Federal Practitioner

Depression affects about 4.4% of the global population.¹ Major depressive disorder (MDD) is currently the fourth highest cause of disability in the world and by 2030 MDD is expected to be third.² Research has determined that 1 in 3 veterans seen in primary care shows depressive symptoms. Of these, 1 in 5 have symptoms severe enough to warrant further evaluation for MDD, and 1 in 10 require treatment.³ With this high rate of depression, optimized treatment strategies are needed, including antidepressants and psychotherapy. Antidepressants have grown in popularity since market entry in the 1950s; currently 1 in 10 US citizens aged ≥ 12 years are prescribed an antidepressant.⁴

Antidepressant Adherence

Antidepressant adherence is crucial for response and remission. Sansone and Sansone reported that, on average, < 50% of patients are adherent to their antidepressant treatment regimen 6 months after initiation (range, 5.4% - 87.6%).⁵ Fortney and colleagues found that, based on patient report, < 20% of veterans maintained at least 80% adherence at 6 months.⁶ Patients who are nonadherent are at an increased risk for relapse and recurrence and are more likely to seek care at an emergency department or to become hospitalized.² In addition to the negative impact on patient outcomes, antidepressant nonadherence may also result in increased economic burden. In the US alone, the annual cost of treating MDD exceeds $210 billion, which will continue to increase if nonadherence is not mitigated.¹

Patient-specific characteristics such as lack of knowledge about proper administration techniques, misguided beliefs, and negative attitudes towards treatment may affect adherence.⁵ In the veteran population, reasons for discontinuation also include lack of perceived benefit and adverse effects, specifically sexual difficulties.⁶ Sociodemographic and other patient characteristics also may be risk factors for nonadherence, including multiple medical comorbidities; substance use disorder (SUD) diagnosis; male gender; younger age; lack of health insurance or a higher medical cost burden; lack of or low involvement in psychotherapy; infrequent follow up visits; and high illness severity.^1,7,8

Appreciating the adherence rates among the different antidepressant classes may help in antidepressant selection. To our knowledge, there have been no prior studies conducted in the veteran population that compared adherence rates among antidepressant classes. Studies in the nonveteran population report differing adherence rates among the antidepressant classes with generally higher adherence in patients prescribed serotonin norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). A retrospective review of commercial, Medicare, and Medicaid claims in > 5000 patients found that SNRIs had a significantly higher 3-month adherence rate based on the portion of days covered model (47%; P < .001) than other antidepressant classes (SSRIs, 42%; other antidepressants, 37%; tricyclic antidepressants [TCAs], 24%).⁷ Monoamine oxidase inhibitors (MAOIs) prescribed to 1% of the study population had the highest adherence rate at 48%.⁷ A study reviewing > 25 000 patient claims sourced from the IBM MarketScan research database (Armonk, NY) found that SSRIs (Odds ratio [OR], 1.26; P < .001) and norepinephrine dopamine reuptake inhibitors (NDRIs) (OR, 1.23; P = .007) had the highest ORs for adherence according to the portion of days covered model, while other serotonin modulators (OR, 0.65; P = .001) and tri/tetracyclic antidepressants (OR, 0.49; P < . 001) had the lowest ORs and were associated with lower adherence.¹

VA Approaches to Adherence

To address antidepressant adherence, the US Department of Veteran Affairs (VA) adopted 2 measures from the Healthcare Effectiveness Data and Information Set: MDD43h and MDD47h. Measure MDD43h is defined as the proportion of patients with a depression diagnosis newly treated with an antidepressant medication who remained on the antidepressant medication for at least 84 out of 114 days (3 months). MDD47h is similar, but assesses patients remaining on an antidepressant medication for at least 180 out of 230 days (6 months).⁹ These constitute a SAIL (Strategic Analytics for Improvement and Learning) measure by which VA hospitals are compared. High performance on these measures aids in improving the comparative status of a VA facility.

To help improve performance on these measures, the VA Psychotropic Drug Safety Initiative developed the Antidepressant Nonadherence Report, which serves as a case finder for clinicians to identify veterans with low adherence and/or those overdue for a refill. The dashboard uses the medication possession ratio (MPR) to calculate adherence. While the optimal value is still widely debated, an MPR of ≥ 80% is generally accepted for many disease states.¹⁰ The dashboard defines low adherence as ≤ 60%.

As of September 2018, the Antidepressant Nonadherence Report for the Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas, included > 5000 patients in both MEDVAMC and associated community-based outpatient clinics. About 30% of patients were categorized as overdue for a refill.

Study Objectives

To better understand the problem of antidepressant adherence within this population, we decided to study the relationship between antidepressant class and adherence rates, as well as how adherence relates to patient-specific characteristics. By highlighting predisposing risk factors to low adherence, we hope to provide better interventions.

The primary objective of this study was to determine whether 3-month adherence rates, measured by the MPR, differ between antidepressant classes in veterans newly initiated on antidepressant therapy. A secondary objective was to identify whether there are differences in patient characteristics between those with high MPR (≥ 80%) and low MPR (≤ 60%).

Methods

This study used a retrospective, cross-sectional chart review of MEDVAMC patients from the Antidepressant Nonadherence Report. Patients were: aged ≥ 18 years; newly initiated on an antidepressant with no previous use of the same medication; outpatient for the entire study period; and seen by a physician, physician assistant, nurse practitioner, or pharmacist mental health provider (MHP) within the 3-month study period. All patients’ charts showed a depression diagnosis—an inclusion criterion for the MDD43h and MDD47h measures. However, for this study, the indication(s) for the chosen antidepressant were determined by the MHP note in the patient electronic health record on the date that the medication was prescribed. Study patients may not have had a current depression diagnosis based upon the MHP assessment on the index date. We chose to determine the antidepressant indication(s) in this way because the MHP note would have the most detailed patient assessment.

Patients with previous use of the prescribed antidepressant were excluded because previous exposure may bias the patient and affect current adherence. Patients who were hospitalized at the VA for any reason during the 3-month study period were excluded because of a known risk during transitions of care for medications to be held or discontinued, which could impact refills and MPR. Some patients were excluded if they were taking the antidepressant for a nonmood-related indication (insomnia, neuropathy, migraine prophylaxis, etc). Patients also were excluded if the antidepressant was prescribed to take as-needed; if trazodone was the only antidepressant prescribed; if they were diagnosed with cognitive impairment including dementia or history of stroke; or if they were diagnosed with schizophrenia, schizoaffective disorder, or borderline personality disorder. Use of trazodone as the only antidepressant was excluded because of the relatively common practice to use it in the treatment of insomnia rather than depression.

Primary and Secondary Outcomes

Information collected for the primary outcome, including antidepressant class and MPR, was obtained from the Antidepressant Nonadherence Report. For the secondary outcome, the following data was collected for each patient: age, gender, race, housing status, Medication Regimen Complexity Index (MRCI), number and type of psychiatric diagnoses, number of previous antidepressants, psychotherapy involvement, and number of mental health visits during the 3-month study period. The MRCI is an objective, validated tool that determines relative medication regimen complexity by taking into consideration the number of medications, route and frequency of administration, splitting/multiple dosage units, and presence of any special instructions.¹¹

The primary outcome was tested using a one-way analysis of variance (ANOVA). Nominal secondary outcomes were analyzed using the Fisher’s Exact. Continuous secondary outcomes were examined using an unpaired t-test.

Results

Of 320 charts, 212 patients were excluded and 108 were included (Figure). The most common reason for exclusion was a previously prescribed antidepressant. Of the included patients 49 had an MPR ≥ 80% and 24 had an MPR ≤ 60%. The characteristics of the study population are found in Table 1 and the antidepressant frequencies and MPRs are included in Table 2.

About 87% of study patients had a diagnosis of depression. Other concomitant psychiatric diagnoses include posttraumatic stress disorder (PTSD), anxiety, insomnia, and 2 cases of intermittent explosive disorder. There were no significant differences in mean MPR between the antidepressant classes (P = .31). Within each drug class, we identified the proportion of patients with high adherence (MPR ≥ 80%). Bupropion had the greatest percentage of highly adherent patients (50%) compared with SSRIs (42.5%), SNRIs (38.5%), and mirtazapine (31.3%).

Table 3 compares the characteristics between high MPR and low MPR patients. The low MPR group showed a significantly greater proportion of patients with an SUD than the high adherence group (41.7% vs 10.2%, respectively; P = .04). The most common type of SUD was alcohol use disorder followed by cannabis use disorder. There were no other statistically significant differences identified between high and low MPR groups. There was a trend towards significance when comparing MRCI between the 2 groups (high MPR, 15.2; low MPR, 10.8; P = .06).

Discussion

In our study, there was no significant difference in 3-month adherence rates between veterans on SSRIs, SNRIs, bupropion, and mirtazapine. This result differs from a study by Keyloun and colleagues that found that SNRIs had a significantly higher adherence rate when compared with other antidepressants.⁷

SSRIs were the most commonly prescribed antidepressant in our study, and also had the greatest mean 3-month MPR. The high use of SSRIs may be due to the greater number of SSRI choices to select from compared with other classes. SSRIs may also have been selected more frequently because nearly half (45.4%) of the patients had comorbid PTSD, for which 3 of the 4 first-line treatment options are SSRIs (sertraline, paroxetine, fluoxetine).

As previously stated, Keyloun and colleagues previously found that SNRIs had the highest 3-month adherence rate in a study of > 5000 patients.⁷ In our study, SNRIs had the second highest mean 3-month MPR at about 75%, but the difference was not considered significant when compared with other antidepressant classes.

Bupropion was prescribed least frequently, but had the largest proportion of adherent patients. Gaspar and colleagues demonstrated similar outcomes, reporting that patients prescribed bupropion had a high OR for adherence.¹ Bupropion may have had relatively low prescribing rates in our study because 64% of patients were diagnosed with a comorbid anxiety disorder and/or PTSD. For these patients, bupropion avoidance may have been intentional so as to not exacerbate anxiety.

Mirtazapine had both the lowest mean MPR and the lowest proportion of adherent patients. While no significant difference between antidepressant 3-month adherence rates were found, this study’s findings were similar to previous studies that found lower adherence to mirtazapine.^1,5 Adverse effects such as sedation, increased appetite, and weight gain may have contributed to low adherence with mirtazapine.⁴ Patients may also have been using the agent on an as needed basis to treat insomnia despite the order being written for daily use.

Substance Use Disorder Influence

A significantly greater proportion of patients had an SUD in the low MPR group, suggesting that an SUD diagnosis may be a risk factor for low adherence. This finding is consistent with previous studies that also found that an SUD was associated with poor medication adherence.¹ Patients with depression and an SUD have been shown to have suboptimal outcomes compared to those without an SUD, including a lower response to antidepressant therapy and increased illness severity.^11,12

In a study of 131 outpatients with dual diagnosis (26% with depression) predictors for low self-reported adherence were a medication-related variable (increased adverse effects), a cognitive variable (low self-efficacy for drug avoidance), and a social factor (low social support for recovery). This variety of predictors seems to indicate that simple memory aids may not improve adherence. “Dual focus” mutual aid groups that provide social support for patients with dual diagnosis have been shown to improve adherence.¹³

The MEDVAMC Substance Dependence Treatment Program (SDTP) is an outpatient program that uses group education to aid veterans, often those with comorbid psychiatric disorders, to build relapse prevention skills and provide social support. Further exploration into the relationship between involvement in SDTP groups and antidepressant adherence in patients with dual diagnosis may be warranted.

