NYHA) class IV HF with reduced ejection fraction (HFrEF) when added to standard therapy.⁹ However, the duration of beneficial effect of reduced mortality could not be assessed because the benefit of enalapril in NYHA class I to III HF was not evaluated, and follow-up data are limited. The average age of patients in the study was 71 years, and individuals with significant comorbidities were excluded.

ACE inhibitors also were found to reduce mortality even in asymptomatic patients with HFrEF in the Studies of Left Ventricular Dysfunction trial (SOLVD).¹⁰ Enalapril was found to reduce 4-year mortality by 16% and decrease HF hospitalizations when added to conventional therapy consisting primarily of digitalis, diuretics, and nitrates in patients with HFrEF. In this trial, patients aged ≥ 80 years were excluded as well as those with serum creatinine > 2 mg/dL or other conditions that could shorten survival or otherwise impede participation in a long-term trial.

PARADIGM-HF trial patients with HFrEF were randomized to enalapril or the angiotensin receptor-neprilysin inhibitor LCZ696. After a median of 27 months of follow-up, treatment with the angiotensin receptor-neprilysin inhibitor demonstrated greater reduction in CV mortality and HF hospitalizations than enalapril did and was associated with reduced all-cause mortality.¹¹ The trial was stopped early because of evidence of overwhelming benefit with LCZ696. This study of mainly white men included no patients aged ≥ 75 years.

Angiotensin Receptor Blockers

Although less studied than ACE inhibitors, angiotensin receptor blockers (ARBs) share similar benefits. Among patients with symptomatic HFrEF taking an ACE inhibitor, the addition of candesartan reduced the risk of CV death and HF hospitalization as demonstrated in the Candesartan in Heart Failure Assessment of Reduction Mortality and Morbidity (CHARM-added and CHARM-alternative trials).^12,13 The CHARM-added trial targeted patients with left ventricular ejection fraction (LVEF) ≤ 40% and NYHA class II to IV HF symptoms who were taking an ACE inhibitor. Adding candesartan reduced CV mortality by 37.9% and HF hospitalization by 42.3% compared with that of placebo.

The CHARM-alternative study found that use of candesartan in symptomatic HFrEF patients who do not tolerate ACE inhibitors,resulted in a 20% reduction in CV mortality as well as a 40% reduction in hospitalization for HF. Among patients with HF with preserved ejection fraction (HFpEF) and NYHA class II to IV symptoms, adding candesartan modestly reduced the rate of HF-related hospitalizations and had no effect on CV mortality in the CHARM-preserved study.¹⁴ The CHARM trials examined mostly white men, but 26% of patients were aged > 75 years. However, there was no subgroup analysis for patients aged > 75 years. The study excluded patients with serum creatinine > 2 mg/dL.

Other ARB trials included the following:

• The I-PRESERVE trial, which found that irbesartan did not improve outcomes of patients with HF with preserved ejection fraction (HFpEF).¹⁵ The study of mostly white patients did not include patients aged ≥ 80 years.
• A randomized trial of valsartan in HF improved symptoms and mortality in NYHA II to IV HF but showed no benefit when added to ACE inhibitors.¹⁶ The trial had no patients aged ≥ 75 years and excluded those with several common comorbidities.
• A randomized, double-blind trial studied the effects of high-dose vs low-dose losartan on clinical outcomes in 3,846 patients with HF and demonstrated that high-dose losartan (150 mg/d) reduces all-cause mortality and hospitalization for HF more effectively than does low-dose losartan (50 mg/d).¹⁷ The study, however, had several exclusion criteria, and no patients were aged ≥ 75 years.

Mineralocorticoid Receptor Antagonists

Major studies of aldosterone antagonists demonstrated extra benefit when added to ACE inhibitors/ARBs in patients with HFrEF and NYHA class II HF.^18,19

In the RALES study, spironolactone was found to reduce all-cause mortality by 30% and symptoms in NYHA III HF without a significant increase in the risk of serious hyperkalemia or renal failure.¹⁸ Most patients were white men aged < 80 years. This study demonstrated the importance of closely following serum potassium levels after initiating aldosterone antagonists in patients with subclinical renal disease because extensive structural damage within the kidney occurs before serum creatinine increases. Patients with advanced renal failure or those who cannot have close monitoring of serum potassium levels have an unfavorable risk–benefit ratio with aldosterone antagonists. Patients with cancer and liver failure were excluded from this trial.

In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study, (EMPHASIS-HF Study) eplerenone was found to reduce all-cause mortality and hospitalization for HFrEF.¹⁹ Similar to RALES, patients were mostly white males aged < 80 years, and patients with clinically significant, coexisting conditions were excluded.

The 2014 Treatment of Preserved Cardiac FunctionHeart Failure with an Aldosterone Antagonist Trial (TOPCAT) randomized 3,445 patients with well-controlled blood pressure to spironolactone or placebo.²⁰ Inclusion criteria were LVEF ≥ 45%, findings of HF, and either a HF hospitalization or elevated B-type natriuretic peptide level. There was no difference in the primary composite outcome of CV mortality, aborted cardiac arrest, or HF hospitalization over the 3.3-year follow-up period. The study found that among patients with HFpEF, spironolactone does not reduce the composite endpoint of CV mortality, aborted cardiac arrest, or HF hospitalizations compared with that of placebo.²⁰ In the trial, 29% of patients were aged > 75 years, and most were white men. There was no subgroup analysis for older patients.²⁰ In all 3 trials, patients with kidney injury (serum creatinine of ≥ 2.5 or estimated glomerular filtration rate of ≤ 30 mL/min) were excluded because of the risk of hyperkalemia.

An observational study after the RALES trial demonstrated a nearly 4-fold increase in admissions for hyperkalemia with a 6-fold increase in associated mortality in patients taking spirolactone.²¹ Therefore, it is important to closely follow serum potassium levels after initiating aldosterone antagonists in older patients with subclinical renal disease. Patients with advanced renal failure or those without close monitoring of serum potassium levels have an unfavorable risk–benefit ratio with aldosterone antagonists.

Antithrombotic Therapy

The large multicenter, double-blind randomized trial WARCEF found no added benefit with warfarin vs aspirin for patients with HFrEF in sinus rhythm.²² There was no reduced time to first stroke or death, and the reduced ischemic stroke risk was offset by an increase in major hemorrhage. It is not clear whether subgroup analysis for the etiology of patients’ HF was performed in WARCEF.

The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial (N = 1,587) found that treatment with warfarin resulted in significantly fewer strokes in patients with ischemic cardiomyopathy.²³ Randomization was not stratified by age group in both trials, and baseline characteristics included mostly white men, and no patients were older than aged > 75 years.

The risk of bleeding with prophylactic aspirin use for CV disease is dose dependent and increases with higher aspirin doses.²⁴ The use of aspirin, 325 mg/d, in the WARCEF study might have contributed to the increased risk of hemorrhage.

Recently published results of COMMANDER HF found that the addition of rivaroxaban at a dose of 2.5 mg twice daily to standard care, including clinically selected antiplatelet therapies was not associated with a significantly lower rate of the composite primary outcome composite outcome of death, myocardial infarction (MI), or stroke among 5,022 patients with a recent episode of worsening heart failure compared with that of placebo.²⁵

Several medical conditions are known to increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes mellitus, renal insufficiency, alcoholism, liver disease, and falls.²⁶ Many of these conditions are common among very old patients and should be considered when estimating risk–benefit ratio of oral anticoagulation therapy.

