The 2022 guideline update released by the KDIGO organization for managing people with diabetes and chronic kidney disease (CKD) highlighted the safety and expanded, evidence-based role for agents from three drug classes: the SGLT2 inhibitors, the GLP-1 receptor agonists, and the nonsteroidal mineralocorticoid receptor antagonists.

But this key take-away from the guideline also underscored the challenges for ensuring fair and affordable access among US patients to these practice-changing medications.

The impact of widespread adoption of these three drug classes into routine US management of people with diabetes and CKD “will be determined by how effective the health care system and its patients and clinicians are at overcoming individual and structural barriers,” write Milda Saunders, MD, and Neda Laiteerapong, MD, in an editorial that accompanied the publication of a synopsis of the 2022 guideline update in Annals of Internal Medicine.

The synopsis is an 11-page distillation of the full 128-page guideline released by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in 2022.

The recommendations in the 2022 guideline update “are exciting for their potential to change the natural history of CKD and diabetes, but their effect could be highly limited by barriers at multiple levels,” write Dr. Saunders and Dr. Laiteerapong, two internal medicine physicians at the University of Chicago.

“Without equitable implementation of the KDIGO 2022 guidelines there is a potential that clinical practice variation will increase and widen health inequities for minoritized people with CKD and diabetes,” they warn.
 

Generics to the rescue

One potentially effective, and likely imminent, way to level the prescribing field for patients with CKD and diabetes is for agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor, glucagonlike peptide-1 (GLP-1) receptor agonist, and nonsteroidal mineralocorticoid receptor antagonist classes to become available in generic formulations.

That should lower prices and thereby boost wider access and will likely occur fairly soon for at least two of the three drug classes, Dr. Laiteerapong predicts.

Some GLP-1 receptor agonists have already escaped patent exclusivity or will do so in 2023, she notes, including the anticipated ability of one drugmaker to start U.S. marketing of generic liraglutide by the end of 2023.

However, whether that manufacturer, Teva, proceeds with generic liraglutide “is a big question,” Dr. Laiteerapong said in an interview. She cited Teva’s history of failing to introduce a generic formulation of exenatide onto the U.S. market even though it has had a green light to do so since 2017.

The only nonsteroidal mineralocorticoid receptor antagonist now on the market is finerenone (Kerendia), which will not go off patent for several more years, but for some branded SGLT2 inhibitors, U.S. patents will expire in 2025. In addition, remogliflozin is an SGLT2 inhibitor that “may have already lost patent exclusivity,” noted Dr. Laiteerapong, although it has also never received U.S. marketing approval.

Dr. Laiteerapong expressed optimism that the overall trajectory of access is on the rise. “Many people have type 2 diabetes, and these drugs are in demand,” she noted. She also pointed to progress recently made on insulin affordability. “Things will get better as long as people advocate and argue for equity,” she maintained.
 

Incentivize formulary listings

Dr. Laiteerapong cited other approaches that could boost access to these medications, such as “creating incentives for pharmaceutical companies to ensure that [these drugs] are on formularies” of large, government-affiliated U.S. health insurance programs, such as Medicare Advantage plans, Medicare Part D, state Medicaid plans, and coverage through U.S. Veterans Affairs and the Tricare health insurance plans available to active members of the US military.

The editorial she coauthored with Dr. Saunders also calls for future collaborations among various medical societies to create “a more unified and streamlined set of recommendations” that benefits patients with diabetes, CKD, and multiple other chronic conditions.

“Over the last decade, we have seen more societies willing to present cooperative guidelines, as well as a surge in research on patients who live with multiple chronic conditions. There is momentum that will allow these different societies to work together,” Dr. Laiteerapong said.

Dr. Laiteerapong and Dr. Saunders have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The 2022 guideline update released by the KDIGO organization for managing people with diabetes and chronic kidney disease (CKD) highlighted the safety and expanded, evidence-based role for agents from three drug classes: the SGLT2 inhibitors, the GLP-1 receptor agonists, and the nonsteroidal mineralocorticoid receptor antagonists.

But this key take-away from the guideline also underscored the challenges for ensuring fair and affordable access among US patients to these practice-changing medications.

The impact of widespread adoption of these three drug classes into routine US management of people with diabetes and CKD “will be determined by how effective the health care system and its patients and clinicians are at overcoming individual and structural barriers,” write Milda Saunders, MD, and Neda Laiteerapong, MD, in an editorial that accompanied the publication of a synopsis of the 2022 guideline update in Annals of Internal Medicine.

The synopsis is an 11-page distillation of the full 128-page guideline released by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in 2022.

The recommendations in the 2022 guideline update “are exciting for their potential to change the natural history of CKD and diabetes, but their effect could be highly limited by barriers at multiple levels,” write Dr. Saunders and Dr. Laiteerapong, two internal medicine physicians at the University of Chicago.

“Without equitable implementation of the KDIGO 2022 guidelines there is a potential that clinical practice variation will increase and widen health inequities for minoritized people with CKD and diabetes,” they warn.
 

Generics to the rescue

One potentially effective, and likely imminent, way to level the prescribing field for patients with CKD and diabetes is for agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor, glucagonlike peptide-1 (GLP-1) receptor agonist, and nonsteroidal mineralocorticoid receptor antagonist classes to become available in generic formulations.

That should lower prices and thereby boost wider access and will likely occur fairly soon for at least two of the three drug classes, Dr. Laiteerapong predicts.

Some GLP-1 receptor agonists have already escaped patent exclusivity or will do so in 2023, she notes, including the anticipated ability of one drugmaker to start U.S. marketing of generic liraglutide by the end of 2023.

However, whether that manufacturer, Teva, proceeds with generic liraglutide “is a big question,” Dr. Laiteerapong said in an interview. She cited Teva’s history of failing to introduce a generic formulation of exenatide onto the U.S. market even though it has had a green light to do so since 2017.

The only nonsteroidal mineralocorticoid receptor antagonist now on the market is finerenone (Kerendia), which will not go off patent for several more years, but for some branded SGLT2 inhibitors, U.S. patents will expire in 2025. In addition, remogliflozin is an SGLT2 inhibitor that “may have already lost patent exclusivity,” noted Dr. Laiteerapong, although it has also never received U.S. marketing approval.

Dr. Laiteerapong expressed optimism that the overall trajectory of access is on the rise. “Many people have type 2 diabetes, and these drugs are in demand,” she noted. She also pointed to progress recently made on insulin affordability. “Things will get better as long as people advocate and argue for equity,” she maintained.
 

Incentivize formulary listings

Dr. Laiteerapong cited other approaches that could boost access to these medications, such as “creating incentives for pharmaceutical companies to ensure that [these drugs] are on formularies” of large, government-affiliated U.S. health insurance programs, such as Medicare Advantage plans, Medicare Part D, state Medicaid plans, and coverage through U.S. Veterans Affairs and the Tricare health insurance plans available to active members of the US military.

The editorial she coauthored with Dr. Saunders also calls for future collaborations among various medical societies to create “a more unified and streamlined set of recommendations” that benefits patients with diabetes, CKD, and multiple other chronic conditions.

“Over the last decade, we have seen more societies willing to present cooperative guidelines, as well as a surge in research on patients who live with multiple chronic conditions. There is momentum that will allow these different societies to work together,” Dr. Laiteerapong said.

Dr. Laiteerapong and Dr. Saunders have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The 2022 guideline update released by the KDIGO organization for managing people with diabetes and chronic kidney disease (CKD) highlighted the safety and expanded, evidence-based role for agents from three drug classes: the SGLT2 inhibitors, the GLP-1 receptor agonists, and the nonsteroidal mineralocorticoid receptor antagonists.

But this key take-away from the guideline also underscored the challenges for ensuring fair and affordable access among US patients to these practice-changing medications.

The impact of widespread adoption of these three drug classes into routine US management of people with diabetes and CKD “will be determined by how effective the health care system and its patients and clinicians are at overcoming individual and structural barriers,” write Milda Saunders, MD, and Neda Laiteerapong, MD, in an editorial that accompanied the publication of a synopsis of the 2022 guideline update in Annals of Internal Medicine.

The synopsis is an 11-page distillation of the full 128-page guideline released by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in 2022.

The recommendations in the 2022 guideline update “are exciting for their potential to change the natural history of CKD and diabetes, but their effect could be highly limited by barriers at multiple levels,” write Dr. Saunders and Dr. Laiteerapong, two internal medicine physicians at the University of Chicago.

“Without equitable implementation of the KDIGO 2022 guidelines there is a potential that clinical practice variation will increase and widen health inequities for minoritized people with CKD and diabetes,” they warn.
 

Generics to the rescue

One potentially effective, and likely imminent, way to level the prescribing field for patients with CKD and diabetes is for agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor, glucagonlike peptide-1 (GLP-1) receptor agonist, and nonsteroidal mineralocorticoid receptor antagonist classes to become available in generic formulations.

That should lower prices and thereby boost wider access and will likely occur fairly soon for at least two of the three drug classes, Dr. Laiteerapong predicts.

Some GLP-1 receptor agonists have already escaped patent exclusivity or will do so in 2023, she notes, including the anticipated ability of one drugmaker to start U.S. marketing of generic liraglutide by the end of 2023.

However, whether that manufacturer, Teva, proceeds with generic liraglutide “is a big question,” Dr. Laiteerapong said in an interview. She cited Teva’s history of failing to introduce a generic formulation of exenatide onto the U.S. market even though it has had a green light to do so since 2017.

The only nonsteroidal mineralocorticoid receptor antagonist now on the market is finerenone (Kerendia), which will not go off patent for several more years, but for some branded SGLT2 inhibitors, U.S. patents will expire in 2025. In addition, remogliflozin is an SGLT2 inhibitor that “may have already lost patent exclusivity,” noted Dr. Laiteerapong, although it has also never received U.S. marketing approval.

Dr. Laiteerapong expressed optimism that the overall trajectory of access is on the rise. “Many people have type 2 diabetes, and these drugs are in demand,” she noted. She also pointed to progress recently made on insulin affordability. “Things will get better as long as people advocate and argue for equity,” she maintained.
 

Incentivize formulary listings

Dr. Laiteerapong cited other approaches that could boost access to these medications, such as “creating incentives for pharmaceutical companies to ensure that [these drugs] are on formularies” of large, government-affiliated U.S. health insurance programs, such as Medicare Advantage plans, Medicare Part D, state Medicaid plans, and coverage through U.S. Veterans Affairs and the Tricare health insurance plans available to active members of the US military.

The editorial she coauthored with Dr. Saunders also calls for future collaborations among various medical societies to create “a more unified and streamlined set of recommendations” that benefits patients with diabetes, CKD, and multiple other chronic conditions.