Secondary Outcomes

Trends identified in the secondary outcome were similar to outcomes of previous studies: younger age, lower therapy involvement, and more comorbid psychiatric diagnoses were associated with lower adherence.^1,7,8 The presence of increased previous use of antidepressants in the low adherence group may suggest that these patients have an increased illness severity, although objective scales, such as the Patient Health Questionnaire 9 (PHQ9), were not consistently conducted and therefore not included in this analysis. It is unknown whether the previous antidepressant prescriptions were of adequate duration. These patients may have also had intolerances that led to multiple different antidepressant prescriptions and self-discontinuation.

The average MRCI of study patients was 13.5 (range 2 - 53), which was significantly lower than a previous study of geriatric patients with depression reporting an average MRCI of 25.4 (range 6 - 64).¹⁴ The positive trend between MRCI and adherence seen in this study was puzzling and counterintuitive. A more complex regimen is generally thought to be associated with poor adherence. Patients with a greater number of comorbid conditions may inherently be on more medications and thus have a more complex medication regimen. Manzano-Garcia and colleagues identified a negative relationship between adherence and the number of comorbidities (OR, 1.04-1.57; P = .021) and the MRCI (OR, 1.14-1.26; P < .001) in patients with HIV.¹⁵ Further studies are needed to clarify the relationship between medication adherence and medication regimen complexity in patients with mental health disorders. A better understanding of this relationship could possibly facilitate improved individualized prescribing practices and follow-up.

Limitations

Findings from our study should be interpreted within several limitations. Generalizability and statistical power were limited due to the small sample size, a practice site limited to 1 facility, and population type. The retrospective design of the study introduces inherent bias that would be minimized had a prospective study been conducted. The primary outcome was based upon MPR, which only accounts for refills within a specified time period and does not assess for actual or accurate use of the medication. Data collection was limited to VA and US Department of Defense records.

Geographically diverse studies with larger sample sizes need to be conducted to better understand antidepressant adherence and its barriers and facilitators in the veteran population. The exclusion of patients with previous trials of the prescribed antidepressant may have led to a possible selection bias favoring inclusion of younger patients. These patients may have a more limited period for assessment and treatment when compared with older patients, and thus may have had a smaller chance of previous exposure to the prescribed antidepressant. Neither MAOIs or TCAs were included in this study. No patients taking MAOIs were identified from the Antidepressant Nonadherence Report during the study period. Three patients on TCAs were chart reviewed, but excluded from the study because of prior use of the antidepressant or a non-mental health indication. Additionally, no newer antidepressants, including vortioxetine and vilazodone, were included, likely secondary to their nonformulary status at the VA.

Conclusion

As this study’s purpose was to improve the quality of care at our facility, we will discuss our findings with local MHPs to develop strategies to improve antidepressant adherence. While larger studies need to be conducted to confirm our findings, it is worthwhile to consider risk factors for low adherence such as SUD when prescribing antidepressant medications. Patients with SUD could be encouraged to enroll in our facility’s telephone nursing depression care management program for more frequent follow up and medication adherence counseling.

This study did not find a significant difference in 3-month adherence rates between SSRIs, SNRIs, bupropion, and mirtazapine. SUD was significantly more common in patients with low adherence than those categorized as adherent and may be a risk factor for low adherence based upon our findings and those of previous studies.

Depression affects about 4.4% of the global population.¹ Major depressive disorder (MDD) is currently the fourth highest cause of disability in the world and by 2030 MDD is expected to be third.² Research has determined that 1 in 3 veterans seen in primary care shows depressive symptoms. Of these, 1 in 5 have symptoms severe enough to warrant further evaluation for MDD, and 1 in 10 require treatment.³ With this high rate of depression, optimized treatment strategies are needed, including antidepressants and psychotherapy. Antidepressants have grown in popularity since market entry in the 1950s; currently 1 in 10 US citizens aged ≥ 12 years are prescribed an antidepressant.⁴

Antidepressant Adherence

Antidepressant adherence is crucial for response and remission. Sansone and Sansone reported that, on average, < 50% of patients are adherent to their antidepressant treatment regimen 6 months after initiation (range, 5.4% - 87.6%).⁵ Fortney and colleagues found that, based on patient report, < 20% of veterans maintained at least 80% adherence at 6 months.⁶ Patients who are nonadherent are at an increased risk for relapse and recurrence and are more likely to seek care at an emergency department or to become hospitalized.² In addition to the negative impact on patient outcomes, antidepressant nonadherence may also result in increased economic burden. In the US alone, the annual cost of treating MDD exceeds $210 billion, which will continue to increase if nonadherence is not mitigated.¹

Patient-specific characteristics such as lack of knowledge about proper administration techniques, misguided beliefs, and negative attitudes towards treatment may affect adherence.⁵ In the veteran population, reasons for discontinuation also include lack of perceived benefit and adverse effects, specifically sexual difficulties.⁶ Sociodemographic and other patient characteristics also may be risk factors for nonadherence, including multiple medical comorbidities; substance use disorder (SUD) diagnosis; male gender; younger age; lack of health insurance or a higher medical cost burden; lack of or low involvement in psychotherapy; infrequent follow up visits; and high illness severity.^1,7,8

Appreciating the adherence rates among the different antidepressant classes may help in antidepressant selection. To our knowledge, there have been no prior studies conducted in the veteran population that compared adherence rates among antidepressant classes. Studies in the nonveteran population report differing adherence rates among the antidepressant classes with generally higher adherence in patients prescribed serotonin norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). A retrospective review of commercial, Medicare, and Medicaid claims in > 5000 patients found that SNRIs had a significantly higher 3-month adherence rate based on the portion of days covered model (47%; P < .001) than other antidepressant classes (SSRIs, 42%; other antidepressants, 37%; tricyclic antidepressants [TCAs], 24%).⁷ Monoamine oxidase inhibitors (MAOIs) prescribed to 1% of the study population had the highest adherence rate at 48%.⁷ A study reviewing > 25 000 patient claims sourced from the IBM MarketScan research database (Armonk, NY) found that SSRIs (Odds ratio [OR], 1.26; P < .001) and norepinephrine dopamine reuptake inhibitors (NDRIs) (OR, 1.23; P = .007) had the highest ORs for adherence according to the portion of days covered model, while other serotonin modulators (OR, 0.65; P = .001) and tri/tetracyclic antidepressants (OR, 0.49; P < . 001) had the lowest ORs and were associated with lower adherence.¹

VA Approaches to Adherence

To address antidepressant adherence, the US Department of Veteran Affairs (VA) adopted 2 measures from the Healthcare Effectiveness Data and Information Set: MDD43h and MDD47h. Measure MDD43h is defined as the proportion of patients with a depression diagnosis newly treated with an antidepressant medication who remained on the antidepressant medication for at least 84 out of 114 days (3 months). MDD47h is similar, but assesses patients remaining on an antidepressant medication for at least 180 out of 230 days (6 months).⁹ These constitute a SAIL (Strategic Analytics for Improvement and Learning) measure by which VA hospitals are compared. High performance on these measures aids in improving the comparative status of a VA facility.

To help improve performance on these measures, the VA Psychotropic Drug Safety Initiative developed the Antidepressant Nonadherence Report, which serves as a case finder for clinicians to identify veterans with low adherence and/or those overdue for a refill. The dashboard uses the medication possession ratio (MPR) to calculate adherence. While the optimal value is still widely debated, an MPR of ≥ 80% is generally accepted for many disease states.¹⁰ The dashboard defines low adherence as ≤ 60%.

As of September 2018, the Antidepressant Nonadherence Report for the Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas, included > 5000 patients in both MEDVAMC and associated community-based outpatient clinics. About 30% of patients were categorized as overdue for a refill.

Study Objectives

To better understand the problem of antidepressant adherence within this population, we decided to study the relationship between antidepressant class and adherence rates, as well as how adherence relates to patient-specific characteristics. By highlighting predisposing risk factors to low adherence, we hope to provide better interventions.

The primary objective of this study was to determine whether 3-month adherence rates, measured by the MPR, differ between antidepressant classes in veterans newly initiated on antidepressant therapy. A secondary objective was to identify whether there are differences in patient characteristics between those with high MPR (≥ 80%) and low MPR (≤ 60%).

Methods

This study used a retrospective, cross-sectional chart review of MEDVAMC patients from the Antidepressant Nonadherence Report. Patients were: aged ≥ 18 years; newly initiated on an antidepressant with no previous use of the same medication; outpatient for the entire study period; and seen by a physician, physician assistant, nurse practitioner, or pharmacist mental health provider (MHP) within the 3-month study period. All patients’ charts showed a depression diagnosis—an inclusion criterion for the MDD43h and MDD47h measures. However, for this study, the indication(s) for the chosen antidepressant were determined by the MHP note in the patient electronic health record on the date that the medication was prescribed. Study patients may not have had a current depression diagnosis based upon the MHP assessment on the index date. We chose to determine the antidepressant indication(s) in this way because the MHP note would have the most detailed patient assessment.

Patients with previous use of the prescribed antidepressant were excluded because previous exposure may bias the patient and affect current adherence. Patients who were hospitalized at the VA for any reason during the 3-month study period were excluded because of a known risk during transitions of care for medications to be held or discontinued, which could impact refills and MPR. Some patients were excluded if they were taking the antidepressant for a nonmood-related indication (insomnia, neuropathy, migraine prophylaxis, etc). Patients also were excluded if the antidepressant was prescribed to take as-needed; if trazodone was the only antidepressant prescribed; if they were diagnosed with cognitive impairment including dementia or history of stroke; or if they were diagnosed with schizophrenia, schizoaffective disorder, or borderline personality disorder. Use of trazodone as the only antidepressant was excluded because of the relatively common practice to use it in the treatment of insomnia rather than depression.

Primary and Secondary Outcomes

Information collected for the primary outcome, including antidepressant class and MPR, was obtained from the Antidepressant Nonadherence Report. For the secondary outcome, the following data was collected for each patient: age, gender, race, housing status, Medication Regimen Complexity Index (MRCI), number and type of psychiatric diagnoses, number of previous antidepressants, psychotherapy involvement, and number of mental health visits during the 3-month study period. The MRCI is an objective, validated tool that determines relative medication regimen complexity by taking into consideration the number of medications, route and frequency of administration, splitting/multiple dosage units, and presence of any special instructions.¹¹

The primary outcome was tested using a one-way analysis of variance (ANOVA). Nominal secondary outcomes were analyzed using the Fisher’s Exact. Continuous secondary outcomes were examined using an unpaired t-test.

Results

Of 320 charts, 212 patients were excluded and 108 were included (Figure). The most common reason for exclusion was a previously prescribed antidepressant. Of the included patients 49 had an MPR ≥ 80% and 24 had an MPR ≤ 60%. The characteristics of the study population are found in Table 1 and the antidepressant frequencies and MPRs are included in Table 2.

About 87% of study patients had a diagnosis of depression. Other concomitant psychiatric diagnoses include posttraumatic stress disorder (PTSD), anxiety, insomnia, and 2 cases of intermittent explosive disorder. There were no significant differences in mean MPR between the antidepressant classes (P = .31). Within each drug class, we identified the proportion of patients with high adherence (MPR ≥ 80%). Bupropion had the greatest percentage of highly adherent patients (50%) compared with SSRIs (42.5%), SNRIs (38.5%), and mirtazapine (31.3%).

Table 3 compares the characteristics between high MPR and low MPR patients. The low MPR group showed a significantly greater proportion of patients with an SUD than the high adherence group (41.7% vs 10.2%, respectively; P = .04). The most common type of SUD was alcohol use disorder followed by cannabis use disorder. There were no other statistically significant differences identified between high and low MPR groups. There was a trend towards significance when comparing MRCI between the 2 groups (high MPR, 15.2; low MPR, 10.8; P = .06).