β-blockers

In several large studies, β-blockers have been shown to be effective in reducing mortality in patients with HFrEF. In the Cardiac Insufficiency Bisoprolol Study II, bisoprolol improved all-cause mortality and all-cause hospitalizations, and reduced sudden death in patients with NYHA III or IV HF.²⁷ In the Carvedilol or Metoprolol European Trial (COMET), carvedilol was superior to metoprolol in reducing all-cause mortality for patients with NYHA II or IV HF.²⁸ Both trials included mostly white men; patients with several comorbidities were excluded, and no patients were aged > 80 years.

COMET compared carvedilol with metoprolol tartrate, the short-acting form of metoprolol that has not shown a survival benefit for patients with HF. However, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure trial demonstrated survival benefits with metoprolol CR/XL and included patients aged > 80 years.²⁹

In the SENIORS study, patients treated with nebivolol had a 4.2% absolute risk reduction in a composite of mortality or hospital admission at a mean follow-up of 21 months.³⁰ It is reasonable to use nebivolol for managing HF in older patients. Careful monitoring of heart rate is necessary when prescribing β-blockers for older patients.

Cardiac Glycosides

Digoxin with diuretics was the first-line treatment for HF for many decades and the mainstay of HF therapy until the first large HF trials were performed in the 1980s. One trial initiated by the Digoxin Investigation Group (DIG) studied patients with HFrEF who were already receiving treatment for HF (including 94% taking ACE inhibitors and 82% on diuretics) and randomized them to either digoxin or placebo.³¹ The study found no significant difference in mortality between the groups at the 3-year follow-up; however, the digoxin group had significantly fewer hospitalizations compared with that of the placebo group.

A post-hoc analysis of patients by age found no difference in mortality between patients aged 70 to 79 years and those ≥ 80 years, with a persistent benefit in fewer hospitalizations. Digoxin continues to be recommended as a reasonable medication for treating symptomatic HFrEF. However, caution is advised in older patients, especially women, who are at higher risk of digoxin toxicity.

No current evidence exists that digoxin adds any benefits for patients with HFpEF of any age and therefore, it should not be used.

Diuretics

Diuretic therapy is important for managing shortness of breath and congestion related to fluid volume overload in patients with HF. Although diuretics have not been shown to reduce mortality in patients with HF, they are the mainstay treatment for patients with HFpEF.³² In a post-hoc analysis of the DIG study, diuretic use was associated with increased risk of mortality and hospitalizations in patients aged > 65 years.³³ Hyponatremia is one of the most serious adverse effects (AEs) with these agents and occurs in about one-fifth of elderly patients taking diuretics.

In severe cases hyponatremia can cause a range of problems, including weakness, confusion, postural giddiness, postural hypotension, falls, transient hemiparesis, and seizures. In older patients with diminished renal reserve, diuretics are more likely to precipitate prerenal uremia than it does in younger patients. Prerequisites for diuretic use are an accurate diagnosis, careful monitoring of blood pressure and serum electrolytes, and regular review of their efficacy, AEs, and the need for continued treatment.

Statins

The Controlled Rosuvastatin Multinational Trial in Heart Failure demonstrated that low-dose rosuvastatin (10 mg/d) does not improve survival among patients with moderate-to-severe ischemic cardiomyopathy but could reduce the rate of CV hospitalizations.³⁴ Patients in this study had a mean age of 73 years, and 41% of them were aged ≥ 75 years. However, the study used a low-dose rosuvastatin, and patients with several common comorbidities were excluded. Evidence exists that treatment with other statins may improve outcomes in patients with HF. There is also evidence that among elderly patients with HF, low serum total cholesterol is independently associated with a worse prognosis.³⁵

Comorbidities

Anemia

In patients with iron-deficiency anemia (ferritin 15-100 ng/mL or 100-299 ng/mL with transferrin saturation < 20%) and symptomatic HFrEF (LVEF ≤ 40% with NYHA II to IV HF), oral iron replacement had no effect on exercise capacity as measured using change in peak oxygen uptake.³⁶ However, IV iron replacement might be a reasonable option to improve functional status and quality of life (QOL) for patients with HF.³⁷ In these studies, participants were aged < 75 years, and there is no evidence that treating other types of anemia improves outcomes in patients with HF.

Hypertension

The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that controlling blood pressure to a goal systolic pressure of < 120 mm Hg is associated with significant reduction in the mortality among patients with increased CV risk (aged > 75 years, vascular disease, kidney injury, or a Framingham Risk Score >15%).³⁸ The SPRINT study included patients aged > 75 (25%); however, the study excluded older adults living in nursing homes and those with diabetes mellitus, symptomatic HF, dementia, or stroke. The subgroup analysis did not stratify patients based on age nor provided sufficient evidence regarding treatment targets for this vulnerable population. Therefore, clinicians cannot draw any conclusions about managing hypertension among patients with HF from this study.

Sleep Apnea

Sleep apnea is common among patients with HF. A study of adults with chronic HF treated with evidence-based therapies found that 61% of participants had central or obstructive sleep apnea.³⁹ In elderly patients, sleep apnea is further complicated by insomnia and disturbance of sleep cycle that often occur with the aging process.

It is crucial to differentiate central sleep apnea from obstructive sleep apnea, because the treatment approaches differ. Central sleep apnea is associated with poor prognosis in patients with HF.⁴⁰ Adaptive servo ventilation for central sleep apnea uses a noninvasive ventilator to delivering servo controlled inspiratory pressure support on top of expiratory positive airway pressure. Adaptive servo ventilation for central sleep apnea is associated with higher all-cause mortality and CV mortality.⁴¹ Continuous positive airway pressure for obstructive sleep apnea improves sleep quality, reduces the apnea-hypopnea index, and improves nocturnal oxygenation.⁴²

Depression

Clinically significant depression occurs in 21% of patients with HF, and the relationship between depression and poor HF outcomes is consistent and strong across several endpoints. However, in a randomized, 12-week study, the selective serotonin reuptake inhibitor sertraline did not improve depression symptoms or clinical status among patients with HF.⁴³ Depression symptoms might overlap with fatigue and low energy expenditure experienced by oldest old patients with HF who do not have depression.

Furthermore, studies describing depression treatments among patients with HF are too small and heterogeneous to permit definitive conclusions about intervention effectiveness. These results identify areas requiring further development, raise questions regarding the association between depression and clinical outcomes in patients with HF, and provide information on depression prevalence that may help researchers design studies with appropriate depression measures and adequately powered sample sizes.

Frailty

Although frailty is prevalent in the elderly and is independently associated with poor outcomes, there is no standardized definition for frailty. The Fried Frailty Index is a widely used scale that incorporates criteria including weakness, slowness, exhaustion, and low physical activity in the diagnosis of frailty.⁴⁴ However these symptoms are common among patients with advanced HF with and without depression or frailty.