“Over the last decade, we have seen more societies willing to present cooperative guidelines, as well as a surge in research on patients who live with multiple chronic conditions. There is momentum that will allow these different societies to work together,” Dr. Laiteerapong said.

Dr. Laiteerapong and Dr. Saunders have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.

“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”

Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.

However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”

The study was published online  in JAMA Cardiology.
 

Interpret with caution

Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.

According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.

• The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
• It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
• It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
• It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.

For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.

At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.

The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.

A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.

Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.

“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”

To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
 

‘Never too old or sick to benefit’

Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”

However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.

Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.

On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”

“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.

The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.

“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”

Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.

However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”

The study was published online  in JAMA Cardiology.
 

Interpret with caution

Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.

According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.

• The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
• It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
• It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
• It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.

For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.

At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.

The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.

A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.

Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.

“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”

To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
 

‘Never too old or sick to benefit’

Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”

However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.

Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.

On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”

“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.

The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.

“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”

Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.

However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”

The study was published online  in JAMA Cardiology.
 

Interpret with caution

Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.

According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.

• The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
• It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
• It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
• It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.

For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.

At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.

The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.

A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.

Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.

“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”

To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
 

‘Never too old or sick to benefit’

Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”

However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.

Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.

On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”

“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.

The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Due to advances in medicine, people are living longer with the aid of increased options for life-prolonging treatments. These treatment options may improve the quantity but not necessarily the quality of life.¹

Kidney failure can be treated with renal replacement therapy (dialysis or renal transplantation) or supportive care.² In 2017, the global prevalence of kidney failure was about 5.3 to 9.7 million.³ In the United States, about 500,000 patients are receiving maintenance dialysis for end-stage renal disease (ESRD), and about 1 in 4 will stop dialysis before death, coupled with hospice enrollment.⁴ ESRD is 2 times more prevalent among veterans than in nonveterans, which can be due in part to high rates of comorbid predisposing conditions, such as diabetes mellitus, hypertension, and advanced age, among others.⁵ The decision to discontinue dialysis and receive hospice care tends to be more difficult than choosing to withhold or forego dialysis.⁶

A study conducted among patients who were taken off hemodialysis before death reported that the 2 most common reasons for the withdrawal were acute medical complications and frailty.⁷ A retrospective study among patients with ESRD receiving hemodialysis highlighted the underutilization of hospice care in this patient population.⁸ The study also found that those patients who were aged > 75 years, had poor functional status, and had dialysis-related complications, such as sepsis and anemia, were more likely to elect withdrawal of hemodialysis. There was no difference in overall survival or quality of life among patients who were aged ≥ 75 years with multiple comorbidities and functional impairment who elected conservative management vs those who started dialysis.⁸ Long-term continuous dialysis has been associated with a lower quality of life, increased dependence on others, and a variety of symptoms, such as pain, nausea, insomnia, anxiety, or depression.⁹

Conservative Care vs Medical Paternalism

In the United States, it is unusual for patients with ESRD to choose conservative care, and supportive services are less available for those who do compared with patients with ESRD in Europe, Asia, Australia, and Canada.¹⁰ A study looking at a small number of US nephrologists has shown they may have limited experience in caring for patients who forego dialysis and they are not comfortable offering conservative management over dialysis.¹⁰ Another small study from Sweden also showed that many nephrologists do not feel prepared for end-of-life care and conversations.¹¹

Patients often rely on knowledgeable recommendations from medical experts. However, medical paternalism occurs when a physician makes decisions deemed to be in the patient’s best interest but are against the patient’s wishes or when the patient is unable to give their consent.¹² Hard paternalism occurs when the patient is competent to make their own medical decisions, while soft paternalism occurs when a patient is not competent to make their own medical decisions.¹³

Patient autonomy is widely recognized as an ethical principle in medicine. It recognizes patients as well-informed decision makers who may act without excessive influence to make intentional determinations on their own behalf.¹⁴ Autonomy can be exercised at any point during the health care process.¹² Although ethical and legal guidelines encourage physicians to recommend appropriate treatment, medical opinion cannot overrule the wishes of a competent patient who refuses treatment.¹²

Case Presentation

Mr. S presented to the emergency department at a US Department of Veterans Affairs (VA) medical center with abdominal pain from recurrent pancreatitis. The patient aged > 65 years had a history of depression, ESRD, and was receiving hemodialysis. A computed tomography scan revealed a new pancreatic mass, and he was referred to the palliative care (PC) department nurse practitioner (NP) for a goals-of-care discussion. PC was informed to assist with hospice care initiation: The patient elected a do-not-resuscitate (DNR) code status and hospice care.

At the consultation, Mr. S stated that he had decided to forego life-prolonging treatments, including hemodialysis, and declined further evaluation for his pancreatic mass. He shared a good understanding of concerns for malignancy with his mass but did not wish to pursue further diagnostics as he knew his life expectancy was very limited without dialysis. He had been dependent on hemodialysis for the past 10 years. He had briefly received hospice care 5 years before but changed his mind and decided to pursue standard care, including life-prolonging dialysis treatments. He reported no depression, suicidal ideation, or intentions of hastening his death. He stated that he was just physically tired from his ongoing dialysis, recurrent hospitalizations, and being repeatedly subjected to diagnostic tests. Mr. S added that he had discussed his plan with his family, including his son and sister-in-law who is married to his brother. Mr. S previously identified his brother as his surrogate decision maker.

Mr. S shared that his brother had sustained a traumatic brain injury and was now unable to engage in a meaningful conversation. He shared that his family supported his decision. He also recognized that with his debility, he would need inpatient hospice care. On finding out that Mr. S’s brother was no longer able to act as the surrogate decision maker, the PC NP asked whether he wanted her to contact his son to share the outcome of their visit. The patient declined, adding that he had discussed his care plans with his family and did not feel that his health care team needed to have additional discussions with them.

Mr. S also reported chronic, recurrent right upper quadrant pain. He was prescribed oxycodone 10 mg every 4 hours as needed; however, it did little to control his pain. He also reported generalized pruritus, a complication of his renal failure.

After 1 week, Mr. S was transferred to the inpatient hospice unit. At that time, he allowed the hospice team to contact his son for medical updates and identified him as the primary point of contact for the hospice team if the need arose to reach his family. Due to the restrictions imposed by the pandemic, Mr. S had virtual video visits with his family. Mr. S developed intermittent confusion and worsening fatigue over time. His son was informed of his deteriorating condition and visited his father. Mr. S died peacefully 2 days later with his family present.

Multidisciplinary Inputs on the Case

Medicine. In discussing the case with medicine, the PC NP was informed that the goals the patient had for his care, which included stopping dialysis, having a DNR code status and pursuing hospice care, along with the patient’s pain symptoms prompted the PC consultation. The resident also shared concerns about the patient’s refusal to have his surrogate decision maker and family contacted regarding his decisions for his care.

Palliative care. After meeting with the patient and assisting in identifying goals for care, the PC NP recommended initiation of hospice care in the hospital while the patient awaited transfer to the inpatient hospice unit. The PC NP also recommended a psychiatric evaluation to rule out untreated depression that might influence the patient’s decision making. A follow-up visit with nephrology was also recommended. Optimal management of his distressing physical symptoms was recommended, including prescribing hydromorphone instead of oxycodone for his pain and starting a topical emollient for pruritus.

Nephrology. The patient’s electronic health records (EHR) showed that he informed nephrology of his desire to pursue hospice care and that he decided against further dialysis, including as-needed dialysis for comfort. The records also indicated that the patient understood the consequences of discontinuing dialysis.

Psychiatry. The patient’s EHR also showed that during his psychiatric visits, Mr. S reported he had no thoughts of suicide, and it was against his spiritual beliefs. He said he made his own medical decisions and expressed that his health care team should not attempt to change his mind. He also said he understood that stopping dialysis could lead to early death. He stated he had a close relationship with his family and discussed his medical decisions with them. He was tearful at times when he talked about his family. Mr. S shared his frustration about repeatedly being asked the same questions on succeeding visits.

After evaluation, psychiatry diagnosed Mr. S with mood disorder with depressive features and he was prescribed methylphenidate 5 mg daily and sertraline 25 mg daily. They also recommended continuing to offer dialysis in a supportive manner since the patient had changed his mind about hospice in the past. However, psychiatry followed the patient daily for 5 days and concluded that his medical decisions were not clouded by mood symptoms.

Discussion

Patients who are aged > 65 years and on dialysis are more likely to experience higher rates of hospitalization, intensive care unit admission, procedures, and death in the hospital compared with patients who have cancer or heart failure. They also use hospice services less.¹⁵ Often this is not consistent with a patient’s wishes but may occur due to limited discussion of goals, values, and preferences between physician and patient.¹⁵ Many nephrologists do not engage in these conversations for fear of upsetting patients, their perceived lack of skill in prognostication and discussing the topic, or the lack of time to have the conversation.¹⁵ It is important to have an honest and open communication with patients that allows them to be fully informed as they make their medical decisions and exercise their autonomy.

Medicare hospice guidelines also are used to help determine hospice appropriateness among veterans in the VA. Medicare requires enrollees to discontinue disease-modifying treatment for the medical condition leading to their hospice diagnosis, which can result in late hospice referrals and shorter hospice stays.¹⁶ Even though hospice referrals for patients with ESRD have increased over time, they are still happening close to the time of death, and patients’ health care utilization near the end of life remains unchanged.¹⁶ According to Medicare, patients qualify for hospice care if they are terminally ill (defined as having a life expectancy of ≤ 6 months), choose comfort care over curative care for their terminal illness, and sign a statement electing hospice care over treatments for their terminal illness.¹⁷ A DNR order is not a condition for hospice admission.¹⁸

The VA defines hospice care as comfort care provided to patients with a terminal condition, a life expectancy of ≤ 6 months, and who are no longer seeking treatment other than those that are palliative.¹⁹ Based on his ESRD, Mr. S was qualified for hospice care, and his goals for care were consistent with the hospice philosophy. Most families of patients who elected to withdraw dialysis reported a good death, using the criteria of the duration of dying, discomfort, and psychosocial circumstances.²⁰

Role of HCPs

Health care practitioners (HCPs) are expected to help patients understand the risks and benefits of their choices and its alternative, align patients’ goals with those risks and benefits, and assist patients in making choices that promote their goals and autonomy.²¹ Family members are often not involved in medical decision making when patients have the capacity to make their own decisions.²² Patients will also have to give permission for protected health information to be shared with their family members.²² On the other hand, families have been shown to provide valuable emotional support to patients and are considered second patients themselves in the sense that they can be impacted by patients’ clinical situation.²² Families may also need care, time, and attention from HCPs.²²

Mr. S was found capable of making his own decisions, and part of that decision was that his family not to be present for the goals-of-care discussion. He added that he would discuss the care decisions with his family. At the time of registering for VA health care services, Mr. S had provided his health care team with his brother and sister-in-law’s emergency contact information as well as named his brother surrogate decision maker. As Mr. S’s condition was expected to rapidly decline wthout dialysis, the HCPs would be able to notify family members once his condition changed, including death.