Discussion

In our study, there was no significant difference in 3-month adherence rates between veterans on SSRIs, SNRIs, bupropion, and mirtazapine. This result differs from a study by Keyloun and colleagues that found that SNRIs had a significantly higher adherence rate when compared with other antidepressants.⁷

SSRIs were the most commonly prescribed antidepressant in our study, and also had the greatest mean 3-month MPR. The high use of SSRIs may be due to the greater number of SSRI choices to select from compared with other classes. SSRIs may also have been selected more frequently because nearly half (45.4%) of the patients had comorbid PTSD, for which 3 of the 4 first-line treatment options are SSRIs (sertraline, paroxetine, fluoxetine).

As previously stated, Keyloun and colleagues previously found that SNRIs had the highest 3-month adherence rate in a study of > 5000 patients.⁷ In our study, SNRIs had the second highest mean 3-month MPR at about 75%, but the difference was not considered significant when compared with other antidepressant classes.

Bupropion was prescribed least frequently, but had the largest proportion of adherent patients. Gaspar and colleagues demonstrated similar outcomes, reporting that patients prescribed bupropion had a high OR for adherence.¹ Bupropion may have had relatively low prescribing rates in our study because 64% of patients were diagnosed with a comorbid anxiety disorder and/or PTSD. For these patients, bupropion avoidance may have been intentional so as to not exacerbate anxiety.

Mirtazapine had both the lowest mean MPR and the lowest proportion of adherent patients. While no significant difference between antidepressant 3-month adherence rates were found, this study’s findings were similar to previous studies that found lower adherence to mirtazapine.^1,5 Adverse effects such as sedation, increased appetite, and weight gain may have contributed to low adherence with mirtazapine.⁴ Patients may also have been using the agent on an as needed basis to treat insomnia despite the order being written for daily use.

Substance Use Disorder Influence

A significantly greater proportion of patients had an SUD in the low MPR group, suggesting that an SUD diagnosis may be a risk factor for low adherence. This finding is consistent with previous studies that also found that an SUD was associated with poor medication adherence.¹ Patients with depression and an SUD have been shown to have suboptimal outcomes compared to those without an SUD, including a lower response to antidepressant therapy and increased illness severity.^11,12

In a study of 131 outpatients with dual diagnosis (26% with depression) predictors for low self-reported adherence were a medication-related variable (increased adverse effects), a cognitive variable (low self-efficacy for drug avoidance), and a social factor (low social support for recovery). This variety of predictors seems to indicate that simple memory aids may not improve adherence. “Dual focus” mutual aid groups that provide social support for patients with dual diagnosis have been shown to improve adherence.¹³

The MEDVAMC Substance Dependence Treatment Program (SDTP) is an outpatient program that uses group education to aid veterans, often those with comorbid psychiatric disorders, to build relapse prevention skills and provide social support. Further exploration into the relationship between involvement in SDTP groups and antidepressant adherence in patients with dual diagnosis may be warranted.

Secondary Outcomes

Trends identified in the secondary outcome were similar to outcomes of previous studies: younger age, lower therapy involvement, and more comorbid psychiatric diagnoses were associated with lower adherence.^1,7,8 The presence of increased previous use of antidepressants in the low adherence group may suggest that these patients have an increased illness severity, although objective scales, such as the Patient Health Questionnaire 9 (PHQ9), were not consistently conducted and therefore not included in this analysis. It is unknown whether the previous antidepressant prescriptions were of adequate duration. These patients may have also had intolerances that led to multiple different antidepressant prescriptions and self-discontinuation.

The average MRCI of study patients was 13.5 (range 2 - 53), which was significantly lower than a previous study of geriatric patients with depression reporting an average MRCI of 25.4 (range 6 - 64).¹⁴ The positive trend between MRCI and adherence seen in this study was puzzling and counterintuitive. A more complex regimen is generally thought to be associated with poor adherence. Patients with a greater number of comorbid conditions may inherently be on more medications and thus have a more complex medication regimen. Manzano-Garcia and colleagues identified a negative relationship between adherence and the number of comorbidities (OR, 1.04-1.57; P = .021) and the MRCI (OR, 1.14-1.26; P < .001) in patients with HIV.¹⁵ Further studies are needed to clarify the relationship between medication adherence and medication regimen complexity in patients with mental health disorders. A better understanding of this relationship could possibly facilitate improved individualized prescribing practices and follow-up.

Limitations

Findings from our study should be interpreted within several limitations. Generalizability and statistical power were limited due to the small sample size, a practice site limited to 1 facility, and population type. The retrospective design of the study introduces inherent bias that would be minimized had a prospective study been conducted. The primary outcome was based upon MPR, which only accounts for refills within a specified time period and does not assess for actual or accurate use of the medication. Data collection was limited to VA and US Department of Defense records.

Geographically diverse studies with larger sample sizes need to be conducted to better understand antidepressant adherence and its barriers and facilitators in the veteran population. The exclusion of patients with previous trials of the prescribed antidepressant may have led to a possible selection bias favoring inclusion of younger patients. These patients may have a more limited period for assessment and treatment when compared with older patients, and thus may have had a smaller chance of previous exposure to the prescribed antidepressant. Neither MAOIs or TCAs were included in this study. No patients taking MAOIs were identified from the Antidepressant Nonadherence Report during the study period. Three patients on TCAs were chart reviewed, but excluded from the study because of prior use of the antidepressant or a non-mental health indication. Additionally, no newer antidepressants, including vortioxetine and vilazodone, were included, likely secondary to their nonformulary status at the VA.

Conclusion

As this study’s purpose was to improve the quality of care at our facility, we will discuss our findings with local MHPs to develop strategies to improve antidepressant adherence. While larger studies need to be conducted to confirm our findings, it is worthwhile to consider risk factors for low adherence such as SUD when prescribing antidepressant medications. Patients with SUD could be encouraged to enroll in our facility’s telephone nursing depression care management program for more frequent follow up and medication adherence counseling.

This study did not find a significant difference in 3-month adherence rates between SSRIs, SNRIs, bupropion, and mirtazapine. SUD was significantly more common in patients with low adherence than those categorized as adherent and may be a risk factor for low adherence based upon our findings and those of previous studies.

Depression affects about 4.4% of the global population.¹ Major depressive disorder (MDD) is currently the fourth highest cause of disability in the world and by 2030 MDD is expected to be third.² Research has determined that 1 in 3 veterans seen in primary care shows depressive symptoms. Of these, 1 in 5 have symptoms severe enough to warrant further evaluation for MDD, and 1 in 10 require treatment.³ With this high rate of depression, optimized treatment strategies are needed, including antidepressants and psychotherapy. Antidepressants have grown in popularity since market entry in the 1950s; currently 1 in 10 US citizens aged ≥ 12 years are prescribed an antidepressant.⁴

Antidepressant Adherence

Antidepressant adherence is crucial for response and remission. Sansone and Sansone reported that, on average, < 50% of patients are adherent to their antidepressant treatment regimen 6 months after initiation (range, 5.4% - 87.6%).⁵ Fortney and colleagues found that, based on patient report, < 20% of veterans maintained at least 80% adherence at 6 months.⁶ Patients who are nonadherent are at an increased risk for relapse and recurrence and are more likely to seek care at an emergency department or to become hospitalized.² In addition to the negative impact on patient outcomes, antidepressant nonadherence may also result in increased economic burden. In the US alone, the annual cost of treating MDD exceeds $210 billion, which will continue to increase if nonadherence is not mitigated.¹

Patient-specific characteristics such as lack of knowledge about proper administration techniques, misguided beliefs, and negative attitudes towards treatment may affect adherence.⁵ In the veteran population, reasons for discontinuation also include lack of perceived benefit and adverse effects, specifically sexual difficulties.⁶ Sociodemographic and other patient characteristics also may be risk factors for nonadherence, including multiple medical comorbidities; substance use disorder (SUD) diagnosis; male gender; younger age; lack of health insurance or a higher medical cost burden; lack of or low involvement in psychotherapy; infrequent follow up visits; and high illness severity.^1,7,8

Appreciating the adherence rates among the different antidepressant classes may help in antidepressant selection. To our knowledge, there have been no prior studies conducted in the veteran population that compared adherence rates among antidepressant classes. Studies in the nonveteran population report differing adherence rates among the antidepressant classes with generally higher adherence in patients prescribed serotonin norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). A retrospective review of commercial, Medicare, and Medicaid claims in > 5000 patients found that SNRIs had a significantly higher 3-month adherence rate based on the portion of days covered model (47%; P < .001) than other antidepressant classes (SSRIs, 42%; other antidepressants, 37%; tricyclic antidepressants [TCAs], 24%).⁷ Monoamine oxidase inhibitors (MAOIs) prescribed to 1% of the study population had the highest adherence rate at 48%.⁷ A study reviewing > 25 000 patient claims sourced from the IBM MarketScan research database (Armonk, NY) found that SSRIs (Odds ratio [OR], 1.26; P < .001) and norepinephrine dopamine reuptake inhibitors (NDRIs) (OR, 1.23; P = .007) had the highest ORs for adherence according to the portion of days covered model, while other serotonin modulators (OR, 0.65; P = .001) and tri/tetracyclic antidepressants (OR, 0.49; P < . 001) had the lowest ORs and were associated with lower adherence.¹

VA Approaches to Adherence

To address antidepressant adherence, the US Department of Veteran Affairs (VA) adopted 2 measures from the Healthcare Effectiveness Data and Information Set: MDD43h and MDD47h. Measure MDD43h is defined as the proportion of patients with a depression diagnosis newly treated with an antidepressant medication who remained on the antidepressant medication for at least 84 out of 114 days (3 months). MDD47h is similar, but assesses patients remaining on an antidepressant medication for at least 180 out of 230 days (6 months).⁹ These constitute a SAIL (Strategic Analytics for Improvement and Learning) measure by which VA hospitals are compared. High performance on these measures aids in improving the comparative status of a VA facility.

To help improve performance on these measures, the VA Psychotropic Drug Safety Initiative developed the Antidepressant Nonadherence Report, which serves as a case finder for clinicians to identify veterans with low adherence and/or those overdue for a refill. The dashboard uses the medication possession ratio (MPR) to calculate adherence. While the optimal value is still widely debated, an MPR of ≥ 80% is generally accepted for many disease states.¹⁰ The dashboard defines low adherence as ≤ 60%.

As of September 2018, the Antidepressant Nonadherence Report for the Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas, included > 5000 patients in both MEDVAMC and associated community-based outpatient clinics. About 30% of patients were categorized as overdue for a refill.

Study Objectives

To better understand the problem of antidepressant adherence within this population, we decided to study the relationship between antidepressant class and adherence rates, as well as how adherence relates to patient-specific characteristics. By highlighting predisposing risk factors to low adherence, we hope to provide better interventions.

The primary objective of this study was to determine whether 3-month adherence rates, measured by the MPR, differ between antidepressant classes in veterans newly initiated on antidepressant therapy. A secondary objective was to identify whether there are differences in patient characteristics between those with high MPR (≥ 80%) and low MPR (≤ 60%).

Methods

This study used a retrospective, cross-sectional chart review of MEDVAMC patients from the Antidepressant Nonadherence Report. Patients were: aged ≥ 18 years; newly initiated on an antidepressant with no previous use of the same medication; outpatient for the entire study period; and seen by a physician, physician assistant, nurse practitioner, or pharmacist mental health provider (MHP) within the 3-month study period. All patients’ charts showed a depression diagnosis—an inclusion criterion for the MDD43h and MDD47h measures. However, for this study, the indication(s) for the chosen antidepressant were determined by the MHP note in the patient electronic health record on the date that the medication was prescribed. Study patients may not have had a current depression diagnosis based upon the MHP assessment on the index date. We chose to determine the antidepressant indication(s) in this way because the MHP note would have the most detailed patient assessment.