Frailty should be defined collaboratively by the clinician and the patient and should include multidimensional aspects of health, function, and well-being. The treatment goal for patients with HF with frailty is to establish patient-centered goals based on preferences of care.⁴⁵

Discussion

Although several novel approaches to improve outcomes of patients with HF have been developed, it continues to be the leading cause of cardiovascular death among older patients and the leading cause of hospital admissions.⁴⁶ About 50% of newly diagnosed patients with HF die within 5 years.⁴⁷ Current guidelines for managing HF are based on clinical trials that either include few or completely exclude patients aged > 80 years, minorities, and patients with comorbidities clinicians encounter daily in clinical practice.

Furthermore, most clinical trials are designed with mortality as the primary endpoint, which might be as important to our patients with advanced age as their ability to function with a reasonable QOL and less dependence on caregivers.

Decision making in managing HF in our oldest patients should start with an open discussion of the disease and its prognosis, goals of care, and available treatment options. The discussion should also cover all dimensions of suffering, including physical, spiritual, and psychosocial domains. Interviews of patients dying of HF and their caregivers conducted in the United Kingdom identified several communication and transition of care challenges specific to treating this population.⁴⁸ The study revealed in most cases, patients did not recall receiving any written information about the severity of their disease and often did not understand the association among symptoms, such as shortness of breath, edema, and HF. Patients and caregivers did not feel involved in the decision-making process regarding their illness.

The concurrent presence of comorbidity, frailty, and cognitive impairment in our aging population with HF might add to the burden of the primary condition. Care often is perceived as fragmented. Polypharmacy negatively impacts HF management by increasing risk of drug nonadherence, drug interactions, and AEs in an already vulnerable population. There is a need for more effective interpersonal and easy to understand communication and resources.

In many situations, support services might be best facilitated by a dedicated palliative medicine team with significant experience in managing patients with HF.Although palliative medicine should always be considered for patients with HF with advanced age,consultations often are not obtained unless the patient decides to forgo medical treatment or until the last month of life.⁴⁹It is important to note that older adults are not a homogeneous group, and the conventional viewpoint that all patients with HF value symptom control and QOL over longevity may not be true. In a large study three-fourths of elderly outpatients with HF were not willing to trade survival time for improved QOL; and their preferences changed over the course of illness.⁵⁰

Although not all end-of-life symptoms can realistically be palliated, earlier involvement of multidisciplinary palliative medicine specialists may improve symptom control, functional status, and QOL. The team may help patients and caregivers cope with uncertainty, and make informed decisions that are person centered based on value system and beliefs.⁵¹

Conclusion

Randomized control trials as well as thoughtful observational studies of HF in patients with advanced age and comorbidities, although challenging, are needed to create the evidence base for treatment interventions and assessing their impact on mortality, morbidity, and QOL in this rapidly growing segment of our population.

Given the lack of evidence for HF treatment in patients with advanced age, the clinician should weigh the knowledge of the effect of aging on the CV system, and the lived experience of patients with HF, with the evidence that exists for making the best decision to relieve bothersome symptoms and improve outcomes of care as determined by patients and their caregivers.

Often the most important intervention we can offer our patients, especially those nearing the end of life, is dedicating our time to truly and actively listen with empathy, understating, and respect for their autonomy and for their decision making. And in doing so we accept our own limitations with humility.
 

Acknowledgments
Dr. Kheirbek received funds from the Veterans Affairs Capitol Health Care Network to establish the Center for Health and Aging at the Washington DC VA Medical Center.

In 2050, persons aged ≥ 85 years, also known as the oldest old, are projected to reach 18 million, accounting for 4.5% of the US population, up from 2.5% in 2030.¹ These patients are the fastest growing segment of the US population.

Advances in treating cardiovascular (CV) disease over the past 2 decades have led to an increased incidence of heart failure (HF) and hospitalizations among older patients.² Total costs of care for persons with HF have exceeded $30 billion annually and are expected to rise to more than $70 billion by 2030 due to growth of the aging population.^3,4 Moreover, the Framingham Study reported mortality increases with advancing age (HR 1.27 and 1.61 per decade in men and women, respectively).⁵

The prevalence of HF is also high and increasing over time. The National Health and Nutrition Examination Survey reported that about 5.7 million Americans have HF.⁶ The prevalence of HF is expected to reach 8 million by 2030.⁶ The higher numbers of HF among patients with advanced age is associated with age-related changes in CV structure and function, including reduced responsiveness to β-adrenergic stimulation, impaired left ventricular diastolic filling, and increased vascular stiffness. In addition, age-related changes in other systems might contribute to a HF diagnosis or worsening of the condition.⁷

Older adults experience physiologic changes in pharmacokinetics and pharmacodynamics, including decreased volume of distribution and creatinine clearance, which lead to significant changes in drug concentration and effectiveness.⁸

Geriatric patients aged > 65 years who have comorbidities and those who reside in long-term care settings are underrepresented in clinical trials, leading clinicians to make treatment decisions based on data from younger, community-dwelling individuals. Researchers have questioned whether to include elderly patients and those with comorbidities in clinical trials, given that their diminished response may produce less conclusive results with smaller treatment effects. Exclusion criteria based on comorbid conditions or functional status disqualify many older adults from clinical trials.

This article reviews evidence from major randomized controlled trials over the past 2 decades and explores their applicability to support HF treatment guidelines in patients with advanced age (Table). 

Pharmacotherapy for Heart Failure

Angiotensin-Converting Enzyme Inhibitors

Several randomized clinical trials have found that angiotensin-converting enzyme (ACE) inhibitors improve symptoms in patients with HF. The CooperativeNorth Scandinavian Enalapril Survival Study (CONSENSUS), demonstrated that enalapril improves survival in patients with New York Heart Association (NYHA) class IV HF with reduced ejection fraction (HFrEF) when added to standard therapy.⁹ However, the duration of beneficial effect of reduced mortality could not be assessed because the benefit of enalapril in NYHA class I to III HF was not evaluated, and follow-up data are limited. The average age of patients in the study was 71 years, and individuals with significant comorbidities were excluded.

ACE inhibitors also were found to reduce mortality even in asymptomatic patients with HFrEF in the Studies of Left Ventricular Dysfunction trial (SOLVD).¹⁰ Enalapril was found to reduce 4-year mortality by 16% and decrease HF hospitalizations when added to conventional therapy consisting primarily of digitalis, diuretics, and nitrates in patients with HFrEF. In this trial, patients aged ≥ 80 years were excluded as well as those with serum creatinine > 2 mg/dL or other conditions that could shorten survival or otherwise impede participation in a long-term trial.

PARADIGM-HF trial patients with HFrEF were randomized to enalapril or the angiotensin receptor-neprilysin inhibitor LCZ696. After a median of 27 months of follow-up, treatment with the angiotensin receptor-neprilysin inhibitor demonstrated greater reduction in CV mortality and HF hospitalizations than enalapril did and was associated with reduced all-cause mortality.¹¹ The trial was stopped early because of evidence of overwhelming benefit with LCZ696. This study of mainly white men included no patients aged ≥ 75 years.