Neuroplasticity changes can contribute to chronic pain that may also lead to depression.²³ Chronic pain and depression may involve the same brain structures, neurotransmitters, and signaling pathway.²³ Factors leading to chronic pain and depression include decreased availability of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine in the central nervous system, decreased brain-derived neurotrophic factor, inflammatory response, and increased glutamate activity.²³ Depression and hopelessness have been associated with the desire to hasten death among patients with a terminal illness.²⁴ Worse mental health has been associated with the desire to hasten death among patients who are older and functionally impaired.²⁵ It was important to optimize Mr. S’s treatment for pain and depression to ensure that these factors were not influencing his medical decisions.

With increasing recognition of the need to improve quality of life, health care utilization, and provide care consistent with patients’ goals in nephrology, the concept of renal PC is emerging but remains limited.²⁶ The need to improve supportive care or PC for patients starting on dialysis for ESRD is high as these patients tend to be older (aged > 75 years), have high rates of cardiovascular comorbidities, can have coexisting cognitive impairment and functional debility, and have an adjusted mortality rate of up to 32.5% within 1 year of starting dialysis.²⁶ Some ways to enhance renal PC programs include incorporating PC skill development and training within nephrology fellowships, educating patients with chronic and ESRD about PC and options for medical management without dialysis, and increasing the collaboration between nephrology and PC.²⁶

Outcomes and Implications

Respect for the ethical principle of autonomy is paramount in health care. Patients should be able to give informed consent for treatment decisions without undue influence from their HCPs and should be able to withdraw that consent at any point during treatment. Factors that may influence patients’ ability to make medical decisions should be considered, including untreated or poorly treated symptoms. The involvement of PC helps optimize symptom management, provide support, and assist in goals-of-care discussions. Advanced practice PC nurses can offer other members of the health care team additional information and support in end-of-life care. Family involvement should be encouraged even for patients who can make their own medical decisions for emotional support and to assist families in what could be a traumatic event, such as the loss of a loved one.

The desire to pursue a comfort-focused approach to terminal illness and stop disease-modifying treatments are criteria for hospice care. An interdisciplinary approach to end-of-life care is beneficial, and every specialty should be equipped to engage in honest communication and skillful prognostication. These conversations should start early in the course of a terminal illness. Multiple factors contribute to poor clinical outcomes among patients with ESRD even with renal replacement therapy, such as dialysis. There is a need to improve PC training in the field of nephrology.

Conclusions

Mr. S was able to choose to withdraw potentially life-prolonging treatments with the support of his family and HCPs. He was able to continue receiving high-quality care and treatment in accordance with his wishes and goals for his care. The provision of interdisciplinary care that focused on supporting him allowed for his peaceful and comfortable death.

Due to advances in medicine, people are living longer with the aid of increased options for life-prolonging treatments. These treatment options may improve the quantity but not necessarily the quality of life.¹

Kidney failure can be treated with renal replacement therapy (dialysis or renal transplantation) or supportive care.² In 2017, the global prevalence of kidney failure was about 5.3 to 9.7 million.³ In the United States, about 500,000 patients are receiving maintenance dialysis for end-stage renal disease (ESRD), and about 1 in 4 will stop dialysis before death, coupled with hospice enrollment.⁴ ESRD is 2 times more prevalent among veterans than in nonveterans, which can be due in part to high rates of comorbid predisposing conditions, such as diabetes mellitus, hypertension, and advanced age, among others.⁵ The decision to discontinue dialysis and receive hospice care tends to be more difficult than choosing to withhold or forego dialysis.⁶

A study conducted among patients who were taken off hemodialysis before death reported that the 2 most common reasons for the withdrawal were acute medical complications and frailty.⁷ A retrospective study among patients with ESRD receiving hemodialysis highlighted the underutilization of hospice care in this patient population.⁸ The study also found that those patients who were aged > 75 years, had poor functional status, and had dialysis-related complications, such as sepsis and anemia, were more likely to elect withdrawal of hemodialysis. There was no difference in overall survival or quality of life among patients who were aged ≥ 75 years with multiple comorbidities and functional impairment who elected conservative management vs those who started dialysis.⁸ Long-term continuous dialysis has been associated with a lower quality of life, increased dependence on others, and a variety of symptoms, such as pain, nausea, insomnia, anxiety, or depression.⁹

Conservative Care vs Medical Paternalism

In the United States, it is unusual for patients with ESRD to choose conservative care, and supportive services are less available for those who do compared with patients with ESRD in Europe, Asia, Australia, and Canada.¹⁰ A study looking at a small number of US nephrologists has shown they may have limited experience in caring for patients who forego dialysis and they are not comfortable offering conservative management over dialysis.¹⁰ Another small study from Sweden also showed that many nephrologists do not feel prepared for end-of-life care and conversations.¹¹

Patients often rely on knowledgeable recommendations from medical experts. However, medical paternalism occurs when a physician makes decisions deemed to be in the patient’s best interest but are against the patient’s wishes or when the patient is unable to give their consent.¹² Hard paternalism occurs when the patient is competent to make their own medical decisions, while soft paternalism occurs when a patient is not competent to make their own medical decisions.¹³

Patient autonomy is widely recognized as an ethical principle in medicine. It recognizes patients as well-informed decision makers who may act without excessive influence to make intentional determinations on their own behalf.¹⁴ Autonomy can be exercised at any point during the health care process.¹² Although ethical and legal guidelines encourage physicians to recommend appropriate treatment, medical opinion cannot overrule the wishes of a competent patient who refuses treatment.¹²

Case Presentation

Mr. S presented to the emergency department at a US Department of Veterans Affairs (VA) medical center with abdominal pain from recurrent pancreatitis. The patient aged > 65 years had a history of depression, ESRD, and was receiving hemodialysis. A computed tomography scan revealed a new pancreatic mass, and he was referred to the palliative care (PC) department nurse practitioner (NP) for a goals-of-care discussion. PC was informed to assist with hospice care initiation: The patient elected a do-not-resuscitate (DNR) code status and hospice care.

At the consultation, Mr. S stated that he had decided to forego life-prolonging treatments, including hemodialysis, and declined further evaluation for his pancreatic mass. He shared a good understanding of concerns for malignancy with his mass but did not wish to pursue further diagnostics as he knew his life expectancy was very limited without dialysis. He had been dependent on hemodialysis for the past 10 years. He had briefly received hospice care 5 years before but changed his mind and decided to pursue standard care, including life-prolonging dialysis treatments. He reported no depression, suicidal ideation, or intentions of hastening his death. He stated that he was just physically tired from his ongoing dialysis, recurrent hospitalizations, and being repeatedly subjected to diagnostic tests. Mr. S added that he had discussed his plan with his family, including his son and sister-in-law who is married to his brother. Mr. S previously identified his brother as his surrogate decision maker.

Mr. S shared that his brother had sustained a traumatic brain injury and was now unable to engage in a meaningful conversation. He shared that his family supported his decision. He also recognized that with his debility, he would need inpatient hospice care. On finding out that Mr. S’s brother was no longer able to act as the surrogate decision maker, the PC NP asked whether he wanted her to contact his son to share the outcome of their visit. The patient declined, adding that he had discussed his care plans with his family and did not feel that his health care team needed to have additional discussions with them.

Mr. S also reported chronic, recurrent right upper quadrant pain. He was prescribed oxycodone 10 mg every 4 hours as needed; however, it did little to control his pain. He also reported generalized pruritus, a complication of his renal failure.

After 1 week, Mr. S was transferred to the inpatient hospice unit. At that time, he allowed the hospice team to contact his son for medical updates and identified him as the primary point of contact for the hospice team if the need arose to reach his family. Due to the restrictions imposed by the pandemic, Mr. S had virtual video visits with his family. Mr. S developed intermittent confusion and worsening fatigue over time. His son was informed of his deteriorating condition and visited his father. Mr. S died peacefully 2 days later with his family present.

Multidisciplinary Inputs on the Case

Medicine. In discussing the case with medicine, the PC NP was informed that the goals the patient had for his care, which included stopping dialysis, having a DNR code status and pursuing hospice care, along with the patient’s pain symptoms prompted the PC consultation. The resident also shared concerns about the patient’s refusal to have his surrogate decision maker and family contacted regarding his decisions for his care.

Palliative care. After meeting with the patient and assisting in identifying goals for care, the PC NP recommended initiation of hospice care in the hospital while the patient awaited transfer to the inpatient hospice unit. The PC NP also recommended a psychiatric evaluation to rule out untreated depression that might influence the patient’s decision making. A follow-up visit with nephrology was also recommended. Optimal management of his distressing physical symptoms was recommended, including prescribing hydromorphone instead of oxycodone for his pain and starting a topical emollient for pruritus.

Nephrology. The patient’s electronic health records (EHR) showed that he informed nephrology of his desire to pursue hospice care and that he decided against further dialysis, including as-needed dialysis for comfort. The records also indicated that the patient understood the consequences of discontinuing dialysis.

Psychiatry. The patient’s EHR also showed that during his psychiatric visits, Mr. S reported he had no thoughts of suicide, and it was against his spiritual beliefs. He said he made his own medical decisions and expressed that his health care team should not attempt to change his mind. He also said he understood that stopping dialysis could lead to early death. He stated he had a close relationship with his family and discussed his medical decisions with them. He was tearful at times when he talked about his family. Mr. S shared his frustration about repeatedly being asked the same questions on succeeding visits.

After evaluation, psychiatry diagnosed Mr. S with mood disorder with depressive features and he was prescribed methylphenidate 5 mg daily and sertraline 25 mg daily. They also recommended continuing to offer dialysis in a supportive manner since the patient had changed his mind about hospice in the past. However, psychiatry followed the patient daily for 5 days and concluded that his medical decisions were not clouded by mood symptoms.