Patients with previous use of the prescribed antidepressant were excluded because previous exposure may bias the patient and affect current adherence. Patients who were hospitalized at the VA for any reason during the 3-month study period were excluded because of a known risk during transitions of care for medications to be held or discontinued, which could impact refills and MPR. Some patients were excluded if they were taking the antidepressant for a nonmood-related indication (insomnia, neuropathy, migraine prophylaxis, etc). Patients also were excluded if the antidepressant was prescribed to take as-needed; if trazodone was the only antidepressant prescribed; if they were diagnosed with cognitive impairment including dementia or history of stroke; or if they were diagnosed with schizophrenia, schizoaffective disorder, or borderline personality disorder. Use of trazodone as the only antidepressant was excluded because of the relatively common practice to use it in the treatment of insomnia rather than depression.

Primary and Secondary Outcomes

Information collected for the primary outcome, including antidepressant class and MPR, was obtained from the Antidepressant Nonadherence Report. For the secondary outcome, the following data was collected for each patient: age, gender, race, housing status, Medication Regimen Complexity Index (MRCI), number and type of psychiatric diagnoses, number of previous antidepressants, psychotherapy involvement, and number of mental health visits during the 3-month study period. The MRCI is an objective, validated tool that determines relative medication regimen complexity by taking into consideration the number of medications, route and frequency of administration, splitting/multiple dosage units, and presence of any special instructions.¹¹

The primary outcome was tested using a one-way analysis of variance (ANOVA). Nominal secondary outcomes were analyzed using the Fisher’s Exact. Continuous secondary outcomes were examined using an unpaired t-test.

Results

Of 320 charts, 212 patients were excluded and 108 were included (Figure). The most common reason for exclusion was a previously prescribed antidepressant. Of the included patients 49 had an MPR ≥ 80% and 24 had an MPR ≤ 60%. The characteristics of the study population are found in Table 1 and the antidepressant frequencies and MPRs are included in Table 2.

About 87% of study patients had a diagnosis of depression. Other concomitant psychiatric diagnoses include posttraumatic stress disorder (PTSD), anxiety, insomnia, and 2 cases of intermittent explosive disorder. There were no significant differences in mean MPR between the antidepressant classes (P = .31). Within each drug class, we identified the proportion of patients with high adherence (MPR ≥ 80%). Bupropion had the greatest percentage of highly adherent patients (50%) compared with SSRIs (42.5%), SNRIs (38.5%), and mirtazapine (31.3%).

Table 3 compares the characteristics between high MPR and low MPR patients. The low MPR group showed a significantly greater proportion of patients with an SUD than the high adherence group (41.7% vs 10.2%, respectively; P = .04). The most common type of SUD was alcohol use disorder followed by cannabis use disorder. There were no other statistically significant differences identified between high and low MPR groups. There was a trend towards significance when comparing MRCI between the 2 groups (high MPR, 15.2; low MPR, 10.8; P = .06).

Discussion

In our study, there was no significant difference in 3-month adherence rates between veterans on SSRIs, SNRIs, bupropion, and mirtazapine. This result differs from a study by Keyloun and colleagues that found that SNRIs had a significantly higher adherence rate when compared with other antidepressants.⁷

SSRIs were the most commonly prescribed antidepressant in our study, and also had the greatest mean 3-month MPR. The high use of SSRIs may be due to the greater number of SSRI choices to select from compared with other classes. SSRIs may also have been selected more frequently because nearly half (45.4%) of the patients had comorbid PTSD, for which 3 of the 4 first-line treatment options are SSRIs (sertraline, paroxetine, fluoxetine).

As previously stated, Keyloun and colleagues previously found that SNRIs had the highest 3-month adherence rate in a study of > 5000 patients.⁷ In our study, SNRIs had the second highest mean 3-month MPR at about 75%, but the difference was not considered significant when compared with other antidepressant classes.

Bupropion was prescribed least frequently, but had the largest proportion of adherent patients. Gaspar and colleagues demonstrated similar outcomes, reporting that patients prescribed bupropion had a high OR for adherence.¹ Bupropion may have had relatively low prescribing rates in our study because 64% of patients were diagnosed with a comorbid anxiety disorder and/or PTSD. For these patients, bupropion avoidance may have been intentional so as to not exacerbate anxiety.

Mirtazapine had both the lowest mean MPR and the lowest proportion of adherent patients. While no significant difference between antidepressant 3-month adherence rates were found, this study’s findings were similar to previous studies that found lower adherence to mirtazapine.^1,5 Adverse effects such as sedation, increased appetite, and weight gain may have contributed to low adherence with mirtazapine.⁴ Patients may also have been using the agent on an as needed basis to treat insomnia despite the order being written for daily use.

Substance Use Disorder Influence

A significantly greater proportion of patients had an SUD in the low MPR group, suggesting that an SUD diagnosis may be a risk factor for low adherence. This finding is consistent with previous studies that also found that an SUD was associated with poor medication adherence.¹ Patients with depression and an SUD have been shown to have suboptimal outcomes compared to those without an SUD, including a lower response to antidepressant therapy and increased illness severity.^11,12

In a study of 131 outpatients with dual diagnosis (26% with depression) predictors for low self-reported adherence were a medication-related variable (increased adverse effects), a cognitive variable (low self-efficacy for drug avoidance), and a social factor (low social support for recovery). This variety of predictors seems to indicate that simple memory aids may not improve adherence. “Dual focus” mutual aid groups that provide social support for patients with dual diagnosis have been shown to improve adherence.¹³

The MEDVAMC Substance Dependence Treatment Program (SDTP) is an outpatient program that uses group education to aid veterans, often those with comorbid psychiatric disorders, to build relapse prevention skills and provide social support. Further exploration into the relationship between involvement in SDTP groups and antidepressant adherence in patients with dual diagnosis may be warranted.

Secondary Outcomes

Trends identified in the secondary outcome were similar to outcomes of previous studies: younger age, lower therapy involvement, and more comorbid psychiatric diagnoses were associated with lower adherence.^1,7,8 The presence of increased previous use of antidepressants in the low adherence group may suggest that these patients have an increased illness severity, although objective scales, such as the Patient Health Questionnaire 9 (PHQ9), were not consistently conducted and therefore not included in this analysis. It is unknown whether the previous antidepressant prescriptions were of adequate duration. These patients may have also had intolerances that led to multiple different antidepressant prescriptions and self-discontinuation.

The average MRCI of study patients was 13.5 (range 2 - 53), which was significantly lower than a previous study of geriatric patients with depression reporting an average MRCI of 25.4 (range 6 - 64).¹⁴ The positive trend between MRCI and adherence seen in this study was puzzling and counterintuitive. A more complex regimen is generally thought to be associated with poor adherence. Patients with a greater number of comorbid conditions may inherently be on more medications and thus have a more complex medication regimen. Manzano-Garcia and colleagues identified a negative relationship between adherence and the number of comorbidities (OR, 1.04-1.57; P = .021) and the MRCI (OR, 1.14-1.26; P < .001) in patients with HIV.¹⁵ Further studies are needed to clarify the relationship between medication adherence and medication regimen complexity in patients with mental health disorders. A better understanding of this relationship could possibly facilitate improved individualized prescribing practices and follow-up.

Limitations

Findings from our study should be interpreted within several limitations. Generalizability and statistical power were limited due to the small sample size, a practice site limited to 1 facility, and population type. The retrospective design of the study introduces inherent bias that would be minimized had a prospective study been conducted. The primary outcome was based upon MPR, which only accounts for refills within a specified time period and does not assess for actual or accurate use of the medication. Data collection was limited to VA and US Department of Defense records.

Geographically diverse studies with larger sample sizes need to be conducted to better understand antidepressant adherence and its barriers and facilitators in the veteran population. The exclusion of patients with previous trials of the prescribed antidepressant may have led to a possible selection bias favoring inclusion of younger patients. These patients may have a more limited period for assessment and treatment when compared with older patients, and thus may have had a smaller chance of previous exposure to the prescribed antidepressant. Neither MAOIs or TCAs were included in this study. No patients taking MAOIs were identified from the Antidepressant Nonadherence Report during the study period. Three patients on TCAs were chart reviewed, but excluded from the study because of prior use of the antidepressant or a non-mental health indication. Additionally, no newer antidepressants, including vortioxetine and vilazodone, were included, likely secondary to their nonformulary status at the VA.

Conclusion

As this study’s purpose was to improve the quality of care at our facility, we will discuss our findings with local MHPs to develop strategies to improve antidepressant adherence. While larger studies need to be conducted to confirm our findings, it is worthwhile to consider risk factors for low adherence such as SUD when prescribing antidepressant medications. Patients with SUD could be encouraged to enroll in our facility’s telephone nursing depression care management program for more frequent follow up and medication adherence counseling.

This study did not find a significant difference in 3-month adherence rates between SSRIs, SNRIs, bupropion, and mirtazapine. SUD was significantly more common in patients with low adherence than those categorized as adherent and may be a risk factor for low adherence based upon our findings and those of previous studies.

A new meta-analysis has largely confirmed what is already known about the lifestyle factors that increase and those that decrease the risk of developing colorectal cancer.

The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk for colorectal cancer, the new article concludes. But it also adds a number of other factors that are associated with a decreased risk for the disease, including taking magnesium and folate supplements and eating dairy products, fiber, soy, and fruits and vegetables.

On the other hand, consumption of meat and alcohol was associated with an increased risk for colorectal cancer in almost all of the analyses included in this article.

The study was published online September 28 in Gut.

However, the authors pointed out that it is important to keep in mind that in most cases, the level of evidence is low or very low, primarily because of the heterogeneity of the various published studies, as well as the type of study.

“Furthermore, in most cases, we were unable to identify an optimal dose and duration of exposure/intake for any of the products, even in the case of low-dose aspirin and other compounds that have been extensively assessed,” they wrote.

The findings of this new meta-analysis echo previous findings on this issue.

A number of studies, for example, have found varying associations between the consumption of red meat and cancer. The American Institute for Cancer Research and the World Cancer Research Fund have published several reports during the past 10 years on the effect of diet, nutrition, and/or physical activity on risk for several cancer types. Their most recent study, published in 2017, concluded that eating red meat and processed meat may increase the risk for colorectal cancer, as may drinking two or more alcoholic beverages per day.

Another large meta-analysis published earlier this year found that regular use of aspirin reduced the risk for cancers of the digestive tract by 22%-38%, compared with nonuse.
 

Umbrella review

In the latest article in Gut, researchers led by Marc Bardou, MD, PhD, Centre Hospitalier Universitaire de Dijon (France), conducted an umbrella review of systematic reviews and meta-analyses of interventions that assessed chemopreventive products for colorectal cancer in an average-risk population.

A total of 80 meta-analyses of interventional and observational studies were included. The studies investigated a wide range of chemopreventive agents in an average-risk population and the risk for colorectal cancer. Agents included medications (aspirin, NSAIDs, statins), vitamins or supplements (magnesium; calcium; folic acid; vitamin A, B, C, E, and D; beta-carotene; and selenium), and dietary items (coffee, tea, fish, dairy products, fiber, fruits, vegetables, meat, and alcohol).

The studies included randomized controlled trials and observational studies. Most of the meta-analyses found a protective effect for aspirin, which lowered the risk by between 14% and 29% even at doses as low as 75 mg/day, with a dose-response effect of up to 325 mg/day. The certainty of evidence was moderate.