Angiotensin Receptor Blockers

Although less studied than ACE inhibitors, angiotensin receptor blockers (ARBs) share similar benefits. Among patients with symptomatic HFrEF taking an ACE inhibitor, the addition of candesartan reduced the risk of CV death and HF hospitalization as demonstrated in the Candesartan in Heart Failure Assessment of Reduction Mortality and Morbidity (CHARM-added and CHARM-alternative trials).^12,13 The CHARM-added trial targeted patients with left ventricular ejection fraction (LVEF) ≤ 40% and NYHA class II to IV HF symptoms who were taking an ACE inhibitor. Adding candesartan reduced CV mortality by 37.9% and HF hospitalization by 42.3% compared with that of placebo.

The CHARM-alternative study found that use of candesartan in symptomatic HFrEF patients who do not tolerate ACE inhibitors,resulted in a 20% reduction in CV mortality as well as a 40% reduction in hospitalization for HF. Among patients with HF with preserved ejection fraction (HFpEF) and NYHA class II to IV symptoms, adding candesartan modestly reduced the rate of HF-related hospitalizations and had no effect on CV mortality in the CHARM-preserved study.¹⁴ The CHARM trials examined mostly white men, but 26% of patients were aged > 75 years. However, there was no subgroup analysis for patients aged > 75 years. The study excluded patients with serum creatinine > 2 mg/dL.

Other ARB trials included the following:

• The I-PRESERVE trial, which found that irbesartan did not improve outcomes of patients with HF with preserved ejection fraction (HFpEF).¹⁵ The study of mostly white patients did not include patients aged ≥ 80 years.
• A randomized trial of valsartan in HF improved symptoms and mortality in NYHA II to IV HF but showed no benefit when added to ACE inhibitors.¹⁶ The trial had no patients aged ≥ 75 years and excluded those with several common comorbidities.
• A randomized, double-blind trial studied the effects of high-dose vs low-dose losartan on clinical outcomes in 3,846 patients with HF and demonstrated that high-dose losartan (150 mg/d) reduces all-cause mortality and hospitalization for HF more effectively than does low-dose losartan (50 mg/d).¹⁷ The study, however, had several exclusion criteria, and no patients were aged ≥ 75 years.

Mineralocorticoid Receptor Antagonists

Major studies of aldosterone antagonists demonstrated extra benefit when added to ACE inhibitors/ARBs in patients with HFrEF and NYHA class II HF.^18,19

In the RALES study, spironolactone was found to reduce all-cause mortality by 30% and symptoms in NYHA III HF without a significant increase in the risk of serious hyperkalemia or renal failure.¹⁸ Most patients were white men aged < 80 years. This study demonstrated the importance of closely following serum potassium levels after initiating aldosterone antagonists in patients with subclinical renal disease because extensive structural damage within the kidney occurs before serum creatinine increases. Patients with advanced renal failure or those who cannot have close monitoring of serum potassium levels have an unfavorable risk–benefit ratio with aldosterone antagonists. Patients with cancer and liver failure were excluded from this trial.

In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study, (EMPHASIS-HF Study) eplerenone was found to reduce all-cause mortality and hospitalization for HFrEF.¹⁹ Similar to RALES, patients were mostly white males aged < 80 years, and patients with clinically significant, coexisting conditions were excluded.

The 2014 Treatment of Preserved Cardiac FunctionHeart Failure with an Aldosterone Antagonist Trial (TOPCAT) randomized 3,445 patients with well-controlled blood pressure to spironolactone or placebo.²⁰ Inclusion criteria were LVEF ≥ 45%, findings of HF, and either a HF hospitalization or elevated B-type natriuretic peptide level. There was no difference in the primary composite outcome of CV mortality, aborted cardiac arrest, or HF hospitalization over the 3.3-year follow-up period. The study found that among patients with HFpEF, spironolactone does not reduce the composite endpoint of CV mortality, aborted cardiac arrest, or HF hospitalizations compared with that of placebo.²⁰ In the trial, 29% of patients were aged > 75 years, and most were white men. There was no subgroup analysis for older patients.²⁰ In all 3 trials, patients with kidney injury (serum creatinine of ≥ 2.5 or estimated glomerular filtration rate of ≤ 30 mL/min) were excluded because of the risk of hyperkalemia.

An observational study after the RALES trial demonstrated a nearly 4-fold increase in admissions for hyperkalemia with a 6-fold increase in associated mortality in patients taking spirolactone.²¹ Therefore, it is important to closely follow serum potassium levels after initiating aldosterone antagonists in older patients with subclinical renal disease. Patients with advanced renal failure or those without close monitoring of serum potassium levels have an unfavorable risk–benefit ratio with aldosterone antagonists.

Antithrombotic Therapy

The large multicenter, double-blind randomized trial WARCEF found no added benefit with warfarin vs aspirin for patients with HFrEF in sinus rhythm.²² There was no reduced time to first stroke or death, and the reduced ischemic stroke risk was offset by an increase in major hemorrhage. It is not clear whether subgroup analysis for the etiology of patients’ HF was performed in WARCEF.

The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial (N = 1,587) found that treatment with warfarin resulted in significantly fewer strokes in patients with ischemic cardiomyopathy.²³ Randomization was not stratified by age group in both trials, and baseline characteristics included mostly white men, and no patients were older than aged > 75 years.

The risk of bleeding with prophylactic aspirin use for CV disease is dose dependent and increases with higher aspirin doses.²⁴ The use of aspirin, 325 mg/d, in the WARCEF study might have contributed to the increased risk of hemorrhage.

Recently published results of COMMANDER HF found that the addition of rivaroxaban at a dose of 2.5 mg twice daily to standard care, including clinically selected antiplatelet therapies was not associated with a significantly lower rate of the composite primary outcome composite outcome of death, myocardial infarction (MI), or stroke among 5,022 patients with a recent episode of worsening heart failure compared with that of placebo.²⁵

Several medical conditions are known to increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes mellitus, renal insufficiency, alcoholism, liver disease, and falls.²⁶ Many of these conditions are common among very old patients and should be considered when estimating risk–benefit ratio of oral anticoagulation therapy.

β-blockers

In several large studies, β-blockers have been shown to be effective in reducing mortality in patients with HFrEF. In the Cardiac Insufficiency Bisoprolol Study II, bisoprolol improved all-cause mortality and all-cause hospitalizations, and reduced sudden death in patients with NYHA III or IV HF.²⁷ In the Carvedilol or Metoprolol European Trial (COMET), carvedilol was superior to metoprolol in reducing all-cause mortality for patients with NYHA II or IV HF.²⁸ Both trials included mostly white men; patients with several comorbidities were excluded, and no patients were aged > 80 years.

COMET compared carvedilol with metoprolol tartrate, the short-acting form of metoprolol that has not shown a survival benefit for patients with HF. However, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure trial demonstrated survival benefits with metoprolol CR/XL and included patients aged > 80 years.²⁹

In the SENIORS study, patients treated with nebivolol had a 4.2% absolute risk reduction in a composite of mortality or hospital admission at a mean follow-up of 21 months.³⁰ It is reasonable to use nebivolol for managing HF in older patients. Careful monitoring of heart rate is necessary when prescribing β-blockers for older patients.

Cardiac Glycosides

Digoxin with diuretics was the first-line treatment for HF for many decades and the mainstay of HF therapy until the first large HF trials were performed in the 1980s. One trial initiated by the Digoxin Investigation Group (DIG) studied patients with HFrEF who were already receiving treatment for HF (including 94% taking ACE inhibitors and 82% on diuretics) and randomized them to either digoxin or placebo.³¹ The study found no significant difference in mortality between the groups at the 3-year follow-up; however, the digoxin group had significantly fewer hospitalizations compared with that of the placebo group.