Discussion

Patients who are aged > 65 years and on dialysis are more likely to experience higher rates of hospitalization, intensive care unit admission, procedures, and death in the hospital compared with patients who have cancer or heart failure. They also use hospice services less.¹⁵ Often this is not consistent with a patient’s wishes but may occur due to limited discussion of goals, values, and preferences between physician and patient.¹⁵ Many nephrologists do not engage in these conversations for fear of upsetting patients, their perceived lack of skill in prognostication and discussing the topic, or the lack of time to have the conversation.¹⁵ It is important to have an honest and open communication with patients that allows them to be fully informed as they make their medical decisions and exercise their autonomy.

Medicare hospice guidelines also are used to help determine hospice appropriateness among veterans in the VA. Medicare requires enrollees to discontinue disease-modifying treatment for the medical condition leading to their hospice diagnosis, which can result in late hospice referrals and shorter hospice stays.¹⁶ Even though hospice referrals for patients with ESRD have increased over time, they are still happening close to the time of death, and patients’ health care utilization near the end of life remains unchanged.¹⁶ According to Medicare, patients qualify for hospice care if they are terminally ill (defined as having a life expectancy of ≤ 6 months), choose comfort care over curative care for their terminal illness, and sign a statement electing hospice care over treatments for their terminal illness.¹⁷ A DNR order is not a condition for hospice admission.¹⁸

The VA defines hospice care as comfort care provided to patients with a terminal condition, a life expectancy of ≤ 6 months, and who are no longer seeking treatment other than those that are palliative.¹⁹ Based on his ESRD, Mr. S was qualified for hospice care, and his goals for care were consistent with the hospice philosophy. Most families of patients who elected to withdraw dialysis reported a good death, using the criteria of the duration of dying, discomfort, and psychosocial circumstances.²⁰

Role of HCPs

Health care practitioners (HCPs) are expected to help patients understand the risks and benefits of their choices and its alternative, align patients’ goals with those risks and benefits, and assist patients in making choices that promote their goals and autonomy.²¹ Family members are often not involved in medical decision making when patients have the capacity to make their own decisions.²² Patients will also have to give permission for protected health information to be shared with their family members.²² On the other hand, families have been shown to provide valuable emotional support to patients and are considered second patients themselves in the sense that they can be impacted by patients’ clinical situation.²² Families may also need care, time, and attention from HCPs.²²

Mr. S was found capable of making his own decisions, and part of that decision was that his family not to be present for the goals-of-care discussion. He added that he would discuss the care decisions with his family. At the time of registering for VA health care services, Mr. S had provided his health care team with his brother and sister-in-law’s emergency contact information as well as named his brother surrogate decision maker. As Mr. S’s condition was expected to rapidly decline wthout dialysis, the HCPs would be able to notify family members once his condition changed, including death.

Neuroplasticity changes can contribute to chronic pain that may also lead to depression.²³ Chronic pain and depression may involve the same brain structures, neurotransmitters, and signaling pathway.²³ Factors leading to chronic pain and depression include decreased availability of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine in the central nervous system, decreased brain-derived neurotrophic factor, inflammatory response, and increased glutamate activity.²³ Depression and hopelessness have been associated with the desire to hasten death among patients with a terminal illness.²⁴ Worse mental health has been associated with the desire to hasten death among patients who are older and functionally impaired.²⁵ It was important to optimize Mr. S’s treatment for pain and depression to ensure that these factors were not influencing his medical decisions.

With increasing recognition of the need to improve quality of life, health care utilization, and provide care consistent with patients’ goals in nephrology, the concept of renal PC is emerging but remains limited.²⁶ The need to improve supportive care or PC for patients starting on dialysis for ESRD is high as these patients tend to be older (aged > 75 years), have high rates of cardiovascular comorbidities, can have coexisting cognitive impairment and functional debility, and have an adjusted mortality rate of up to 32.5% within 1 year of starting dialysis.²⁶ Some ways to enhance renal PC programs include incorporating PC skill development and training within nephrology fellowships, educating patients with chronic and ESRD about PC and options for medical management without dialysis, and increasing the collaboration between nephrology and PC.²⁶

Outcomes and Implications

Respect for the ethical principle of autonomy is paramount in health care. Patients should be able to give informed consent for treatment decisions without undue influence from their HCPs and should be able to withdraw that consent at any point during treatment. Factors that may influence patients’ ability to make medical decisions should be considered, including untreated or poorly treated symptoms. The involvement of PC helps optimize symptom management, provide support, and assist in goals-of-care discussions. Advanced practice PC nurses can offer other members of the health care team additional information and support in end-of-life care. Family involvement should be encouraged even for patients who can make their own medical decisions for emotional support and to assist families in what could be a traumatic event, such as the loss of a loved one.

The desire to pursue a comfort-focused approach to terminal illness and stop disease-modifying treatments are criteria for hospice care. An interdisciplinary approach to end-of-life care is beneficial, and every specialty should be equipped to engage in honest communication and skillful prognostication. These conversations should start early in the course of a terminal illness. Multiple factors contribute to poor clinical outcomes among patients with ESRD even with renal replacement therapy, such as dialysis. There is a need to improve PC training in the field of nephrology.

Conclusions

Mr. S was able to choose to withdraw potentially life-prolonging treatments with the support of his family and HCPs. He was able to continue receiving high-quality care and treatment in accordance with his wishes and goals for his care. The provision of interdisciplinary care that focused on supporting him allowed for his peaceful and comfortable death.

Due to advances in medicine, people are living longer with the aid of increased options for life-prolonging treatments. These treatment options may improve the quantity but not necessarily the quality of life.¹

Kidney failure can be treated with renal replacement therapy (dialysis or renal transplantation) or supportive care.² In 2017, the global prevalence of kidney failure was about 5.3 to 9.7 million.³ In the United States, about 500,000 patients are receiving maintenance dialysis for end-stage renal disease (ESRD), and about 1 in 4 will stop dialysis before death, coupled with hospice enrollment.⁴ ESRD is 2 times more prevalent among veterans than in nonveterans, which can be due in part to high rates of comorbid predisposing conditions, such as diabetes mellitus, hypertension, and advanced age, among others.⁵ The decision to discontinue dialysis and receive hospice care tends to be more difficult than choosing to withhold or forego dialysis.⁶

A study conducted among patients who were taken off hemodialysis before death reported that the 2 most common reasons for the withdrawal were acute medical complications and frailty.⁷ A retrospective study among patients with ESRD receiving hemodialysis highlighted the underutilization of hospice care in this patient population.⁸ The study also found that those patients who were aged > 75 years, had poor functional status, and had dialysis-related complications, such as sepsis and anemia, were more likely to elect withdrawal of hemodialysis. There was no difference in overall survival or quality of life among patients who were aged ≥ 75 years with multiple comorbidities and functional impairment who elected conservative management vs those who started dialysis.⁸ Long-term continuous dialysis has been associated with a lower quality of life, increased dependence on others, and a variety of symptoms, such as pain, nausea, insomnia, anxiety, or depression.⁹

Conservative Care vs Medical Paternalism

In the United States, it is unusual for patients with ESRD to choose conservative care, and supportive services are less available for those who do compared with patients with ESRD in Europe, Asia, Australia, and Canada.¹⁰ A study looking at a small number of US nephrologists has shown they may have limited experience in caring for patients who forego dialysis and they are not comfortable offering conservative management over dialysis.¹⁰ Another small study from Sweden also showed that many nephrologists do not feel prepared for end-of-life care and conversations.¹¹

Patients often rely on knowledgeable recommendations from medical experts. However, medical paternalism occurs when a physician makes decisions deemed to be in the patient’s best interest but are against the patient’s wishes or when the patient is unable to give their consent.¹² Hard paternalism occurs when the patient is competent to make their own medical decisions, while soft paternalism occurs when a patient is not competent to make their own medical decisions.¹³

Patient autonomy is widely recognized as an ethical principle in medicine. It recognizes patients as well-informed decision makers who may act without excessive influence to make intentional determinations on their own behalf.¹⁴ Autonomy can be exercised at any point during the health care process.¹² Although ethical and legal guidelines encourage physicians to recommend appropriate treatment, medical opinion cannot overrule the wishes of a competent patient who refuses treatment.¹²

Case Presentation

Mr. S presented to the emergency department at a US Department of Veterans Affairs (VA) medical center with abdominal pain from recurrent pancreatitis. The patient aged > 65 years had a history of depression, ESRD, and was receiving hemodialysis. A computed tomography scan revealed a new pancreatic mass, and he was referred to the palliative care (PC) department nurse practitioner (NP) for a goals-of-care discussion. PC was informed to assist with hospice care initiation: The patient elected a do-not-resuscitate (DNR) code status and hospice care.

At the consultation, Mr. S stated that he had decided to forego life-prolonging treatments, including hemodialysis, and declined further evaluation for his pancreatic mass. He shared a good understanding of concerns for malignancy with his mass but did not wish to pursue further diagnostics as he knew his life expectancy was very limited without dialysis. He had been dependent on hemodialysis for the past 10 years. He had briefly received hospice care 5 years before but changed his mind and decided to pursue standard care, including life-prolonging dialysis treatments. He reported no depression, suicidal ideation, or intentions of hastening his death. He stated that he was just physically tired from his ongoing dialysis, recurrent hospitalizations, and being repeatedly subjected to diagnostic tests. Mr. S added that he had discussed his plan with his family, including his son and sister-in-law who is married to his brother. Mr. S previously identified his brother as his surrogate decision maker.

Mr. S shared that his brother had sustained a traumatic brain injury and was now unable to engage in a meaningful conversation. He shared that his family supported his decision. He also recognized that with his debility, he would need inpatient hospice care. On finding out that Mr. S’s brother was no longer able to act as the surrogate decision maker, the PC NP asked whether he wanted her to contact his son to share the outcome of their visit. The patient declined, adding that he had discussed his care plans with his family and did not feel that his health care team needed to have additional discussions with them.

Mr. S also reported chronic, recurrent right upper quadrant pain. He was prescribed oxycodone 10 mg every 4 hours as needed; however, it did little to control his pain. He also reported generalized pruritus, a complication of his renal failure.

After 1 week, Mr. S was transferred to the inpatient hospice unit. At that time, he allowed the hospice team to contact his son for medical updates and identified him as the primary point of contact for the hospice team if the need arose to reach his family. Due to the restrictions imposed by the pandemic, Mr. S had virtual video visits with his family. Mr. S developed intermittent confusion and worsening fatigue over time. His son was informed of his deteriorating condition and visited his father. Mr. S died peacefully 2 days later with his family present.

Multidisciplinary Inputs on the Case

Medicine. In discussing the case with medicine, the PC NP was informed that the goals the patient had for his care, which included stopping dialysis, having a DNR code status and pursuing hospice care, along with the patient’s pain symptoms prompted the PC consultation. The resident also shared concerns about the patient’s refusal to have his surrogate decision maker and family contacted regarding his decisions for his care.