NSAID use was also associated with a protective effect, with a significant 26%-43% decrease in the incidence in colorectal cancer. The optimal duration for the observed protective effect remains unclear. Two meta-analyses suggested that NSAIDs may need to be taken for at least 5 years, although one article suggested a protective effect after the first year. The certainty of evidence was low.

Use of magnesium was found to be protective, with a relative risk (RR) of 0.78-0.87. High intake of folic acid was associated with a significant decrease in risk (RR, 0.85-0.88). The certainty of evidence was low and very low, respectively.

Consumption of dairy products was associated with 13%-19% lower risk for the disease. However, the authors note that, because of the small number of available meta-analyses, the multiplicity of outcomes, and the variety of dairy products, it was not possible to reach any firm conclusions about the amount needed or the duration necessary for a protective effect.

Another dietary item, fiber, was associated with a 22%-43% lower risk. Consumption of fruits and vegetables was associated with up to a 52% lower risk, with an added benefit for every additional 100 g/day increase in intake. Soy intake was also associated with a small but significant decrease in risk (8%-15%).

For many of the other items reviewed, evidence was either weak or no beneficial effect was seen.
 

Increased risk

Consumption of both meat and alcohol was found to increase the risk for colorectal cancer.

Most of the meta-analyses of observational studies have reported a significant increase in risk (RR, 1.12-1.21) with meat consumption (particularly red and processed) and the incidence of colorectal cancer. Studies of the dose effect reported a 10%-30% increased risk for each increment of 100 g/day of total or red meat.

Alcohol consumption was also associated with a significantly increased risk. The higher the intake, the greater the risk. The risk was evident even at the lowest consumption doses that were investigated (1-2 drinks per day).
 

Balanced for the individual patient

Commenting on the article, Thomas J. George Jr, MD, professor of medicine and director, GI Oncology Program, the University of Florida Health Cancer Center, Gainesville, feels that the take-home message for clinicians and patients alike is that these data help to reinforce behaviors that have already been recommended.

“We know that excessive alcohol and red meat consumption is not healthy, so seeing that there may be a negative effect on colorectal cancer is just more evidence that we should be avoiding that and recommend avoiding that,” said Dr. George. “So yes, I recommend minimizing those, and likewise, a diet that is inclusive of fruits, vegetables, fiber, soy – perhaps as an alternative to meat consumption – is healthier than a diet devoid of these, so again, more reassuring data to support doing what we should already be doing.”

However, he pointed out that there are risks associated with medications such as NSAIDs and aspirin, including bleeding, gastric ulcer formation, and kidney damage. “The risks are low but very real,” Dr. George said. “So I think those recommendations need to be considered on a very individual level, balancing any other risk factors that the patient may have for both colorectal cancer, as well as risks from the medications.”

The study had no outside funding. The authors have disclosed no relevant financial relationships.

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

A new meta-analysis has largely confirmed what is already known about the lifestyle factors that increase and those that decrease the risk of developing colorectal cancer.

The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk for colorectal cancer, the new article concludes. But it also adds a number of other factors that are associated with a decreased risk for the disease, including taking magnesium and folate supplements and eating dairy products, fiber, soy, and fruits and vegetables.

On the other hand, consumption of meat and alcohol was associated with an increased risk for colorectal cancer in almost all of the analyses included in this article.

The study was published online September 28 in Gut.

However, the authors pointed out that it is important to keep in mind that in most cases, the level of evidence is low or very low, primarily because of the heterogeneity of the various published studies, as well as the type of study.

“Furthermore, in most cases, we were unable to identify an optimal dose and duration of exposure/intake for any of the products, even in the case of low-dose aspirin and other compounds that have been extensively assessed,” they wrote.

The findings of this new meta-analysis echo previous findings on this issue.

A number of studies, for example, have found varying associations between the consumption of red meat and cancer. The American Institute for Cancer Research and the World Cancer Research Fund have published several reports during the past 10 years on the effect of diet, nutrition, and/or physical activity on risk for several cancer types. Their most recent study, published in 2017, concluded that eating red meat and processed meat may increase the risk for colorectal cancer, as may drinking two or more alcoholic beverages per day.

Another large meta-analysis published earlier this year found that regular use of aspirin reduced the risk for cancers of the digestive tract by 22%-38%, compared with nonuse.
 

Umbrella review

In the latest article in Gut, researchers led by Marc Bardou, MD, PhD, Centre Hospitalier Universitaire de Dijon (France), conducted an umbrella review of systematic reviews and meta-analyses of interventions that assessed chemopreventive products for colorectal cancer in an average-risk population.

A total of 80 meta-analyses of interventional and observational studies were included. The studies investigated a wide range of chemopreventive agents in an average-risk population and the risk for colorectal cancer. Agents included medications (aspirin, NSAIDs, statins), vitamins or supplements (magnesium; calcium; folic acid; vitamin A, B, C, E, and D; beta-carotene; and selenium), and dietary items (coffee, tea, fish, dairy products, fiber, fruits, vegetables, meat, and alcohol).

The studies included randomized controlled trials and observational studies. Most of the meta-analyses found a protective effect for aspirin, which lowered the risk by between 14% and 29% even at doses as low as 75 mg/day, with a dose-response effect of up to 325 mg/day. The certainty of evidence was moderate.

NSAID use was also associated with a protective effect, with a significant 26%-43% decrease in the incidence in colorectal cancer. The optimal duration for the observed protective effect remains unclear. Two meta-analyses suggested that NSAIDs may need to be taken for at least 5 years, although one article suggested a protective effect after the first year. The certainty of evidence was low.

Use of magnesium was found to be protective, with a relative risk (RR) of 0.78-0.87. High intake of folic acid was associated with a significant decrease in risk (RR, 0.85-0.88). The certainty of evidence was low and very low, respectively.

Consumption of dairy products was associated with 13%-19% lower risk for the disease. However, the authors note that, because of the small number of available meta-analyses, the multiplicity of outcomes, and the variety of dairy products, it was not possible to reach any firm conclusions about the amount needed or the duration necessary for a protective effect.

Another dietary item, fiber, was associated with a 22%-43% lower risk. Consumption of fruits and vegetables was associated with up to a 52% lower risk, with an added benefit for every additional 100 g/day increase in intake. Soy intake was also associated with a small but significant decrease in risk (8%-15%).

For many of the other items reviewed, evidence was either weak or no beneficial effect was seen.
 

Increased risk

Consumption of both meat and alcohol was found to increase the risk for colorectal cancer.

Most of the meta-analyses of observational studies have reported a significant increase in risk (RR, 1.12-1.21) with meat consumption (particularly red and processed) and the incidence of colorectal cancer. Studies of the dose effect reported a 10%-30% increased risk for each increment of 100 g/day of total or red meat.

Alcohol consumption was also associated with a significantly increased risk. The higher the intake, the greater the risk. The risk was evident even at the lowest consumption doses that were investigated (1-2 drinks per day).
 

Balanced for the individual patient

Commenting on the article, Thomas J. George Jr, MD, professor of medicine and director, GI Oncology Program, the University of Florida Health Cancer Center, Gainesville, feels that the take-home message for clinicians and patients alike is that these data help to reinforce behaviors that have already been recommended.

“We know that excessive alcohol and red meat consumption is not healthy, so seeing that there may be a negative effect on colorectal cancer is just more evidence that we should be avoiding that and recommend avoiding that,” said Dr. George. “So yes, I recommend minimizing those, and likewise, a diet that is inclusive of fruits, vegetables, fiber, soy – perhaps as an alternative to meat consumption – is healthier than a diet devoid of these, so again, more reassuring data to support doing what we should already be doing.”

However, he pointed out that there are risks associated with medications such as NSAIDs and aspirin, including bleeding, gastric ulcer formation, and kidney damage. “The risks are low but very real,” Dr. George said. “So I think those recommendations need to be considered on a very individual level, balancing any other risk factors that the patient may have for both colorectal cancer, as well as risks from the medications.”

The study had no outside funding. The authors have disclosed no relevant financial relationships.

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

A new meta-analysis has largely confirmed what is already known about the lifestyle factors that increase and those that decrease the risk of developing colorectal cancer.

The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk for colorectal cancer, the new article concludes. But it also adds a number of other factors that are associated with a decreased risk for the disease, including taking magnesium and folate supplements and eating dairy products, fiber, soy, and fruits and vegetables.

On the other hand, consumption of meat and alcohol was associated with an increased risk for colorectal cancer in almost all of the analyses included in this article.

The study was published online September 28 in Gut.

However, the authors pointed out that it is important to keep in mind that in most cases, the level of evidence is low or very low, primarily because of the heterogeneity of the various published studies, as well as the type of study.

“Furthermore, in most cases, we were unable to identify an optimal dose and duration of exposure/intake for any of the products, even in the case of low-dose aspirin and other compounds that have been extensively assessed,” they wrote.

The findings of this new meta-analysis echo previous findings on this issue.

A number of studies, for example, have found varying associations between the consumption of red meat and cancer. The American Institute for Cancer Research and the World Cancer Research Fund have published several reports during the past 10 years on the effect of diet, nutrition, and/or physical activity on risk for several cancer types. Their most recent study, published in 2017, concluded that eating red meat and processed meat may increase the risk for colorectal cancer, as may drinking two or more alcoholic beverages per day.

Another large meta-analysis published earlier this year found that regular use of aspirin reduced the risk for cancers of the digestive tract by 22%-38%, compared with nonuse.
 

Umbrella review

In the latest article in Gut, researchers led by Marc Bardou, MD, PhD, Centre Hospitalier Universitaire de Dijon (France), conducted an umbrella review of systematic reviews and meta-analyses of interventions that assessed chemopreventive products for colorectal cancer in an average-risk population.

A total of 80 meta-analyses of interventional and observational studies were included. The studies investigated a wide range of chemopreventive agents in an average-risk population and the risk for colorectal cancer. Agents included medications (aspirin, NSAIDs, statins), vitamins or supplements (magnesium; calcium; folic acid; vitamin A, B, C, E, and D; beta-carotene; and selenium), and dietary items (coffee, tea, fish, dairy products, fiber, fruits, vegetables, meat, and alcohol).

The studies included randomized controlled trials and observational studies. Most of the meta-analyses found a protective effect for aspirin, which lowered the risk by between 14% and 29% even at doses as low as 75 mg/day, with a dose-response effect of up to 325 mg/day. The certainty of evidence was moderate.

NSAID use was also associated with a protective effect, with a significant 26%-43% decrease in the incidence in colorectal cancer. The optimal duration for the observed protective effect remains unclear. Two meta-analyses suggested that NSAIDs may need to be taken for at least 5 years, although one article suggested a protective effect after the first year. The certainty of evidence was low.

Use of magnesium was found to be protective, with a relative risk (RR) of 0.78-0.87. High intake of folic acid was associated with a significant decrease in risk (RR, 0.85-0.88). The certainty of evidence was low and very low, respectively.

Consumption of dairy products was associated with 13%-19% lower risk for the disease. However, the authors note that, because of the small number of available meta-analyses, the multiplicity of outcomes, and the variety of dairy products, it was not possible to reach any firm conclusions about the amount needed or the duration necessary for a protective effect.

Another dietary item, fiber, was associated with a 22%-43% lower risk. Consumption of fruits and vegetables was associated with up to a 52% lower risk, with an added benefit for every additional 100 g/day increase in intake. Soy intake was also associated with a small but significant decrease in risk (8%-15%).

For many of the other items reviewed, evidence was either weak or no beneficial effect was seen.
 

Increased risk

Consumption of both meat and alcohol was found to increase the risk for colorectal cancer.

Most of the meta-analyses of observational studies have reported a significant increase in risk (RR, 1.12-1.21) with meat consumption (particularly red and processed) and the incidence of colorectal cancer. Studies of the dose effect reported a 10%-30% increased risk for each increment of 100 g/day of total or red meat.