A post-hoc analysis of patients by age found no difference in mortality between patients aged 70 to 79 years and those ≥ 80 years, with a persistent benefit in fewer hospitalizations. Digoxin continues to be recommended as a reasonable medication for treating symptomatic HFrEF. However, caution is advised in older patients, especially women, who are at higher risk of digoxin toxicity.

No current evidence exists that digoxin adds any benefits for patients with HFpEF of any age and therefore, it should not be used.

Diuretics

Diuretic therapy is important for managing shortness of breath and congestion related to fluid volume overload in patients with HF. Although diuretics have not been shown to reduce mortality in patients with HF, they are the mainstay treatment for patients with HFpEF.³² In a post-hoc analysis of the DIG study, diuretic use was associated with increased risk of mortality and hospitalizations in patients aged > 65 years.³³ Hyponatremia is one of the most serious adverse effects (AEs) with these agents and occurs in about one-fifth of elderly patients taking diuretics.

In severe cases hyponatremia can cause a range of problems, including weakness, confusion, postural giddiness, postural hypotension, falls, transient hemiparesis, and seizures. In older patients with diminished renal reserve, diuretics are more likely to precipitate prerenal uremia than it does in younger patients. Prerequisites for diuretic use are an accurate diagnosis, careful monitoring of blood pressure and serum electrolytes, and regular review of their efficacy, AEs, and the need for continued treatment.

Statins

The Controlled Rosuvastatin Multinational Trial in Heart Failure demonstrated that low-dose rosuvastatin (10 mg/d) does not improve survival among patients with moderate-to-severe ischemic cardiomyopathy but could reduce the rate of CV hospitalizations.³⁴ Patients in this study had a mean age of 73 years, and 41% of them were aged ≥ 75 years. However, the study used a low-dose rosuvastatin, and patients with several common comorbidities were excluded. Evidence exists that treatment with other statins may improve outcomes in patients with HF. There is also evidence that among elderly patients with HF, low serum total cholesterol is independently associated with a worse prognosis.³⁵

Comorbidities

Anemia

In patients with iron-deficiency anemia (ferritin 15-100 ng/mL or 100-299 ng/mL with transferrin saturation < 20%) and symptomatic HFrEF (LVEF ≤ 40% with NYHA II to IV HF), oral iron replacement had no effect on exercise capacity as measured using change in peak oxygen uptake.³⁶ However, IV iron replacement might be a reasonable option to improve functional status and quality of life (QOL) for patients with HF.³⁷ In these studies, participants were aged < 75 years, and there is no evidence that treating other types of anemia improves outcomes in patients with HF.

Hypertension

The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that controlling blood pressure to a goal systolic pressure of < 120 mm Hg is associated with significant reduction in the mortality among patients with increased CV risk (aged > 75 years, vascular disease, kidney injury, or a Framingham Risk Score >15%).³⁸ The SPRINT study included patients aged > 75 (25%); however, the study excluded older adults living in nursing homes and those with diabetes mellitus, symptomatic HF, dementia, or stroke. The subgroup analysis did not stratify patients based on age nor provided sufficient evidence regarding treatment targets for this vulnerable population. Therefore, clinicians cannot draw any conclusions about managing hypertension among patients with HF from this study.

Sleep Apnea

Sleep apnea is common among patients with HF. A study of adults with chronic HF treated with evidence-based therapies found that 61% of participants had central or obstructive sleep apnea.³⁹ In elderly patients, sleep apnea is further complicated by insomnia and disturbance of sleep cycle that often occur with the aging process.

It is crucial to differentiate central sleep apnea from obstructive sleep apnea, because the treatment approaches differ. Central sleep apnea is associated with poor prognosis in patients with HF.⁴⁰ Adaptive servo ventilation for central sleep apnea uses a noninvasive ventilator to delivering servo controlled inspiratory pressure support on top of expiratory positive airway pressure. Adaptive servo ventilation for central sleep apnea is associated with higher all-cause mortality and CV mortality.⁴¹ Continuous positive airway pressure for obstructive sleep apnea improves sleep quality, reduces the apnea-hypopnea index, and improves nocturnal oxygenation.⁴²

Depression

Clinically significant depression occurs in 21% of patients with HF, and the relationship between depression and poor HF outcomes is consistent and strong across several endpoints. However, in a randomized, 12-week study, the selective serotonin reuptake inhibitor sertraline did not improve depression symptoms or clinical status among patients with HF.⁴³ Depression symptoms might overlap with fatigue and low energy expenditure experienced by oldest old patients with HF who do not have depression.

Furthermore, studies describing depression treatments among patients with HF are too small and heterogeneous to permit definitive conclusions about intervention effectiveness. These results identify areas requiring further development, raise questions regarding the association between depression and clinical outcomes in patients with HF, and provide information on depression prevalence that may help researchers design studies with appropriate depression measures and adequately powered sample sizes.

Frailty

Although frailty is prevalent in the elderly and is independently associated with poor outcomes, there is no standardized definition for frailty. The Fried Frailty Index is a widely used scale that incorporates criteria including weakness, slowness, exhaustion, and low physical activity in the diagnosis of frailty.⁴⁴ However these symptoms are common among patients with advanced HF with and without depression or frailty.

Frailty should be defined collaboratively by the clinician and the patient and should include multidimensional aspects of health, function, and well-being. The treatment goal for patients with HF with frailty is to establish patient-centered goals based on preferences of care.⁴⁵

Discussion

Although several novel approaches to improve outcomes of patients with HF have been developed, it continues to be the leading cause of cardiovascular death among older patients and the leading cause of hospital admissions.⁴⁶ About 50% of newly diagnosed patients with HF die within 5 years.⁴⁷ Current guidelines for managing HF are based on clinical trials that either include few or completely exclude patients aged > 80 years, minorities, and patients with comorbidities clinicians encounter daily in clinical practice.

Furthermore, most clinical trials are designed with mortality as the primary endpoint, which might be as important to our patients with advanced age as their ability to function with a reasonable QOL and less dependence on caregivers.

Decision making in managing HF in our oldest patients should start with an open discussion of the disease and its prognosis, goals of care, and available treatment options. The discussion should also cover all dimensions of suffering, including physical, spiritual, and psychosocial domains. Interviews of patients dying of HF and their caregivers conducted in the United Kingdom identified several communication and transition of care challenges specific to treating this population.⁴⁸ The study revealed in most cases, patients did not recall receiving any written information about the severity of their disease and often did not understand the association among symptoms, such as shortness of breath, edema, and HF. Patients and caregivers did not feel involved in the decision-making process regarding their illness.

The concurrent presence of comorbidity, frailty, and cognitive impairment in our aging population with HF might add to the burden of the primary condition. Care often is perceived as fragmented. Polypharmacy negatively impacts HF management by increasing risk of drug nonadherence, drug interactions, and AEs in an already vulnerable population. There is a need for more effective interpersonal and easy to understand communication and resources.