Palliative care. After meeting with the patient and assisting in identifying goals for care, the PC NP recommended initiation of hospice care in the hospital while the patient awaited transfer to the inpatient hospice unit. The PC NP also recommended a psychiatric evaluation to rule out untreated depression that might influence the patient’s decision making. A follow-up visit with nephrology was also recommended. Optimal management of his distressing physical symptoms was recommended, including prescribing hydromorphone instead of oxycodone for his pain and starting a topical emollient for pruritus.

Nephrology. The patient’s electronic health records (EHR) showed that he informed nephrology of his desire to pursue hospice care and that he decided against further dialysis, including as-needed dialysis for comfort. The records also indicated that the patient understood the consequences of discontinuing dialysis.

Psychiatry. The patient’s EHR also showed that during his psychiatric visits, Mr. S reported he had no thoughts of suicide, and it was against his spiritual beliefs. He said he made his own medical decisions and expressed that his health care team should not attempt to change his mind. He also said he understood that stopping dialysis could lead to early death. He stated he had a close relationship with his family and discussed his medical decisions with them. He was tearful at times when he talked about his family. Mr. S shared his frustration about repeatedly being asked the same questions on succeeding visits.

After evaluation, psychiatry diagnosed Mr. S with mood disorder with depressive features and he was prescribed methylphenidate 5 mg daily and sertraline 25 mg daily. They also recommended continuing to offer dialysis in a supportive manner since the patient had changed his mind about hospice in the past. However, psychiatry followed the patient daily for 5 days and concluded that his medical decisions were not clouded by mood symptoms.

Discussion

Patients who are aged > 65 years and on dialysis are more likely to experience higher rates of hospitalization, intensive care unit admission, procedures, and death in the hospital compared with patients who have cancer or heart failure. They also use hospice services less.¹⁵ Often this is not consistent with a patient’s wishes but may occur due to limited discussion of goals, values, and preferences between physician and patient.¹⁵ Many nephrologists do not engage in these conversations for fear of upsetting patients, their perceived lack of skill in prognostication and discussing the topic, or the lack of time to have the conversation.¹⁵ It is important to have an honest and open communication with patients that allows them to be fully informed as they make their medical decisions and exercise their autonomy.

Medicare hospice guidelines also are used to help determine hospice appropriateness among veterans in the VA. Medicare requires enrollees to discontinue disease-modifying treatment for the medical condition leading to their hospice diagnosis, which can result in late hospice referrals and shorter hospice stays.¹⁶ Even though hospice referrals for patients with ESRD have increased over time, they are still happening close to the time of death, and patients’ health care utilization near the end of life remains unchanged.¹⁶ According to Medicare, patients qualify for hospice care if they are terminally ill (defined as having a life expectancy of ≤ 6 months), choose comfort care over curative care for their terminal illness, and sign a statement electing hospice care over treatments for their terminal illness.¹⁷ A DNR order is not a condition for hospice admission.¹⁸

The VA defines hospice care as comfort care provided to patients with a terminal condition, a life expectancy of ≤ 6 months, and who are no longer seeking treatment other than those that are palliative.¹⁹ Based on his ESRD, Mr. S was qualified for hospice care, and his goals for care were consistent with the hospice philosophy. Most families of patients who elected to withdraw dialysis reported a good death, using the criteria of the duration of dying, discomfort, and psychosocial circumstances.²⁰

Role of HCPs

Health care practitioners (HCPs) are expected to help patients understand the risks and benefits of their choices and its alternative, align patients’ goals with those risks and benefits, and assist patients in making choices that promote their goals and autonomy.²¹ Family members are often not involved in medical decision making when patients have the capacity to make their own decisions.²² Patients will also have to give permission for protected health information to be shared with their family members.²² On the other hand, families have been shown to provide valuable emotional support to patients and are considered second patients themselves in the sense that they can be impacted by patients’ clinical situation.²² Families may also need care, time, and attention from HCPs.²²

Mr. S was found capable of making his own decisions, and part of that decision was that his family not to be present for the goals-of-care discussion. He added that he would discuss the care decisions with his family. At the time of registering for VA health care services, Mr. S had provided his health care team with his brother and sister-in-law’s emergency contact information as well as named his brother surrogate decision maker. As Mr. S’s condition was expected to rapidly decline wthout dialysis, the HCPs would be able to notify family members once his condition changed, including death.

Neuroplasticity changes can contribute to chronic pain that may also lead to depression.²³ Chronic pain and depression may involve the same brain structures, neurotransmitters, and signaling pathway.²³ Factors leading to chronic pain and depression include decreased availability of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine in the central nervous system, decreased brain-derived neurotrophic factor, inflammatory response, and increased glutamate activity.²³ Depression and hopelessness have been associated with the desire to hasten death among patients with a terminal illness.²⁴ Worse mental health has been associated with the desire to hasten death among patients who are older and functionally impaired.²⁵ It was important to optimize Mr. S’s treatment for pain and depression to ensure that these factors were not influencing his medical decisions.

With increasing recognition of the need to improve quality of life, health care utilization, and provide care consistent with patients’ goals in nephrology, the concept of renal PC is emerging but remains limited.²⁶ The need to improve supportive care or PC for patients starting on dialysis for ESRD is high as these patients tend to be older (aged > 75 years), have high rates of cardiovascular comorbidities, can have coexisting cognitive impairment and functional debility, and have an adjusted mortality rate of up to 32.5% within 1 year of starting dialysis.²⁶ Some ways to enhance renal PC programs include incorporating PC skill development and training within nephrology fellowships, educating patients with chronic and ESRD about PC and options for medical management without dialysis, and increasing the collaboration between nephrology and PC.²⁶

Outcomes and Implications

Respect for the ethical principle of autonomy is paramount in health care. Patients should be able to give informed consent for treatment decisions without undue influence from their HCPs and should be able to withdraw that consent at any point during treatment. Factors that may influence patients’ ability to make medical decisions should be considered, including untreated or poorly treated symptoms. The involvement of PC helps optimize symptom management, provide support, and assist in goals-of-care discussions. Advanced practice PC nurses can offer other members of the health care team additional information and support in end-of-life care. Family involvement should be encouraged even for patients who can make their own medical decisions for emotional support and to assist families in what could be a traumatic event, such as the loss of a loved one.

The desire to pursue a comfort-focused approach to terminal illness and stop disease-modifying treatments are criteria for hospice care. An interdisciplinary approach to end-of-life care is beneficial, and every specialty should be equipped to engage in honest communication and skillful prognostication. These conversations should start early in the course of a terminal illness. Multiple factors contribute to poor clinical outcomes among patients with ESRD even with renal replacement therapy, such as dialysis. There is a need to improve PC training in the field of nephrology.

Conclusions

Mr. S was able to choose to withdraw potentially life-prolonging treatments with the support of his family and HCPs. He was able to continue receiving high-quality care and treatment in accordance with his wishes and goals for his care. The provision of interdisciplinary care that focused on supporting him allowed for his peaceful and comfortable death.

Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.

Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.

“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.

The findings were published online in JAMA Network Open.
 

Medicare beneficiaries

Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.

The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.

Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.

Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.

“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.

The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.

For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.

The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.

Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
 

Unanswered questions

After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).

The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.

As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).

Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).

A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.

“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
 

Stimulators instead of inhibitors?

The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.

But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.

Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.

“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.

However, “we’re not suggesting [that all patients] have their regimen switched,” he added.

That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.

As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.

The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
 

‘More convincing’

Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.

“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.

However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.

As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.

For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.

He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.

Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.

“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.

Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.

Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.

She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”

The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.

Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.

“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.

The findings were published online in JAMA Network Open.
 

Medicare beneficiaries

Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.

The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.

Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.

Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.

“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.

The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.

For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.

The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.

Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
 

Unanswered questions

After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).

The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.

As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).

Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).

A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.

“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
 

Stimulators instead of inhibitors?

The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.

But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.

Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.

“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.

However, “we’re not suggesting [that all patients] have their regimen switched,” he added.

That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.

As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.

The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
 

‘More convincing’

Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.

“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.

However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.

As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.

For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.

He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.

Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.

“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.

Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.

Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.

She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”

The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.

Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.

“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.

The findings were published online in JAMA Network Open.
 

Medicare beneficiaries

Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.

The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.

Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.

Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.

“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.

The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.

For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.

The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.

Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
 

Unanswered questions

After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).

The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.

As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).

Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).

A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.

“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
 

Stimulators instead of inhibitors?

The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.

But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.

Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.

“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.

However, “we’re not suggesting [that all patients] have their regimen switched,” he added.

That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.

As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.

The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
 

‘More convincing’

Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.

“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.

However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.

As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.

For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.

He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.

Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.

“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.

Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.

Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.

She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”

The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.

The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.

“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.

“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
 

Background

Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”

Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
 

Study results

The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).

Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).

The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.

Prolonged or heavy menstrual periods were reported by 37.3% of female patients.

Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.

Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.

Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.

Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.

“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”

Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.

“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”

According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
 

Limitation

The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.

The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.

*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen. 

A version of this article first appeared on Medscape.com.

A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.

The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.

“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.

“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
 

Background

Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”

Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
 

Study results

The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).

Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).

The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.

Prolonged or heavy menstrual periods were reported by 37.3% of female patients.

Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.

Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.

Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.

Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.

“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”

Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.

“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”

According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
 

Limitation

The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.

The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.

*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen. 

A version of this article first appeared on Medscape.com.

A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.

The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.

“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.

“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
 

Background

Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”

Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
 

Study results

The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).

Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).

The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.

Prolonged or heavy menstrual periods were reported by 37.3% of female patients.

Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.

Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.

Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.

Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.

“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”

Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.

“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”

According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
 

Limitation

The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.

The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.

*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen. 

A version of this article first appeared on Medscape.com.

Reporting on chronic lymphocytic leukemia (CLL) highlights from the American Society of Hematology meetings, Dr Nicholas Burwick of the Puget Sound Veterans Administration Health Care System discusses studies ranging from first-line treatment to options for relapsed/refractory disease. 

Dr Burwick cites a Veterans Health Administration study documenting the increasing movement toward novel agents as frontline treatment in CLL since 2018, and the emerging trend toward use of second-generation Bruton tyrosine kinase (BTK) inhibitors. 

Next, he discusses a study examining the frontline combination of ibrutinib and venetoclax, which may help overcome poor prognosis associated with unmutated IGHV CLL. 

In another study, the combination of venetoclax and ibrutinib was examined in high-risk patients treated with ibrutinib for 1 year. The results showed the combination deepens responses and even offers the potential for discontinuation of therapy. 