Alcohol consumption was also associated with a significantly increased risk. The higher the intake, the greater the risk. The risk was evident even at the lowest consumption doses that were investigated (1-2 drinks per day).
 

Balanced for the individual patient

Commenting on the article, Thomas J. George Jr, MD, professor of medicine and director, GI Oncology Program, the University of Florida Health Cancer Center, Gainesville, feels that the take-home message for clinicians and patients alike is that these data help to reinforce behaviors that have already been recommended.

“We know that excessive alcohol and red meat consumption is not healthy, so seeing that there may be a negative effect on colorectal cancer is just more evidence that we should be avoiding that and recommend avoiding that,” said Dr. George. “So yes, I recommend minimizing those, and likewise, a diet that is inclusive of fruits, vegetables, fiber, soy – perhaps as an alternative to meat consumption – is healthier than a diet devoid of these, so again, more reassuring data to support doing what we should already be doing.”

However, he pointed out that there are risks associated with medications such as NSAIDs and aspirin, including bleeding, gastric ulcer formation, and kidney damage. “The risks are low but very real,” Dr. George said. “So I think those recommendations need to be considered on a very individual level, balancing any other risk factors that the patient may have for both colorectal cancer, as well as risks from the medications.”

The study had no outside funding. The authors have disclosed no relevant financial relationships.

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

To protect the heart and kidneys, sodium-glucose transporter 2 (SGLT2) inhibitors and glucagonlike peptide–1 (GLP-1) receptor agonists should be considered for people with type 2 diabetes and chronic kidney disease (CKD), the American Heart Association advised in a new scientific statement.

Taken together, the results of relevant clinical trials indicate that SGLT2 inhibitors and GLP-1 receptor agonists safely and significantly reduce the risk for cardiovascular (CV) events, death, and the slow progression of CKD to end-stage kidney disease, including the risks for dialysis, transplantation, and death, the writing group says.

The scientific statement was published online Sept. 28 in Circulation.

“There has been rapid reporting of high-quality data in the cardio-renal-metabolic space with significant heart and kidney benefits, particularly with these two newer classes of antihyperglycemic agents,” Janani Rangaswami, MD, who chaired the writing group, said in an interview.

“More recent data show benefits in chronic kidney disease and heart failure even in patients without diabetes,” said Dr. Rangaswami, Einstein Medical Center and Sidney Kimmel Medical College, both in Philadelphia.

“These data are practice-changing in both cardiology and nephrology, and usher in a new era of disease-modifying therapies in heart and kidney disease,” Dr. Rangaswami added.
 

Recommendations at a glance

• Provide early and ongoing assessment of risks for CVD and CKD to patients who may benefit from SGLT2 inhibitors of GLP-1 receptor agonists.
• Tailor medication choices that meet the needs of individual patients. Realize that, given “consistent class-wide effects,” the choice of a specific SGLT2 inhibitor or GLP-1 receptor agonist may be dictated by affordability, coverage, and formulary considerations.
• Adjust all medications in tandem with these medicines and consider the burden of polypharmacy, which is common among people with type 2 diabetes. Adjust concomitant therapies and deprescribe where possible.
• Identify risks for hypoglycemia and educate patients on the signs so they can seek treatment quickly.
• Monitor and control high blood pressure.
• Counsel patients about the risks for and symptoms of euglycemic diabetic ketoacidosis when taking SGLT2 inhibitors, as well as classic DKA, which can be fatal.
• Regularly screen and counsel patients about foot care to prevent foot ulcers or blisters that can quickly become infected and lead to amputation.

The writing group identified two additional patient subgroups that may benefit from SGLT2 inhibitors and GLP-1 receptor agonists: those with heart failure with reduced ejection fraction with or without diabetes; and those with CKD who do not have diabetes. They say more data are anticipated to validate the use of SGLT2 inhibitors and GLP-1 receptor agonists in these “at-risk” patients.
 

Collaborative care model

The writing group proposed a collaborative care model, bridging cardiologists, nephrologists, endocrinologists, and primary care physicians, to help facilitate the “prompt and appropriate” integration of these new classes of medications in the management of patients with type 2 diabetes and CKD.

There is “an unmet need for a cardio-renal-metabolic care model that incorporates best practices in the real world to help align these therapies, especially with vulnerable high-risk patients with cardiorenal disease, and to overcome barriers toward uptake of these agents. Hopefully this statement provides some guidance to the cardiology and nephrology communities in that area,” Dr. Rangaswami said in an interview.

But old habits die hard, as research continues to show the slow adoption of these newer medications in the real world.

For example, a large observational study published last year showed a “striking” discordance between evidence-based, guideline-recommended use of SGLT2 inhibitors for the treatment of type 2 diabetes and their actual uptake in clinical practice.

Paradoxically, patients with CVD, heart failure, hypertension, CKD, and those at risk for hypoglycemia were less apt to receive an SGLT2 inhibitor than other patients.

“The relatively slow uptake of these agents is multifactorial,” Dr. Rangaswami said. “Cardiologists and nephrologists may suffer from some level of ‘therapeutic inertia’ when using new agents they are unfamiliar with and originally branded as ‘antidiabetic’ agents, with the perception of these agents being outside the scope of their practice.”

Two other factors are also at play. “The current health care system is based on ‘specialty silos,’ where specialists tend to stick to the traditional scope of their specialty and are reluctant to view these agents as part of their therapeutic armamentarium. Finally, insurance coverage barriers and affordability also limit the use on a widespread basis,” Dr. Rangaswami said.

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

To protect the heart and kidneys, sodium-glucose transporter 2 (SGLT2) inhibitors and glucagonlike peptide–1 (GLP-1) receptor agonists should be considered for people with type 2 diabetes and chronic kidney disease (CKD), the American Heart Association advised in a new scientific statement.

Taken together, the results of relevant clinical trials indicate that SGLT2 inhibitors and GLP-1 receptor agonists safely and significantly reduce the risk for cardiovascular (CV) events, death, and the slow progression of CKD to end-stage kidney disease, including the risks for dialysis, transplantation, and death, the writing group says.

The scientific statement was published online Sept. 28 in Circulation.

“There has been rapid reporting of high-quality data in the cardio-renal-metabolic space with significant heart and kidney benefits, particularly with these two newer classes of antihyperglycemic agents,” Janani Rangaswami, MD, who chaired the writing group, said in an interview.

“More recent data show benefits in chronic kidney disease and heart failure even in patients without diabetes,” said Dr. Rangaswami, Einstein Medical Center and Sidney Kimmel Medical College, both in Philadelphia.

“These data are practice-changing in both cardiology and nephrology, and usher in a new era of disease-modifying therapies in heart and kidney disease,” Dr. Rangaswami added.
 

Recommendations at a glance

• Provide early and ongoing assessment of risks for CVD and CKD to patients who may benefit from SGLT2 inhibitors of GLP-1 receptor agonists.
• Tailor medication choices that meet the needs of individual patients. Realize that, given “consistent class-wide effects,” the choice of a specific SGLT2 inhibitor or GLP-1 receptor agonist may be dictated by affordability, coverage, and formulary considerations.
• Adjust all medications in tandem with these medicines and consider the burden of polypharmacy, which is common among people with type 2 diabetes. Adjust concomitant therapies and deprescribe where possible.
• Identify risks for hypoglycemia and educate patients on the signs so they can seek treatment quickly.
• Monitor and control high blood pressure.
• Counsel patients about the risks for and symptoms of euglycemic diabetic ketoacidosis when taking SGLT2 inhibitors, as well as classic DKA, which can be fatal.
• Regularly screen and counsel patients about foot care to prevent foot ulcers or blisters that can quickly become infected and lead to amputation.

The writing group identified two additional patient subgroups that may benefit from SGLT2 inhibitors and GLP-1 receptor agonists: those with heart failure with reduced ejection fraction with or without diabetes; and those with CKD who do not have diabetes. They say more data are anticipated to validate the use of SGLT2 inhibitors and GLP-1 receptor agonists in these “at-risk” patients.
 

Collaborative care model

The writing group proposed a collaborative care model, bridging cardiologists, nephrologists, endocrinologists, and primary care physicians, to help facilitate the “prompt and appropriate” integration of these new classes of medications in the management of patients with type 2 diabetes and CKD.

There is “an unmet need for a cardio-renal-metabolic care model that incorporates best practices in the real world to help align these therapies, especially with vulnerable high-risk patients with cardiorenal disease, and to overcome barriers toward uptake of these agents. Hopefully this statement provides some guidance to the cardiology and nephrology communities in that area,” Dr. Rangaswami said in an interview.

But old habits die hard, as research continues to show the slow adoption of these newer medications in the real world.

For example, a large observational study published last year showed a “striking” discordance between evidence-based, guideline-recommended use of SGLT2 inhibitors for the treatment of type 2 diabetes and their actual uptake in clinical practice.

Paradoxically, patients with CVD, heart failure, hypertension, CKD, and those at risk for hypoglycemia were less apt to receive an SGLT2 inhibitor than other patients.

“The relatively slow uptake of these agents is multifactorial,” Dr. Rangaswami said. “Cardiologists and nephrologists may suffer from some level of ‘therapeutic inertia’ when using new agents they are unfamiliar with and originally branded as ‘antidiabetic’ agents, with the perception of these agents being outside the scope of their practice.”

Two other factors are also at play. “The current health care system is based on ‘specialty silos,’ where specialists tend to stick to the traditional scope of their specialty and are reluctant to view these agents as part of their therapeutic armamentarium. Finally, insurance coverage barriers and affordability also limit the use on a widespread basis,” Dr. Rangaswami said.

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

To protect the heart and kidneys, sodium-glucose transporter 2 (SGLT2) inhibitors and glucagonlike peptide–1 (GLP-1) receptor agonists should be considered for people with type 2 diabetes and chronic kidney disease (CKD), the American Heart Association advised in a new scientific statement.

Taken together, the results of relevant clinical trials indicate that SGLT2 inhibitors and GLP-1 receptor agonists safely and significantly reduce the risk for cardiovascular (CV) events, death, and the slow progression of CKD to end-stage kidney disease, including the risks for dialysis, transplantation, and death, the writing group says.

The scientific statement was published online Sept. 28 in Circulation.

“There has been rapid reporting of high-quality data in the cardio-renal-metabolic space with significant heart and kidney benefits, particularly with these two newer classes of antihyperglycemic agents,” Janani Rangaswami, MD, who chaired the writing group, said in an interview.

“More recent data show benefits in chronic kidney disease and heart failure even in patients without diabetes,” said Dr. Rangaswami, Einstein Medical Center and Sidney Kimmel Medical College, both in Philadelphia.

“These data are practice-changing in both cardiology and nephrology, and usher in a new era of disease-modifying therapies in heart and kidney disease,” Dr. Rangaswami added.
 

Recommendations at a glance

• Provide early and ongoing assessment of risks for CVD and CKD to patients who may benefit from SGLT2 inhibitors of GLP-1 receptor agonists.
• Tailor medication choices that meet the needs of individual patients. Realize that, given “consistent class-wide effects,” the choice of a specific SGLT2 inhibitor or GLP-1 receptor agonist may be dictated by affordability, coverage, and formulary considerations.
• Adjust all medications in tandem with these medicines and consider the burden of polypharmacy, which is common among people with type 2 diabetes. Adjust concomitant therapies and deprescribe where possible.
• Identify risks for hypoglycemia and educate patients on the signs so they can seek treatment quickly.
• Monitor and control high blood pressure.
• Counsel patients about the risks for and symptoms of euglycemic diabetic ketoacidosis when taking SGLT2 inhibitors, as well as classic DKA, which can be fatal.
• Regularly screen and counsel patients about foot care to prevent foot ulcers or blisters that can quickly become infected and lead to amputation.