In many situations, support services might be best facilitated by a dedicated palliative medicine team with significant experience in managing patients with HF.Although palliative medicine should always be considered for patients with HF with advanced age,consultations often are not obtained unless the patient decides to forgo medical treatment or until the last month of life.⁴⁹It is important to note that older adults are not a homogeneous group, and the conventional viewpoint that all patients with HF value symptom control and QOL over longevity may not be true. In a large study three-fourths of elderly outpatients with HF were not willing to trade survival time for improved QOL; and their preferences changed over the course of illness.⁵⁰

Although not all end-of-life symptoms can realistically be palliated, earlier involvement of multidisciplinary palliative medicine specialists may improve symptom control, functional status, and QOL. The team may help patients and caregivers cope with uncertainty, and make informed decisions that are person centered based on value system and beliefs.⁵¹

Conclusion

Randomized control trials as well as thoughtful observational studies of HF in patients with advanced age and comorbidities, although challenging, are needed to create the evidence base for treatment interventions and assessing their impact on mortality, morbidity, and QOL in this rapidly growing segment of our population.

Given the lack of evidence for HF treatment in patients with advanced age, the clinician should weigh the knowledge of the effect of aging on the CV system, and the lived experience of patients with HF, with the evidence that exists for making the best decision to relieve bothersome symptoms and improve outcomes of care as determined by patients and their caregivers.

Often the most important intervention we can offer our patients, especially those nearing the end of life, is dedicating our time to truly and actively listen with empathy, understating, and respect for their autonomy and for their decision making. And in doing so we accept our own limitations with humility.
 

Acknowledgments
Dr. Kheirbek received funds from the Veterans Affairs Capitol Health Care Network to establish the Center for Health and Aging at the Washington DC VA Medical Center.

In 2050, persons aged ≥ 85 years, also known as the oldest old, are projected to reach 18 million, accounting for 4.5% of the US population, up from 2.5% in 2030.¹ These patients are the fastest growing segment of the US population.

Advances in treating cardiovascular (CV) disease over the past 2 decades have led to an increased incidence of heart failure (HF) and hospitalizations among older patients.² Total costs of care for persons with HF have exceeded $30 billion annually and are expected to rise to more than $70 billion by 2030 due to growth of the aging population.^3,4 Moreover, the Framingham Study reported mortality increases with advancing age (HR 1.27 and 1.61 per decade in men and women, respectively).⁵

The prevalence of HF is also high and increasing over time. The National Health and Nutrition Examination Survey reported that about 5.7 million Americans have HF.⁶ The prevalence of HF is expected to reach 8 million by 2030.⁶ The higher numbers of HF among patients with advanced age is associated with age-related changes in CV structure and function, including reduced responsiveness to β-adrenergic stimulation, impaired left ventricular diastolic filling, and increased vascular stiffness. In addition, age-related changes in other systems might contribute to a HF diagnosis or worsening of the condition.⁷

Older adults experience physiologic changes in pharmacokinetics and pharmacodynamics, including decreased volume of distribution and creatinine clearance, which lead to significant changes in drug concentration and effectiveness.⁸

Geriatric patients aged > 65 years who have comorbidities and those who reside in long-term care settings are underrepresented in clinical trials, leading clinicians to make treatment decisions based on data from younger, community-dwelling individuals. Researchers have questioned whether to include elderly patients and those with comorbidities in clinical trials, given that their diminished response may produce less conclusive results with smaller treatment effects. Exclusion criteria based on comorbid conditions or functional status disqualify many older adults from clinical trials.

This article reviews evidence from major randomized controlled trials over the past 2 decades and explores their applicability to support HF treatment guidelines in patients with advanced age (Table). 

Pharmacotherapy for Heart Failure

Angiotensin-Converting Enzyme Inhibitors

Several randomized clinical trials have found that angiotensin-converting enzyme (ACE) inhibitors improve symptoms in patients with HF. The CooperativeNorth Scandinavian Enalapril Survival Study (CONSENSUS), demonstrated that enalapril improves survival in patients with New York Heart Association (NYHA) class IV HF with reduced ejection fraction (HFrEF) when added to standard therapy.⁹ However, the duration of beneficial effect of reduced mortality could not be assessed because the benefit of enalapril in NYHA class I to III HF was not evaluated, and follow-up data are limited. The average age of patients in the study was 71 years, and individuals with significant comorbidities were excluded.

ACE inhibitors also were found to reduce mortality even in asymptomatic patients with HFrEF in the Studies of Left Ventricular Dysfunction trial (SOLVD).¹⁰ Enalapril was found to reduce 4-year mortality by 16% and decrease HF hospitalizations when added to conventional therapy consisting primarily of digitalis, diuretics, and nitrates in patients with HFrEF. In this trial, patients aged ≥ 80 years were excluded as well as those with serum creatinine > 2 mg/dL or other conditions that could shorten survival or otherwise impede participation in a long-term trial.

PARADIGM-HF trial patients with HFrEF were randomized to enalapril or the angiotensin receptor-neprilysin inhibitor LCZ696. After a median of 27 months of follow-up, treatment with the angiotensin receptor-neprilysin inhibitor demonstrated greater reduction in CV mortality and HF hospitalizations than enalapril did and was associated with reduced all-cause mortality.¹¹ The trial was stopped early because of evidence of overwhelming benefit with LCZ696. This study of mainly white men included no patients aged ≥ 75 years.

Angiotensin Receptor Blockers

Although less studied than ACE inhibitors, angiotensin receptor blockers (ARBs) share similar benefits. Among patients with symptomatic HFrEF taking an ACE inhibitor, the addition of candesartan reduced the risk of CV death and HF hospitalization as demonstrated in the Candesartan in Heart Failure Assessment of Reduction Mortality and Morbidity (CHARM-added and CHARM-alternative trials).^12,13 The CHARM-added trial targeted patients with left ventricular ejection fraction (LVEF) ≤ 40% and NYHA class II to IV HF symptoms who were taking an ACE inhibitor. Adding candesartan reduced CV mortality by 37.9% and HF hospitalization by 42.3% compared with that of placebo.

The CHARM-alternative study found that use of candesartan in symptomatic HFrEF patients who do not tolerate ACE inhibitors,resulted in a 20% reduction in CV mortality as well as a 40% reduction in hospitalization for HF. Among patients with HF with preserved ejection fraction (HFpEF) and NYHA class II to IV symptoms, adding candesartan modestly reduced the rate of HF-related hospitalizations and had no effect on CV mortality in the CHARM-preserved study.¹⁴ The CHARM trials examined mostly white men, but 26% of patients were aged > 75 years. However, there was no subgroup analysis for patients aged > 75 years. The study excluded patients with serum creatinine > 2 mg/dL.

Other ARB trials included the following:

• The I-PRESERVE trial, which found that irbesartan did not improve outcomes of patients with HF with preserved ejection fraction (HFpEF).¹⁵ The study of mostly white patients did not include patients aged ≥ 80 years.
• A randomized trial of valsartan in HF improved symptoms and mortality in NYHA II to IV HF but showed no benefit when added to ACE inhibitors.¹⁶ The trial had no patients aged ≥ 75 years and excluded those with several common comorbidities.
• A randomized, double-blind trial studied the effects of high-dose vs low-dose losartan on clinical outcomes in 3,846 patients with HF and demonstrated that high-dose losartan (150 mg/d) reduces all-cause mortality and hospitalization for HF more effectively than does low-dose losartan (50 mg/d).¹⁷ The study, however, had several exclusion criteria, and no patients were aged ≥ 75 years.