Turning to relapsed/refractory disease, Dr Burwick highlights the latest results of pirtobrutinib, which continues to show efficacy among heavily pretreated patients regardless of prior therapy, reason for discontinuation, or mutation status. 

Finally, he points to zanubrutinib, which demonstrated superiority to ibrutinib in a long-range study of progression-free survival.  

--

Nicholas R. Burwick, MD, Associate Professor, Division of Hematology, Department of Medicine, University of Washington; Attending Physician, Division of Hematology, Department of Medicine, Puget Sound VA Health Care System, Seattle, Washington 

Nicholas R. Burwick, MD, has disclosed no relevant financial relationships. 

Reporting on chronic lymphocytic leukemia (CLL) highlights from the American Society of Hematology meetings, Dr Nicholas Burwick of the Puget Sound Veterans Administration Health Care System discusses studies ranging from first-line treatment to options for relapsed/refractory disease. 

Dr Burwick cites a Veterans Health Administration study documenting the increasing movement toward novel agents as frontline treatment in CLL since 2018, and the emerging trend toward use of second-generation Bruton tyrosine kinase (BTK) inhibitors. 

Next, he discusses a study examining the frontline combination of ibrutinib and venetoclax, which may help overcome poor prognosis associated with unmutated IGHV CLL. 

In another study, the combination of venetoclax and ibrutinib was examined in high-risk patients treated with ibrutinib for 1 year. The results showed the combination deepens responses and even offers the potential for discontinuation of therapy. 

Turning to relapsed/refractory disease, Dr Burwick highlights the latest results of pirtobrutinib, which continues to show efficacy among heavily pretreated patients regardless of prior therapy, reason for discontinuation, or mutation status. 

Finally, he points to zanubrutinib, which demonstrated superiority to ibrutinib in a long-range study of progression-free survival.  

--

Nicholas R. Burwick, MD, Associate Professor, Division of Hematology, Department of Medicine, University of Washington; Attending Physician, Division of Hematology, Department of Medicine, Puget Sound VA Health Care System, Seattle, Washington 

Nicholas R. Burwick, MD, has disclosed no relevant financial relationships. 

Reporting on chronic lymphocytic leukemia (CLL) highlights from the American Society of Hematology meetings, Dr Nicholas Burwick of the Puget Sound Veterans Administration Health Care System discusses studies ranging from first-line treatment to options for relapsed/refractory disease. 

Dr Burwick cites a Veterans Health Administration study documenting the increasing movement toward novel agents as frontline treatment in CLL since 2018, and the emerging trend toward use of second-generation Bruton tyrosine kinase (BTK) inhibitors. 

Next, he discusses a study examining the frontline combination of ibrutinib and venetoclax, which may help overcome poor prognosis associated with unmutated IGHV CLL. 

In another study, the combination of venetoclax and ibrutinib was examined in high-risk patients treated with ibrutinib for 1 year. The results showed the combination deepens responses and even offers the potential for discontinuation of therapy. 

Turning to relapsed/refractory disease, Dr Burwick highlights the latest results of pirtobrutinib, which continues to show efficacy among heavily pretreated patients regardless of prior therapy, reason for discontinuation, or mutation status. 

Finally, he points to zanubrutinib, which demonstrated superiority to ibrutinib in a long-range study of progression-free survival.  

--

Nicholas R. Burwick, MD, Associate Professor, Division of Hematology, Department of Medicine, University of Washington; Attending Physician, Division of Hematology, Department of Medicine, Puget Sound VA Health Care System, Seattle, Washington 

Nicholas R. Burwick, MD, has disclosed no relevant financial relationships. 

You discuss and decide on the best course of treatment for your patients, write prescriptions, and recommend lifestyle modifications to enhance treatment outcomes and overall wellness. But once they leave your office, following through is up to the patient. What happens when they don’t listen?

The term “nonadherent” has gradually replaced “noncompliant” in the physician lexicon as a nod to the evolving doctor-patient relationship. Noncompliance implies that a patient isn’t following their doctor’s orders. Adherence, on the other hand, is a measure of how closely your patient’s behavior matches the recommendations you’ve made. It’s a subtle difference but an important distinction in approaching care.

“Noncompliance is inherently negative feedback to the patient, whereas there’s a reason for nonadherence, and it’s usually external,” said Sharon Rabinovitz, MD, president of the Georgia Academy of Family Physicians.
 

Why won’t patients listen?

The reasons behind a patient’s nonadherence are multifaceted, but they are often driven by social determinants of health, such as transportation, poor health literacy, finances, and lack of access to pharmacies.

Other times, patients don’t want to take medicine, don’t prioritize their health, or they find the dietary and lifestyle modifications doctors suggest too hard to make or they struggle at losing weight, eating more healthfully, or cutting back on alcohol, for instance.

“When you come down to it, the big hindrance of it all is cost and the ability for the patient to be able to afford some of the things that we think they should be able to do,” said Teresa Lovins, MD, a physician in private practice Columbus, Ind., and a member of the board of directors of the American Academy of Family Physicians.

Another common deterrent to treatment is undesired side effects that a patient may not want to mention.

“For example, a lot of patients who are taking antidepressants have sexual dysfunction associated with those medications,” said Dr. Rabinovitz. “If you don’t ask the right questions, you’re not going to be able to fully assess the experience the patient is having and a reason why they might not take it [the medication].”

Much nonadherence is intentional and is based on experience, belief systems, and knowledge. For example, the American Medical Association finds that patients may not understand why they need a certain treatment (and therefore dismiss it), or they may be overloaded with multiple medications, fear dependency on a drug, have a mistrust of pharmaceutical companies or the medical system as a whole, or have symptoms of depression that make taking healthy actions more difficult. In addition, patients may be unable to afford their medication, or their lack of symptoms may lead them to believe they don’t really need the prescription, as occurs with disorders such as hypertension or high cholesterol.

“In my training, we did something called Balint training, where we would get together as a group with attendings and discuss cases that were difficult from a biopsychosocial perspective and consider all the factors in the patient perspective, including family dynamics, social systems, and economic realities,” said Russell Blackwelder, MD, director of geriatric education and associate professor of family medicine at the Medical University of South Carolina, Charleston.

“That training was, for me, very helpful for opening up and being more empathetic and really examining the patient’s point of view and everything that impacts them.”

Dr. Lovins agreed that it’s crucial to establish a good rapport and build mutual trust.

“If you don’t know the patient, you have a harder time asking the right questions to get to the meat of why they’re not taking their medicine or what they’re not doing to help their health,” she said. “It takes a little bit of trust on both parts to get to that question that really gets to the heart of why they’re not doing what you’re asking them to do.”
 

How to encourage adherence

Although there may not be a one-size-fits-all approach for achieving general adherence or adherence to a medication regimen, some methods may increase success.

Kenneth Zweig, MD, an internist at Northern Virginia Family Practice Associates, Alexandria, said that convincing patients to make one small change that they can sustain can get the ball rolling.

“I had one patient who was very overweight and had high blood pressure, high cholesterol, back pain, insomnia, and depression, who was also drinking three to four beers a night,” Dr. Zweig said. “After a long discussion, I challenged him to stop all alcohol for 1 week. At the end of the week, he noticed that he slept better, lost some weight, had lower blood pressure, and had more energy. Once he saw the benefits of this one change, he was motivated to improve other aspects of his health as well. He improved his diet, started exercising, and lost over 50 pounds. He has persisted with these lifestyle changes ever since.”

A team-based approach may also increase treatment understanding and adherence. In one older study, patients who were assigned to team-based care, including care by pharmacists, were significantly more adherent to medication regimens. Patients were more comfortable asking questions and raising concerns when they felt their treatment plan was a collaboration between several providers and themselves.

Dr. Lovins said to always approach the patient with a positive. “Say, what can we do together to make this work? What are your questions about this medication? And try and focus on the positive things that you can change instead of leaving the patient with a negative feeling or that you’re angry with them or that you’re unhappy with their choices. Patients respond better when they are treated as part of the team.”

Fear of judgment can also be a barrier to honesty between patients and their doctors. Shame creates a reluctance to admit nonadherence. Dr. Lovins said in an interview that it’s the physician’s responsibility to create a blame-free space for patients to speak openly about their struggles with treatment and reasons for nonadherence.
 

When should you redirect care?

Ultimately, the goal is good care and treatment of disease. However, if you and your patient are at an impasse and progress is stalling or failing, it may be appropriate to encourage the patient to seek care elsewhere.

“Just like any relationship, some physician-patient relationships are just not a good fit,” said Dr. Blackwelder. And this may be the reason why the patient is nonadherent — something between the two of you doesn’t click.

While there are ethical considerations for this decision, most medical boards have guidelines on how to go about it, Dr. Blackwelder said in an interview. “In the state of South Carolina, we have to be available to provide urgent coverage for at least 30 days and notify the patient in writing that they need to find somebody else and to help them find somebody else if we can.”

Just as with care, a clear conversation is the best practice if you’re proposing a potential shift away from a physician-patient relationship. You might say: We’re not making the kind of progress I’d like to see, and I’m wondering if you think working with another doctor may help you.

“The most important thing is being very honest and transparent with the patient that you’re concerned you’re not making the appropriate strides forward,” said Dr. Rabinovitz. Then you can ask, ‘Am I the right doctor to help you reach your goals? And if not, how can I help you get to where you need to be?’ ”

A version of this article first appeared on Medscape.com.

You discuss and decide on the best course of treatment for your patients, write prescriptions, and recommend lifestyle modifications to enhance treatment outcomes and overall wellness. But once they leave your office, following through is up to the patient. What happens when they don’t listen?

The term “nonadherent” has gradually replaced “noncompliant” in the physician lexicon as a nod to the evolving doctor-patient relationship. Noncompliance implies that a patient isn’t following their doctor’s orders. Adherence, on the other hand, is a measure of how closely your patient’s behavior matches the recommendations you’ve made. It’s a subtle difference but an important distinction in approaching care.

“Noncompliance is inherently negative feedback to the patient, whereas there’s a reason for nonadherence, and it’s usually external,” said Sharon Rabinovitz, MD, president of the Georgia Academy of Family Physicians.
 

Why won’t patients listen?

The reasons behind a patient’s nonadherence are multifaceted, but they are often driven by social determinants of health, such as transportation, poor health literacy, finances, and lack of access to pharmacies.

Other times, patients don’t want to take medicine, don’t prioritize their health, or they find the dietary and lifestyle modifications doctors suggest too hard to make or they struggle at losing weight, eating more healthfully, or cutting back on alcohol, for instance.

“When you come down to it, the big hindrance of it all is cost and the ability for the patient to be able to afford some of the things that we think they should be able to do,” said Teresa Lovins, MD, a physician in private practice Columbus, Ind., and a member of the board of directors of the American Academy of Family Physicians.