The writing group identified two additional patient subgroups that may benefit from SGLT2 inhibitors and GLP-1 receptor agonists: those with heart failure with reduced ejection fraction with or without diabetes; and those with CKD who do not have diabetes. They say more data are anticipated to validate the use of SGLT2 inhibitors and GLP-1 receptor agonists in these “at-risk” patients.
 

Collaborative care model

The writing group proposed a collaborative care model, bridging cardiologists, nephrologists, endocrinologists, and primary care physicians, to help facilitate the “prompt and appropriate” integration of these new classes of medications in the management of patients with type 2 diabetes and CKD.

There is “an unmet need for a cardio-renal-metabolic care model that incorporates best practices in the real world to help align these therapies, especially with vulnerable high-risk patients with cardiorenal disease, and to overcome barriers toward uptake of these agents. Hopefully this statement provides some guidance to the cardiology and nephrology communities in that area,” Dr. Rangaswami said in an interview.

But old habits die hard, as research continues to show the slow adoption of these newer medications in the real world.

For example, a large observational study published last year showed a “striking” discordance between evidence-based, guideline-recommended use of SGLT2 inhibitors for the treatment of type 2 diabetes and their actual uptake in clinical practice.

Paradoxically, patients with CVD, heart failure, hypertension, CKD, and those at risk for hypoglycemia were less apt to receive an SGLT2 inhibitor than other patients.

“The relatively slow uptake of these agents is multifactorial,” Dr. Rangaswami said. “Cardiologists and nephrologists may suffer from some level of ‘therapeutic inertia’ when using new agents they are unfamiliar with and originally branded as ‘antidiabetic’ agents, with the perception of these agents being outside the scope of their practice.”

Two other factors are also at play. “The current health care system is based on ‘specialty silos,’ where specialists tend to stick to the traditional scope of their specialty and are reluctant to view these agents as part of their therapeutic armamentarium. Finally, insurance coverage barriers and affordability also limit the use on a widespread basis,” Dr. Rangaswami said.

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

I have been in practice for 31 years, so many of my patients are now in their 80s and 90s. Practices age with us, and I have been seeing many of these patients for 25-30 years. I have three rules I try to encourage my elderly patients follow, and I wanted to share them with you.

Absolutely, positively make sure you move!

Our older patients often have many reasons not to move, including pain from arthritis, deconditioning, muscle weakness, fatigue, and depression. “Keeping moving” is probably the most important thing a patient can do for their health.

Holme and Anderssen studied a large cohort of men for cardiovascular risk in 1972 and again in 2000. The surviving men were followed over an additional 12 years.¹ They found that 30 minutes of physical activity 6 days a week was associated with a 40% reduction in mortality. Sedentary men had a reduced life expectancy of about 5 years, compared with men who were moderately to vigorously physically active.

Stewart etal. studied the benefit of physical activity in people with stable coronary disease.² They concluded that, in patients with stable coronary heart disease, more physical activity was associated with lower mortality, and the largest benefit occurred in the sedentary patient groups and the highest cardiac risk groups.

Saint-Maurice et al. studied the effects of total daily step count and step intensity on mortality risk.³ They found that the risk of all-cause mortality decreases as the total number of daily steps increases, but that the speed of those steps did not make a difference. This is very encouraging data for our elderly patients. Moving is the secret, even if it may not be moving at a fast pace!
 

Never, ever get on a ladder!

This one should be part of every geriatric’s assessment and every Medicare wellness exam. I first experienced the horror of what can happen when elderly people climb when a 96-year-old healthy patient of mine fell off his roof and died. I never thought to tell him climbing on the roof was an awful idea.

Akland et al. looked at the epidemiology and outcomes of ladder-related falls that required ICU admission.⁴ Hospital mortality was 26%, and almost all of the mortalities occurred in older males in domestic falls, who died as a result of traumatic brain injury. Fewer than half of the survivors were living independently 1 year after the fall.

Valmuur et al. studied ladder related falls in Australia.⁵ They found that rates of ladder related falls requiring hospitalization rose from about 20/100,000 for men ages 15-29 years to 78/100,000 for men aged over 60 years. Of those who died from fall-related injury, 82% were over the age of 60, with more than 70% dying from head injuries.

Schaffarczyk et al. looked at the impact of nonoccupational falls from ladders in men aged over 50 years.⁶ The mean age of the patients in the study was 64 years (range, 50-85), with 27% suffering severe trauma. There was a striking impact on long-term function occurring in over half the study patients. The authors did interviews with patients in follow-up long after the falls and found that most never thought of themselves at risk for a fall, and after the experience of a bad fall, would never consider going on a ladder again. I think it is important for health care professionals to discuss the dangers of ladder use with our older patients, pointing out the higher risk of falling and the potential for the fall to be a life-changing or life-ending event.
 

Let them eat!

Many patients have a reduced appetite as they age. We work hard with our patients to choose a healthy diet throughout their lives, to help ward off obesity, treat hypertension, prevent or control diabetes, or provide heart health. Many patients just stop being interested in food, reduce intake, and may lose weight and muscle mass. When my patients pass the age of 85, I change my focus to encouraging them to eat for calories, socialization, and joy. I think the marginal benefits of more restrictive diets are small, compared with the benefits of helping your patients enjoy eating again. I ask patients what their very favorite foods are and encourage them to have them.

Pearl

Keep your patients eating and moving, except not onto a ladder!

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Holme I, Anderssen SA. Increases in physical activity is as important as smoking cessation for reduction in total mortality in elderly men: 12 years of follow-up of the Oslo II study. Br J Sports Med. 2015; 49:743-8.

2. Stewart RAH et al. Physical activity and mortality in patients with stable coronary heart disease. J Am Coll Cardiol. 2017 Oct 3;70(14):1689-1700..

3. Saint-Maurice PF et al. Association of daily step count and step intensity with mortality among U.S. adults. JAMA 2020;323:1151-60.

4. Ackland HM et al. Danger at every rung: Epidemiology and outcomes of ICU-admitted ladder-related trauma. Injury. 2016;47:1109-117.

5. Vallmuur K et al. Falls from ladders in Australia: comparing occupational and nonoccupational injuries across age groups. Aust N Z J Public Health. 2016 Dec;40(6):559-63.

6. Schaffarczyk K et al. Nonoccupational falls from ladders in men 50 years and over: Contributing factors and impact. Injury. 2020 Aug;51(8):1798-1804.

I have been in practice for 31 years, so many of my patients are now in their 80s and 90s. Practices age with us, and I have been seeing many of these patients for 25-30 years. I have three rules I try to encourage my elderly patients follow, and I wanted to share them with you.

Absolutely, positively make sure you move!

Our older patients often have many reasons not to move, including pain from arthritis, deconditioning, muscle weakness, fatigue, and depression. “Keeping moving” is probably the most important thing a patient can do for their health.

Holme and Anderssen studied a large cohort of men for cardiovascular risk in 1972 and again in 2000. The surviving men were followed over an additional 12 years.¹ They found that 30 minutes of physical activity 6 days a week was associated with a 40% reduction in mortality. Sedentary men had a reduced life expectancy of about 5 years, compared with men who were moderately to vigorously physically active.

Stewart etal. studied the benefit of physical activity in people with stable coronary disease.² They concluded that, in patients with stable coronary heart disease, more physical activity was associated with lower mortality, and the largest benefit occurred in the sedentary patient groups and the highest cardiac risk groups.

Saint-Maurice et al. studied the effects of total daily step count and step intensity on mortality risk.³ They found that the risk of all-cause mortality decreases as the total number of daily steps increases, but that the speed of those steps did not make a difference. This is very encouraging data for our elderly patients. Moving is the secret, even if it may not be moving at a fast pace!
 

Never, ever get on a ladder!

This one should be part of every geriatric’s assessment and every Medicare wellness exam. I first experienced the horror of what can happen when elderly people climb when a 96-year-old healthy patient of mine fell off his roof and died. I never thought to tell him climbing on the roof was an awful idea.

Akland et al. looked at the epidemiology and outcomes of ladder-related falls that required ICU admission.⁴ Hospital mortality was 26%, and almost all of the mortalities occurred in older males in domestic falls, who died as a result of traumatic brain injury. Fewer than half of the survivors were living independently 1 year after the fall.

Valmuur et al. studied ladder related falls in Australia.⁵ They found that rates of ladder related falls requiring hospitalization rose from about 20/100,000 for men ages 15-29 years to 78/100,000 for men aged over 60 years. Of those who died from fall-related injury, 82% were over the age of 60, with more than 70% dying from head injuries.

Schaffarczyk et al. looked at the impact of nonoccupational falls from ladders in men aged over 50 years.⁶ The mean age of the patients in the study was 64 years (range, 50-85), with 27% suffering severe trauma. There was a striking impact on long-term function occurring in over half the study patients. The authors did interviews with patients in follow-up long after the falls and found that most never thought of themselves at risk for a fall, and after the experience of a bad fall, would never consider going on a ladder again. I think it is important for health care professionals to discuss the dangers of ladder use with our older patients, pointing out the higher risk of falling and the potential for the fall to be a life-changing or life-ending event.
 

Let them eat!

Many patients have a reduced appetite as they age. We work hard with our patients to choose a healthy diet throughout their lives, to help ward off obesity, treat hypertension, prevent or control diabetes, or provide heart health. Many patients just stop being interested in food, reduce intake, and may lose weight and muscle mass. When my patients pass the age of 85, I change my focus to encouraging them to eat for calories, socialization, and joy. I think the marginal benefits of more restrictive diets are small, compared with the benefits of helping your patients enjoy eating again. I ask patients what their very favorite foods are and encourage them to have them.

Pearl

Keep your patients eating and moving, except not onto a ladder!

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Holme I, Anderssen SA. Increases in physical activity is as important as smoking cessation for reduction in total mortality in elderly men: 12 years of follow-up of the Oslo II study. Br J Sports Med. 2015; 49:743-8.

2. Stewart RAH et al. Physical activity and mortality in patients with stable coronary heart disease. J Am Coll Cardiol. 2017 Oct 3;70(14):1689-1700..

3. Saint-Maurice PF et al. Association of daily step count and step intensity with mortality among U.S. adults. JAMA 2020;323:1151-60.

4. Ackland HM et al. Danger at every rung: Epidemiology and outcomes of ICU-admitted ladder-related trauma. Injury. 2016;47:1109-117.

5. Vallmuur K et al. Falls from ladders in Australia: comparing occupational and nonoccupational injuries across age groups. Aust N Z J Public Health. 2016 Dec;40(6):559-63.

6. Schaffarczyk K et al. Nonoccupational falls from ladders in men 50 years and over: Contributing factors and impact. Injury. 2020 Aug;51(8):1798-1804.

I have been in practice for 31 years, so many of my patients are now in their 80s and 90s. Practices age with us, and I have been seeing many of these patients for 25-30 years. I have three rules I try to encourage my elderly patients follow, and I wanted to share them with you.

Absolutely, positively make sure you move!

Our older patients often have many reasons not to move, including pain from arthritis, deconditioning, muscle weakness, fatigue, and depression. “Keeping moving” is probably the most important thing a patient can do for their health.

Holme and Anderssen studied a large cohort of men for cardiovascular risk in 1972 and again in 2000. The surviving men were followed over an additional 12 years.¹ They found that 30 minutes of physical activity 6 days a week was associated with a 40% reduction in mortality. Sedentary men had a reduced life expectancy of about 5 years, compared with men who were moderately to vigorously physically active.