Mineralocorticoid Receptor Antagonists

Major studies of aldosterone antagonists demonstrated extra benefit when added to ACE inhibitors/ARBs in patients with HFrEF and NYHA class II HF.^18,19

In the RALES study, spironolactone was found to reduce all-cause mortality by 30% and symptoms in NYHA III HF without a significant increase in the risk of serious hyperkalemia or renal failure.¹⁸ Most patients were white men aged < 80 years. This study demonstrated the importance of closely following serum potassium levels after initiating aldosterone antagonists in patients with subclinical renal disease because extensive structural damage within the kidney occurs before serum creatinine increases. Patients with advanced renal failure or those who cannot have close monitoring of serum potassium levels have an unfavorable risk–benefit ratio with aldosterone antagonists. Patients with cancer and liver failure were excluded from this trial.

In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study, (EMPHASIS-HF Study) eplerenone was found to reduce all-cause mortality and hospitalization for HFrEF.¹⁹ Similar to RALES, patients were mostly white males aged < 80 years, and patients with clinically significant, coexisting conditions were excluded.

The 2014 Treatment of Preserved Cardiac FunctionHeart Failure with an Aldosterone Antagonist Trial (TOPCAT) randomized 3,445 patients with well-controlled blood pressure to spironolactone or placebo.²⁰ Inclusion criteria were LVEF ≥ 45%, findings of HF, and either a HF hospitalization or elevated B-type natriuretic peptide level. There was no difference in the primary composite outcome of CV mortality, aborted cardiac arrest, or HF hospitalization over the 3.3-year follow-up period. The study found that among patients with HFpEF, spironolactone does not reduce the composite endpoint of CV mortality, aborted cardiac arrest, or HF hospitalizations compared with that of placebo.²⁰ In the trial, 29% of patients were aged > 75 years, and most were white men. There was no subgroup analysis for older patients.²⁰ In all 3 trials, patients with kidney injury (serum creatinine of ≥ 2.5 or estimated glomerular filtration rate of ≤ 30 mL/min) were excluded because of the risk of hyperkalemia.

An observational study after the RALES trial demonstrated a nearly 4-fold increase in admissions for hyperkalemia with a 6-fold increase in associated mortality in patients taking spirolactone.²¹ Therefore, it is important to closely follow serum potassium levels after initiating aldosterone antagonists in older patients with subclinical renal disease. Patients with advanced renal failure or those without close monitoring of serum potassium levels have an unfavorable risk–benefit ratio with aldosterone antagonists.

Antithrombotic Therapy

The large multicenter, double-blind randomized trial WARCEF found no added benefit with warfarin vs aspirin for patients with HFrEF in sinus rhythm.²² There was no reduced time to first stroke or death, and the reduced ischemic stroke risk was offset by an increase in major hemorrhage. It is not clear whether subgroup analysis for the etiology of patients’ HF was performed in WARCEF.

The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial (N = 1,587) found that treatment with warfarin resulted in significantly fewer strokes in patients with ischemic cardiomyopathy.²³ Randomization was not stratified by age group in both trials, and baseline characteristics included mostly white men, and no patients were older than aged > 75 years.

The risk of bleeding with prophylactic aspirin use for CV disease is dose dependent and increases with higher aspirin doses.²⁴ The use of aspirin, 325 mg/d, in the WARCEF study might have contributed to the increased risk of hemorrhage.

Recently published results of COMMANDER HF found that the addition of rivaroxaban at a dose of 2.5 mg twice daily to standard care, including clinically selected antiplatelet therapies was not associated with a significantly lower rate of the composite primary outcome composite outcome of death, myocardial infarction (MI), or stroke among 5,022 patients with a recent episode of worsening heart failure compared with that of placebo.²⁵

Several medical conditions are known to increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes mellitus, renal insufficiency, alcoholism, liver disease, and falls.²⁶ Many of these conditions are common among very old patients and should be considered when estimating risk–benefit ratio of oral anticoagulation therapy.

β-blockers

In several large studies, β-blockers have been shown to be effective in reducing mortality in patients with HFrEF. In the Cardiac Insufficiency Bisoprolol Study II, bisoprolol improved all-cause mortality and all-cause hospitalizations, and reduced sudden death in patients with NYHA III or IV HF.²⁷ In the Carvedilol or Metoprolol European Trial (COMET), carvedilol was superior to metoprolol in reducing all-cause mortality for patients with NYHA II or IV HF.²⁸ Both trials included mostly white men; patients with several comorbidities were excluded, and no patients were aged > 80 years.

COMET compared carvedilol with metoprolol tartrate, the short-acting form of metoprolol that has not shown a survival benefit for patients with HF. However, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure trial demonstrated survival benefits with metoprolol CR/XL and included patients aged > 80 years.²⁹

In the SENIORS study, patients treated with nebivolol had a 4.2% absolute risk reduction in a composite of mortality or hospital admission at a mean follow-up of 21 months.³⁰ It is reasonable to use nebivolol for managing HF in older patients. Careful monitoring of heart rate is necessary when prescribing β-blockers for older patients.

Cardiac Glycosides

Digoxin with diuretics was the first-line treatment for HF for many decades and the mainstay of HF therapy until the first large HF trials were performed in the 1980s. One trial initiated by the Digoxin Investigation Group (DIG) studied patients with HFrEF who were already receiving treatment for HF (including 94% taking ACE inhibitors and 82% on diuretics) and randomized them to either digoxin or placebo.³¹ The study found no significant difference in mortality between the groups at the 3-year follow-up; however, the digoxin group had significantly fewer hospitalizations compared with that of the placebo group.

A post-hoc analysis of patients by age found no difference in mortality between patients aged 70 to 79 years and those ≥ 80 years, with a persistent benefit in fewer hospitalizations. Digoxin continues to be recommended as a reasonable medication for treating symptomatic HFrEF. However, caution is advised in older patients, especially women, who are at higher risk of digoxin toxicity.

No current evidence exists that digoxin adds any benefits for patients with HFpEF of any age and therefore, it should not be used.

Diuretics

Diuretic therapy is important for managing shortness of breath and congestion related to fluid volume overload in patients with HF. Although diuretics have not been shown to reduce mortality in patients with HF, they are the mainstay treatment for patients with HFpEF.³² In a post-hoc analysis of the DIG study, diuretic use was associated with increased risk of mortality and hospitalizations in patients aged > 65 years.³³ Hyponatremia is one of the most serious adverse effects (AEs) with these agents and occurs in about one-fifth of elderly patients taking diuretics.

In severe cases hyponatremia can cause a range of problems, including weakness, confusion, postural giddiness, postural hypotension, falls, transient hemiparesis, and seizures. In older patients with diminished renal reserve, diuretics are more likely to precipitate prerenal uremia than it does in younger patients. Prerequisites for diuretic use are an accurate diagnosis, careful monitoring of blood pressure and serum electrolytes, and regular review of their efficacy, AEs, and the need for continued treatment.