Another common deterrent to treatment is undesired side effects that a patient may not want to mention.

“For example, a lot of patients who are taking antidepressants have sexual dysfunction associated with those medications,” said Dr. Rabinovitz. “If you don’t ask the right questions, you’re not going to be able to fully assess the experience the patient is having and a reason why they might not take it [the medication].”

Much nonadherence is intentional and is based on experience, belief systems, and knowledge. For example, the American Medical Association finds that patients may not understand why they need a certain treatment (and therefore dismiss it), or they may be overloaded with multiple medications, fear dependency on a drug, have a mistrust of pharmaceutical companies or the medical system as a whole, or have symptoms of depression that make taking healthy actions more difficult. In addition, patients may be unable to afford their medication, or their lack of symptoms may lead them to believe they don’t really need the prescription, as occurs with disorders such as hypertension or high cholesterol.

“In my training, we did something called Balint training, where we would get together as a group with attendings and discuss cases that were difficult from a biopsychosocial perspective and consider all the factors in the patient perspective, including family dynamics, social systems, and economic realities,” said Russell Blackwelder, MD, director of geriatric education and associate professor of family medicine at the Medical University of South Carolina, Charleston.

“That training was, for me, very helpful for opening up and being more empathetic and really examining the patient’s point of view and everything that impacts them.”

Dr. Lovins agreed that it’s crucial to establish a good rapport and build mutual trust.

“If you don’t know the patient, you have a harder time asking the right questions to get to the meat of why they’re not taking their medicine or what they’re not doing to help their health,” she said. “It takes a little bit of trust on both parts to get to that question that really gets to the heart of why they’re not doing what you’re asking them to do.”
 

How to encourage adherence

Although there may not be a one-size-fits-all approach for achieving general adherence or adherence to a medication regimen, some methods may increase success.

Kenneth Zweig, MD, an internist at Northern Virginia Family Practice Associates, Alexandria, said that convincing patients to make one small change that they can sustain can get the ball rolling.

“I had one patient who was very overweight and had high blood pressure, high cholesterol, back pain, insomnia, and depression, who was also drinking three to four beers a night,” Dr. Zweig said. “After a long discussion, I challenged him to stop all alcohol for 1 week. At the end of the week, he noticed that he slept better, lost some weight, had lower blood pressure, and had more energy. Once he saw the benefits of this one change, he was motivated to improve other aspects of his health as well. He improved his diet, started exercising, and lost over 50 pounds. He has persisted with these lifestyle changes ever since.”

A team-based approach may also increase treatment understanding and adherence. In one older study, patients who were assigned to team-based care, including care by pharmacists, were significantly more adherent to medication regimens. Patients were more comfortable asking questions and raising concerns when they felt their treatment plan was a collaboration between several providers and themselves.

Dr. Lovins said to always approach the patient with a positive. “Say, what can we do together to make this work? What are your questions about this medication? And try and focus on the positive things that you can change instead of leaving the patient with a negative feeling or that you’re angry with them or that you’re unhappy with their choices. Patients respond better when they are treated as part of the team.”

Fear of judgment can also be a barrier to honesty between patients and their doctors. Shame creates a reluctance to admit nonadherence. Dr. Lovins said in an interview that it’s the physician’s responsibility to create a blame-free space for patients to speak openly about their struggles with treatment and reasons for nonadherence.
 

When should you redirect care?

Ultimately, the goal is good care and treatment of disease. However, if you and your patient are at an impasse and progress is stalling or failing, it may be appropriate to encourage the patient to seek care elsewhere.

“Just like any relationship, some physician-patient relationships are just not a good fit,” said Dr. Blackwelder. And this may be the reason why the patient is nonadherent — something between the two of you doesn’t click.

While there are ethical considerations for this decision, most medical boards have guidelines on how to go about it, Dr. Blackwelder said in an interview. “In the state of South Carolina, we have to be available to provide urgent coverage for at least 30 days and notify the patient in writing that they need to find somebody else and to help them find somebody else if we can.”

Just as with care, a clear conversation is the best practice if you’re proposing a potential shift away from a physician-patient relationship. You might say: We’re not making the kind of progress I’d like to see, and I’m wondering if you think working with another doctor may help you.

“The most important thing is being very honest and transparent with the patient that you’re concerned you’re not making the appropriate strides forward,” said Dr. Rabinovitz. Then you can ask, ‘Am I the right doctor to help you reach your goals? And if not, how can I help you get to where you need to be?’ ”

A version of this article first appeared on Medscape.com.

You discuss and decide on the best course of treatment for your patients, write prescriptions, and recommend lifestyle modifications to enhance treatment outcomes and overall wellness. But once they leave your office, following through is up to the patient. What happens when they don’t listen?

The term “nonadherent” has gradually replaced “noncompliant” in the physician lexicon as a nod to the evolving doctor-patient relationship. Noncompliance implies that a patient isn’t following their doctor’s orders. Adherence, on the other hand, is a measure of how closely your patient’s behavior matches the recommendations you’ve made. It’s a subtle difference but an important distinction in approaching care.

“Noncompliance is inherently negative feedback to the patient, whereas there’s a reason for nonadherence, and it’s usually external,” said Sharon Rabinovitz, MD, president of the Georgia Academy of Family Physicians.
 

Why won’t patients listen?

The reasons behind a patient’s nonadherence are multifaceted, but they are often driven by social determinants of health, such as transportation, poor health literacy, finances, and lack of access to pharmacies.

Other times, patients don’t want to take medicine, don’t prioritize their health, or they find the dietary and lifestyle modifications doctors suggest too hard to make or they struggle at losing weight, eating more healthfully, or cutting back on alcohol, for instance.

“When you come down to it, the big hindrance of it all is cost and the ability for the patient to be able to afford some of the things that we think they should be able to do,” said Teresa Lovins, MD, a physician in private practice Columbus, Ind., and a member of the board of directors of the American Academy of Family Physicians.

Another common deterrent to treatment is undesired side effects that a patient may not want to mention.

“For example, a lot of patients who are taking antidepressants have sexual dysfunction associated with those medications,” said Dr. Rabinovitz. “If you don’t ask the right questions, you’re not going to be able to fully assess the experience the patient is having and a reason why they might not take it [the medication].”

Much nonadherence is intentional and is based on experience, belief systems, and knowledge. For example, the American Medical Association finds that patients may not understand why they need a certain treatment (and therefore dismiss it), or they may be overloaded with multiple medications, fear dependency on a drug, have a mistrust of pharmaceutical companies or the medical system as a whole, or have symptoms of depression that make taking healthy actions more difficult. In addition, patients may be unable to afford their medication, or their lack of symptoms may lead them to believe they don’t really need the prescription, as occurs with disorders such as hypertension or high cholesterol.

“In my training, we did something called Balint training, where we would get together as a group with attendings and discuss cases that were difficult from a biopsychosocial perspective and consider all the factors in the patient perspective, including family dynamics, social systems, and economic realities,” said Russell Blackwelder, MD, director of geriatric education and associate professor of family medicine at the Medical University of South Carolina, Charleston.

“That training was, for me, very helpful for opening up and being more empathetic and really examining the patient’s point of view and everything that impacts them.”

Dr. Lovins agreed that it’s crucial to establish a good rapport and build mutual trust.

“If you don’t know the patient, you have a harder time asking the right questions to get to the meat of why they’re not taking their medicine or what they’re not doing to help their health,” she said. “It takes a little bit of trust on both parts to get to that question that really gets to the heart of why they’re not doing what you’re asking them to do.”
 

How to encourage adherence

Although there may not be a one-size-fits-all approach for achieving general adherence or adherence to a medication regimen, some methods may increase success.

Kenneth Zweig, MD, an internist at Northern Virginia Family Practice Associates, Alexandria, said that convincing patients to make one small change that they can sustain can get the ball rolling.

“I had one patient who was very overweight and had high blood pressure, high cholesterol, back pain, insomnia, and depression, who was also drinking three to four beers a night,” Dr. Zweig said. “After a long discussion, I challenged him to stop all alcohol for 1 week. At the end of the week, he noticed that he slept better, lost some weight, had lower blood pressure, and had more energy. Once he saw the benefits of this one change, he was motivated to improve other aspects of his health as well. He improved his diet, started exercising, and lost over 50 pounds. He has persisted with these lifestyle changes ever since.”

A team-based approach may also increase treatment understanding and adherence. In one older study, patients who were assigned to team-based care, including care by pharmacists, were significantly more adherent to medication regimens. Patients were more comfortable asking questions and raising concerns when they felt their treatment plan was a collaboration between several providers and themselves.

Dr. Lovins said to always approach the patient with a positive. “Say, what can we do together to make this work? What are your questions about this medication? And try and focus on the positive things that you can change instead of leaving the patient with a negative feeling or that you’re angry with them or that you’re unhappy with their choices. Patients respond better when they are treated as part of the team.”

Fear of judgment can also be a barrier to honesty between patients and their doctors. Shame creates a reluctance to admit nonadherence. Dr. Lovins said in an interview that it’s the physician’s responsibility to create a blame-free space for patients to speak openly about their struggles with treatment and reasons for nonadherence.
 

When should you redirect care?

Ultimately, the goal is good care and treatment of disease. However, if you and your patient are at an impasse and progress is stalling or failing, it may be appropriate to encourage the patient to seek care elsewhere.

“Just like any relationship, some physician-patient relationships are just not a good fit,” said Dr. Blackwelder. And this may be the reason why the patient is nonadherent — something between the two of you doesn’t click.

While there are ethical considerations for this decision, most medical boards have guidelines on how to go about it, Dr. Blackwelder said in an interview. “In the state of South Carolina, we have to be available to provide urgent coverage for at least 30 days and notify the patient in writing that they need to find somebody else and to help them find somebody else if we can.”

Just as with care, a clear conversation is the best practice if you’re proposing a potential shift away from a physician-patient relationship. You might say: We’re not making the kind of progress I’d like to see, and I’m wondering if you think working with another doctor may help you.

“The most important thing is being very honest and transparent with the patient that you’re concerned you’re not making the appropriate strides forward,” said Dr. Rabinovitz. Then you can ask, ‘Am I the right doctor to help you reach your goals? And if not, how can I help you get to where you need to be?’ ”

A version of this article first appeared on Medscape.com.

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

A version of this article first appeared on Medscape.com.

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

A version of this article first appeared on Medscape.com.

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

A version of this article first appeared on Medscape.com.

Dementia prevalence is 61% higher among older people with moderate to severe hearing loss compared with those with normal hearing, new national data show.