Statins

The Controlled Rosuvastatin Multinational Trial in Heart Failure demonstrated that low-dose rosuvastatin (10 mg/d) does not improve survival among patients with moderate-to-severe ischemic cardiomyopathy but could reduce the rate of CV hospitalizations.³⁴ Patients in this study had a mean age of 73 years, and 41% of them were aged ≥ 75 years. However, the study used a low-dose rosuvastatin, and patients with several common comorbidities were excluded. Evidence exists that treatment with other statins may improve outcomes in patients with HF. There is also evidence that among elderly patients with HF, low serum total cholesterol is independently associated with a worse prognosis.³⁵

Comorbidities

Anemia

In patients with iron-deficiency anemia (ferritin 15-100 ng/mL or 100-299 ng/mL with transferrin saturation < 20%) and symptomatic HFrEF (LVEF ≤ 40% with NYHA II to IV HF), oral iron replacement had no effect on exercise capacity as measured using change in peak oxygen uptake.³⁶ However, IV iron replacement might be a reasonable option to improve functional status and quality of life (QOL) for patients with HF.³⁷ In these studies, participants were aged < 75 years, and there is no evidence that treating other types of anemia improves outcomes in patients with HF.

Hypertension

The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that controlling blood pressure to a goal systolic pressure of < 120 mm Hg is associated with significant reduction in the mortality among patients with increased CV risk (aged > 75 years, vascular disease, kidney injury, or a Framingham Risk Score >15%).³⁸ The SPRINT study included patients aged > 75 (25%); however, the study excluded older adults living in nursing homes and those with diabetes mellitus, symptomatic HF, dementia, or stroke. The subgroup analysis did not stratify patients based on age nor provided sufficient evidence regarding treatment targets for this vulnerable population. Therefore, clinicians cannot draw any conclusions about managing hypertension among patients with HF from this study.

Sleep Apnea

Sleep apnea is common among patients with HF. A study of adults with chronic HF treated with evidence-based therapies found that 61% of participants had central or obstructive sleep apnea.³⁹ In elderly patients, sleep apnea is further complicated by insomnia and disturbance of sleep cycle that often occur with the aging process.

It is crucial to differentiate central sleep apnea from obstructive sleep apnea, because the treatment approaches differ. Central sleep apnea is associated with poor prognosis in patients with HF.⁴⁰ Adaptive servo ventilation for central sleep apnea uses a noninvasive ventilator to delivering servo controlled inspiratory pressure support on top of expiratory positive airway pressure. Adaptive servo ventilation for central sleep apnea is associated with higher all-cause mortality and CV mortality.⁴¹ Continuous positive airway pressure for obstructive sleep apnea improves sleep quality, reduces the apnea-hypopnea index, and improves nocturnal oxygenation.⁴²

Depression

Clinically significant depression occurs in 21% of patients with HF, and the relationship between depression and poor HF outcomes is consistent and strong across several endpoints. However, in a randomized, 12-week study, the selective serotonin reuptake inhibitor sertraline did not improve depression symptoms or clinical status among patients with HF.⁴³ Depression symptoms might overlap with fatigue and low energy expenditure experienced by oldest old patients with HF who do not have depression.

Furthermore, studies describing depression treatments among patients with HF are too small and heterogeneous to permit definitive conclusions about intervention effectiveness. These results identify areas requiring further development, raise questions regarding the association between depression and clinical outcomes in patients with HF, and provide information on depression prevalence that may help researchers design studies with appropriate depression measures and adequately powered sample sizes.

Frailty

Although frailty is prevalent in the elderly and is independently associated with poor outcomes, there is no standardized definition for frailty. The Fried Frailty Index is a widely used scale that incorporates criteria including weakness, slowness, exhaustion, and low physical activity in the diagnosis of frailty.⁴⁴ However these symptoms are common among patients with advanced HF with and without depression or frailty.

Frailty should be defined collaboratively by the clinician and the patient and should include multidimensional aspects of health, function, and well-being. The treatment goal for patients with HF with frailty is to establish patient-centered goals based on preferences of care.⁴⁵

Discussion

Although several novel approaches to improve outcomes of patients with HF have been developed, it continues to be the leading cause of cardiovascular death among older patients and the leading cause of hospital admissions.⁴⁶ About 50% of newly diagnosed patients with HF die within 5 years.⁴⁷ Current guidelines for managing HF are based on clinical trials that either include few or completely exclude patients aged > 80 years, minorities, and patients with comorbidities clinicians encounter daily in clinical practice.

Furthermore, most clinical trials are designed with mortality as the primary endpoint, which might be as important to our patients with advanced age as their ability to function with a reasonable QOL and less dependence on caregivers.

Decision making in managing HF in our oldest patients should start with an open discussion of the disease and its prognosis, goals of care, and available treatment options. The discussion should also cover all dimensions of suffering, including physical, spiritual, and psychosocial domains. Interviews of patients dying of HF and their caregivers conducted in the United Kingdom identified several communication and transition of care challenges specific to treating this population.⁴⁸ The study revealed in most cases, patients did not recall receiving any written information about the severity of their disease and often did not understand the association among symptoms, such as shortness of breath, edema, and HF. Patients and caregivers did not feel involved in the decision-making process regarding their illness.

The concurrent presence of comorbidity, frailty, and cognitive impairment in our aging population with HF might add to the burden of the primary condition. Care often is perceived as fragmented. Polypharmacy negatively impacts HF management by increasing risk of drug nonadherence, drug interactions, and AEs in an already vulnerable population. There is a need for more effective interpersonal and easy to understand communication and resources.

In many situations, support services might be best facilitated by a dedicated palliative medicine team with significant experience in managing patients with HF.Although palliative medicine should always be considered for patients with HF with advanced age,consultations often are not obtained unless the patient decides to forgo medical treatment or until the last month of life.⁴⁹It is important to note that older adults are not a homogeneous group, and the conventional viewpoint that all patients with HF value symptom control and QOL over longevity may not be true. In a large study three-fourths of elderly outpatients with HF were not willing to trade survival time for improved QOL; and their preferences changed over the course of illness.⁵⁰

Although not all end-of-life symptoms can realistically be palliated, earlier involvement of multidisciplinary palliative medicine specialists may improve symptom control, functional status, and QOL. The team may help patients and caregivers cope with uncertainty, and make informed decisions that are person centered based on value system and beliefs.⁵¹

Conclusion

Randomized control trials as well as thoughtful observational studies of HF in patients with advanced age and comorbidities, although challenging, are needed to create the evidence base for treatment interventions and assessing their impact on mortality, morbidity, and QOL in this rapidly growing segment of our population.

Given the lack of evidence for HF treatment in patients with advanced age, the clinician should weigh the knowledge of the effect of aging on the CV system, and the lived experience of patients with HF, with the evidence that exists for making the best decision to relieve bothersome symptoms and improve outcomes of care as determined by patients and their caregivers.

Often the most important intervention we can offer our patients, especially those nearing the end of life, is dedicating our time to truly and actively listen with empathy, understating, and respect for their autonomy and for their decision making. And in doing so we accept our own limitations with humility.
 

Acknowledgments
Dr. Kheirbek received funds from the Veterans Affairs Capitol Health Care Network to establish the Center for Health and Aging at the Washington DC VA Medical Center.