Investigators also found that even mild hearing loss was associated with increased dementia risk, although it was not statistically significant, and that hearing aid use was tied to a 32% decrease in dementia prevalence.

“Every 10-decibel increase in hearing loss was associated with 16% greater prevalence of dementia, such that prevalence of dementia in older adults with moderate or greater hearing loss was 61% higher than prevalence in those with normal hearing,” lead investigator Alison Huang, PhD, senior research associate in epidemiology at Johns Hopkins Bloomberg School of Public Health and core faculty in the Cochlear Center for Hearing and Public Health, Baltimore, Md., told this news organization.

The findings were published online in JAMA.
 

Dose-dependent effect

For the study, researchers analyzed data on 2,413 community-dwelling participants in the National Health and Aging Trends Study, a nationally representative, continuous panel study of U.S. Medicare beneficiaries aged 65 and older.

Data from the study were collected during in-home interviews, setting it apart from previous work that relied on data collected in a clinical setting, Dr. Huang said.

“This study was able to capture more vulnerable populations, such as the oldest old and older adults with disabilities, typically excluded from prior epidemiologic studies of the hearing loss–dementia association that use clinic-based data collection, which only captures people who have the ability and means to get to clinics,” Dr. Huang said.

Weighted hearing loss prevalence was 36.7% for mild and 29.8% for moderate to severe hearing loss, and weighted prevalence of dementia was 10.3%.

Those with moderate to severe hearing loss were 61% more likely to have dementia than those with normal hearing (prevalence ratio, 1.61; 95% confidence interval, 1.09-2.38).

Dementia prevalence increased with increasing severity of hearing loss: normal hearing: 6.19% (95% CI, 4.31-8.80); mild hearing loss: 8.93% (95% CI, 6.99-11.34); moderate/severe hearing loss: 16.52% (95% CI, 13.81-19.64). But only moderate to severe hearing loss showed a statistically significant association with dementia (P = .02).

Dementia prevalence increased 16% per 10-decibel increase in hearing loss (prevalence ratio 1.16; P < .001).

Among the 853 individuals in the study with moderate to severe hearing loss, those who used hearing aids (n = 414) had a 32% lower risk of dementia compared with those who didn’t use assistive devices (prevalence ratio, 0.68; 95% CI, 0.47-1.00). This news organization last month reported on similar data published in JAMA Neurology suggesting that hearing aids reduce dementia risk.

“With this study, we were able to refine our understanding of the strength of the hearing loss–dementia association in a study more representative of older adults in the United States,” said Dr. Huang.
 

Robust association

Commenting on the findings, Justin S. Golub, MD, associate professor in the department of otolaryngology–head and neck surgery at Columbia University, New York, said the study supports earlier research and suggests a “robust” association between hearing loss and dementia.

“The particular advantage of this study was that it was high quality and nationally representative,” Dr. Golub said. “It is also among a smaller set of studies that have shown hearing aid use to be associated with lower risk of dementia.”

Although not statistically significant, researchers did find increasing prevalence of dementia among people with only mild hearing loss, and clinicians should take note, said Dr. Golub, who was not involved with this study.

“We would expect the relationship between mild hearing loss and dementia to be weaker than severe hearing loss and dementia and, as a result, it might take more participants to show an association among the mild group,” Dr. Golub said.

“Even though this particular study did not specifically find a relationship between mild hearing loss and dementia, I would still recommend people to start treating their hearing loss when it is early,” Dr. Golub added.

The study was funded by the National Institute on Aging. Dr. Golub reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Dementia prevalence is 61% higher among older people with moderate to severe hearing loss compared with those with normal hearing, new national data show.

Investigators also found that even mild hearing loss was associated with increased dementia risk, although it was not statistically significant, and that hearing aid use was tied to a 32% decrease in dementia prevalence.

“Every 10-decibel increase in hearing loss was associated with 16% greater prevalence of dementia, such that prevalence of dementia in older adults with moderate or greater hearing loss was 61% higher than prevalence in those with normal hearing,” lead investigator Alison Huang, PhD, senior research associate in epidemiology at Johns Hopkins Bloomberg School of Public Health and core faculty in the Cochlear Center for Hearing and Public Health, Baltimore, Md., told this news organization.

The findings were published online in JAMA.
 

Dose-dependent effect

For the study, researchers analyzed data on 2,413 community-dwelling participants in the National Health and Aging Trends Study, a nationally representative, continuous panel study of U.S. Medicare beneficiaries aged 65 and older.

Data from the study were collected during in-home interviews, setting it apart from previous work that relied on data collected in a clinical setting, Dr. Huang said.

“This study was able to capture more vulnerable populations, such as the oldest old and older adults with disabilities, typically excluded from prior epidemiologic studies of the hearing loss–dementia association that use clinic-based data collection, which only captures people who have the ability and means to get to clinics,” Dr. Huang said.

Weighted hearing loss prevalence was 36.7% for mild and 29.8% for moderate to severe hearing loss, and weighted prevalence of dementia was 10.3%.

Those with moderate to severe hearing loss were 61% more likely to have dementia than those with normal hearing (prevalence ratio, 1.61; 95% confidence interval, 1.09-2.38).

Dementia prevalence increased with increasing severity of hearing loss: normal hearing: 6.19% (95% CI, 4.31-8.80); mild hearing loss: 8.93% (95% CI, 6.99-11.34); moderate/severe hearing loss: 16.52% (95% CI, 13.81-19.64). But only moderate to severe hearing loss showed a statistically significant association with dementia (P = .02).

Dementia prevalence increased 16% per 10-decibel increase in hearing loss (prevalence ratio 1.16; P < .001).

Among the 853 individuals in the study with moderate to severe hearing loss, those who used hearing aids (n = 414) had a 32% lower risk of dementia compared with those who didn’t use assistive devices (prevalence ratio, 0.68; 95% CI, 0.47-1.00). This news organization last month reported on similar data published in JAMA Neurology suggesting that hearing aids reduce dementia risk.

“With this study, we were able to refine our understanding of the strength of the hearing loss–dementia association in a study more representative of older adults in the United States,” said Dr. Huang.
 

Robust association

Commenting on the findings, Justin S. Golub, MD, associate professor in the department of otolaryngology–head and neck surgery at Columbia University, New York, said the study supports earlier research and suggests a “robust” association between hearing loss and dementia.

“The particular advantage of this study was that it was high quality and nationally representative,” Dr. Golub said. “It is also among a smaller set of studies that have shown hearing aid use to be associated with lower risk of dementia.”

Although not statistically significant, researchers did find increasing prevalence of dementia among people with only mild hearing loss, and clinicians should take note, said Dr. Golub, who was not involved with this study.

“We would expect the relationship between mild hearing loss and dementia to be weaker than severe hearing loss and dementia and, as a result, it might take more participants to show an association among the mild group,” Dr. Golub said.

“Even though this particular study did not specifically find a relationship between mild hearing loss and dementia, I would still recommend people to start treating their hearing loss when it is early,” Dr. Golub added.

The study was funded by the National Institute on Aging. Dr. Golub reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Dementia prevalence is 61% higher among older people with moderate to severe hearing loss compared with those with normal hearing, new national data show.

Investigators also found that even mild hearing loss was associated with increased dementia risk, although it was not statistically significant, and that hearing aid use was tied to a 32% decrease in dementia prevalence.

“Every 10-decibel increase in hearing loss was associated with 16% greater prevalence of dementia, such that prevalence of dementia in older adults with moderate or greater hearing loss was 61% higher than prevalence in those with normal hearing,” lead investigator Alison Huang, PhD, senior research associate in epidemiology at Johns Hopkins Bloomberg School of Public Health and core faculty in the Cochlear Center for Hearing and Public Health, Baltimore, Md., told this news organization.

The findings were published online in JAMA.
 

Dose-dependent effect

For the study, researchers analyzed data on 2,413 community-dwelling participants in the National Health and Aging Trends Study, a nationally representative, continuous panel study of U.S. Medicare beneficiaries aged 65 and older.

Data from the study were collected during in-home interviews, setting it apart from previous work that relied on data collected in a clinical setting, Dr. Huang said.

“This study was able to capture more vulnerable populations, such as the oldest old and older adults with disabilities, typically excluded from prior epidemiologic studies of the hearing loss–dementia association that use clinic-based data collection, which only captures people who have the ability and means to get to clinics,” Dr. Huang said.

Weighted hearing loss prevalence was 36.7% for mild and 29.8% for moderate to severe hearing loss, and weighted prevalence of dementia was 10.3%.

Those with moderate to severe hearing loss were 61% more likely to have dementia than those with normal hearing (prevalence ratio, 1.61; 95% confidence interval, 1.09-2.38).

Dementia prevalence increased with increasing severity of hearing loss: normal hearing: 6.19% (95% CI, 4.31-8.80); mild hearing loss: 8.93% (95% CI, 6.99-11.34); moderate/severe hearing loss: 16.52% (95% CI, 13.81-19.64). But only moderate to severe hearing loss showed a statistically significant association with dementia (P = .02).

Dementia prevalence increased 16% per 10-decibel increase in hearing loss (prevalence ratio 1.16; P < .001).

Among the 853 individuals in the study with moderate to severe hearing loss, those who used hearing aids (n = 414) had a 32% lower risk of dementia compared with those who didn’t use assistive devices (prevalence ratio, 0.68; 95% CI, 0.47-1.00). This news organization last month reported on similar data published in JAMA Neurology suggesting that hearing aids reduce dementia risk.

“With this study, we were able to refine our understanding of the strength of the hearing loss–dementia association in a study more representative of older adults in the United States,” said Dr. Huang.
 

Robust association

Commenting on the findings, Justin S. Golub, MD, associate professor in the department of otolaryngology–head and neck surgery at Columbia University, New York, said the study supports earlier research and suggests a “robust” association between hearing loss and dementia.

“The particular advantage of this study was that it was high quality and nationally representative,” Dr. Golub said. “It is also among a smaller set of studies that have shown hearing aid use to be associated with lower risk of dementia.”

Although not statistically significant, researchers did find increasing prevalence of dementia among people with only mild hearing loss, and clinicians should take note, said Dr. Golub, who was not involved with this study.

“We would expect the relationship between mild hearing loss and dementia to be weaker than severe hearing loss and dementia and, as a result, it might take more participants to show an association among the mild group,” Dr. Golub said.

“Even though this particular study did not specifically find a relationship between mild hearing loss and dementia, I would still recommend people to start treating their hearing loss when it is early,” Dr. Golub added.

The study was funded by the National Institute on Aging. Dr. Golub reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.