Stewart etal. studied the benefit of physical activity in people with stable coronary disease.² They concluded that, in patients with stable coronary heart disease, more physical activity was associated with lower mortality, and the largest benefit occurred in the sedentary patient groups and the highest cardiac risk groups.

Saint-Maurice et al. studied the effects of total daily step count and step intensity on mortality risk.³ They found that the risk of all-cause mortality decreases as the total number of daily steps increases, but that the speed of those steps did not make a difference. This is very encouraging data for our elderly patients. Moving is the secret, even if it may not be moving at a fast pace!
 

Never, ever get on a ladder!

This one should be part of every geriatric’s assessment and every Medicare wellness exam. I first experienced the horror of what can happen when elderly people climb when a 96-year-old healthy patient of mine fell off his roof and died. I never thought to tell him climbing on the roof was an awful idea.

Akland et al. looked at the epidemiology and outcomes of ladder-related falls that required ICU admission.⁴ Hospital mortality was 26%, and almost all of the mortalities occurred in older males in domestic falls, who died as a result of traumatic brain injury. Fewer than half of the survivors were living independently 1 year after the fall.

Valmuur et al. studied ladder related falls in Australia.⁵ They found that rates of ladder related falls requiring hospitalization rose from about 20/100,000 for men ages 15-29 years to 78/100,000 for men aged over 60 years. Of those who died from fall-related injury, 82% were over the age of 60, with more than 70% dying from head injuries.

Schaffarczyk et al. looked at the impact of nonoccupational falls from ladders in men aged over 50 years.⁶ The mean age of the patients in the study was 64 years (range, 50-85), with 27% suffering severe trauma. There was a striking impact on long-term function occurring in over half the study patients. The authors did interviews with patients in follow-up long after the falls and found that most never thought of themselves at risk for a fall, and after the experience of a bad fall, would never consider going on a ladder again. I think it is important for health care professionals to discuss the dangers of ladder use with our older patients, pointing out the higher risk of falling and the potential for the fall to be a life-changing or life-ending event.
 

Let them eat!

Many patients have a reduced appetite as they age. We work hard with our patients to choose a healthy diet throughout their lives, to help ward off obesity, treat hypertension, prevent or control diabetes, or provide heart health. Many patients just stop being interested in food, reduce intake, and may lose weight and muscle mass. When my patients pass the age of 85, I change my focus to encouraging them to eat for calories, socialization, and joy. I think the marginal benefits of more restrictive diets are small, compared with the benefits of helping your patients enjoy eating again. I ask patients what their very favorite foods are and encourage them to have them.

Pearl

Keep your patients eating and moving, except not onto a ladder!

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Holme I, Anderssen SA. Increases in physical activity is as important as smoking cessation for reduction in total mortality in elderly men: 12 years of follow-up of the Oslo II study. Br J Sports Med. 2015; 49:743-8.

2. Stewart RAH et al. Physical activity and mortality in patients with stable coronary heart disease. J Am Coll Cardiol. 2017 Oct 3;70(14):1689-1700..

3. Saint-Maurice PF et al. Association of daily step count and step intensity with mortality among U.S. adults. JAMA 2020;323:1151-60.

4. Ackland HM et al. Danger at every rung: Epidemiology and outcomes of ICU-admitted ladder-related trauma. Injury. 2016;47:1109-117.

5. Vallmuur K et al. Falls from ladders in Australia: comparing occupational and nonoccupational injuries across age groups. Aust N Z J Public Health. 2016 Dec;40(6):559-63.

6. Schaffarczyk K et al. Nonoccupational falls from ladders in men 50 years and over: Contributing factors and impact. Injury. 2020 Aug;51(8):1798-1804.

Jun Yang, MBBS, had watched as her father, who had battled hypertension for decades, ended up on four medications that still couldn’t bring his blood pressure to a healthy level. The cardiovascular endocrinologist then ran some tests, and soon thereafter her father had his blood pressure optimized on just one targeted medication.

Courtesy Dr. Jun Yang

Dr. Yang’s father was found to have a hormonal condition known as primary aldosteronism (PA) as the cause of his hypertension.

It turns out that PA is not as rare as once thought.

An eye-catching report in Annals of Internal Medicine this spring of an unexpectedly high prevalence of primary aldosteronism among a diverse cross section of U.S. patients with hypertension has raised issues that could dramatically change the way doctors in America, and elsewhere, assess and manage high blood pressure.

Foremost is the question of whether primary care physicians – the clinicians at the front line for diagnosing and initially treating most patients with hypertension – will absorb and act on this new evidence. For them, aldosteronism doesn’t automatically come to mind when they see high numbers on a BP monitor, and yet this latest research found that up to a third of all 726 patients in the study who were diagnosed with hypertension and with high urinary salt levels had PA.

That translates to a roughly three- to fivefold increase over standard prevalence estimates, and is a ”game changer” for how clinicians should approach hypertension management and PA diagnosis going forward, said John W. Funder, MD, in an editorial accompanying the Annals study.

Long considered relatively uncommon, hypertension driven by an excess of the hormone aldosterone, often because of an adenoma on the adrenal gland, is not the same as conventional “essential” hypertension. The former benefits from early diagnosis because its treatment is completely different – close to half of all PA patients can be treated definitively and quickly with surgical removal of an adenoma from one side of the adrenal gland.

For other PA patients, who have bilateral adrenal hyperplasia that is impossible to resolve surgically, treatment with drugs called mineralocorticoid receptor antagonists (MRAs), such as spironolactone, is needed because they target the hormonal cause of the high BP.

But what usually happens is that a patient with PA is mistakenly diagnosed with essential hypertension, in which the classic approach to treatment is to start with one regular antihypertensive drug, and add on further ones from different drug classes if blood pressure is not adequately controlled. When patients are taking three drugs, without adequate control, they are labeled as having “resistant hypertension.”

But in the case of PA, none of these conventional antihypertensives work, and the process of continuing to monitor and add different drugs wastes time, during which patients deteriorate.

“We need to change the culture of waiting for hypertension to be resistant and have patients riddled with end-organ damage,” due to years of persistently high BP and excess aldosterone “before we look for a secondary cause” like PA, declared Dr. Yang, of Hudson Institute of Medical Research and Monash University in Melbourne, during an interview.

So early diagnosis and prompt treatment of PA is key.

In addition to boosting the public health importance of early PA detection in hypertensive patients, the new up-sized PA prevalence numbers throw a spotlight on primary care physicians (PCPs) as key players who will need to apply the findings to practice on a public health scale.

These novel results create a need for “new guidelines, and a radically revised game plan with the key role of PCPs” emphasized in future management of patients with hypertension, said Dr. Funder, a professor of medicine at Monash University, in a second recent editorial in Hypertension.

“Buy-in by PCPs is essential,” agrees Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville, and a coauthor of the new study.

But he too acknowledges that this presents a major challenge. PCPs and internists, who diagnose a lot of hypertension, are “not used to thinking about aldosterone,” he said in an interview, encapsulating the key problem faced by proponents of earlier and more widespread PA assessment.

This dilemma looms as a “huge public health issue,” Dr. Carey warned.
 

‘We’re a long way from getting’ PCPs to buy in to PA screening

Will PCPs grow more comfortable with screening patients for PA themselves, or might they become more willing to refer hypertensive individuals for assessment at an expert center?

One skeptic is Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg. The finding about high PA prevalence in patients with hypertension “is brand new, [and] the message needs to get to PCPs,” he said. But, “We’re a long way from getting it” to them. “I don’t know how to do that. It will be a tough sell.”

In addition, repositioning MRAs as an earlier option for many hypertensive patients won’t be easy either, because “we’ll never have outcome-trial data for MRAs,” given that they are now generic drugs, he noted.

“No clinical trial data show [MRAs] are first-line drugs,” said Dr. Feldman, who explained that, instead, MRAs are considered “go-to drugs” for patients with treatment-resistant hypertension, a niche therapeutic area. Results from the PATHWAY-2 trial published 5 years ago in Lancet showed “spironolactone was clearly the most effective treatment for the condition,” according to the report authors.

But even among patients with resistant hypertension, screening for PA dramatically lags despite being enshrined in guidelines.

“PCPs should start checking aldosterone-to-renin ratios [a widely used PA screen] in all patients with resistant hypertension or hypertension with hypokalemia, and then refer patients to specialists for testing and management,” said Jordana B. Cohen, MD, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia.

But recent studies of U.S. patient populations with clinical characteristics that meet existing criteria for PA screening showed that just 1%-2% of these individuals underwent an initial PA assessment, she noted, citing reports in the journals Surgery and Hypertension.

“We need to prioritize improving screening in these high-risk patients,” she stressed in an interview.

This illustrates that, in some respects, the new prevalence numbers are beside the point, because PA has been going unscreened and overlooked far too often even in the context of historical, lower prevalence rates, said Dr. Yang.

“The key point is that approximately 1 in 10 people with hypertension, and even more with resistant hypertension, have a form of the disease that is worse than essential hypertension but is routinely missed at present” and is also highly treatable.

“Evidence for the need for increased awareness of PA has been building for 2 decades,” stressed Dr. Yang, who has coauthored several commentaries and reviews that have bemoaned PA’s underappreciated status.
 

Interest in partnering with PCPs on guidance grows

One potential solution is to have endocrinologists and hypertension specialists’ partner with PCPs to come up with diagnostic and management recommendations. Both Dr. Funder and Dr. Carey are opinion leaders regarding the role of aldosterone in hypertension, and both were coauthors of the 2016 Endocrine Society guideline for PA assessment and management published in the Journal of Clinical Endocrinology & Metabolism , with Dr. Funder chairing the writing panel.

Now approaching its fifth year in effect, this guideline is “due for revision,” and “my hope is that we’ll be able to partner with one or more PCP organizations to come up with a version of the guideline targeted to PCPs,” Dr. Carey said.

He voiced interest in working on this with the American College of Physicians, which represents U.S. internal medicine physicians, and the American Academy of Family Physicians.

“We definitely need a partnership and educational efforts to get the word out from these organizations and not from a specialty society,” said Dr. Carey.

Dr. Funder said he has submitted a proposal to the Endocrine Society for a guidelines update he would chair with Dr. Carey’s assistance and with a diverse writing group that includes PCPs. Dr. Carey said that ideally this panel would write and release a revised guideline in 2021.

“Several of us are chomping at the bit to get this done,” he noted.

But participation by the ACP and AAFP remain uncertain as of September 2020. When approached about this, an ACP spokesperson said the organization had no comment. A spokesperson for the AAFP said, “It’s too early to tell if we will partner with any other organizations to develop guidelines specific to excess aldosterone, and how such guidelines might be received by our members.”

Recent history shows little cooperation between ACP, AAFP, and what might be termed the U.S. hypertension “establishment.” For example, when the American College of Cardiology and the American Heart Association released their most recent essential hypertension management guidelines in Hypertension in 2018, it was never adopted by ACP or AAFP.

The latter two organizations continue to endorse a higher BP threshold for diagnosing hypertension, and higher treatment targets set by alternative expert panels to those of the AHA/ACC.
 

Collaboration feasible, although PCPs overworked

Dr. Carey hopes that this episode will not preclude agreement over PA screening.

“I think it is still possible to partner with [the ACP and AAFP],” he observed, adding that he believes high PA prevalence among hypertensive patients and its consequences when unrecognized is “noncontentious.”

But he acknowledges that other, substantial hurdles also exist, notably the “overwhelming workload” that American PCPs already face.

David O’Gurek, MD, a family and community medicine physician at the Lewis Katz School of Medicine of Temple University in Philadelphia, agrees that a revamped approach to PA screening developed cooperatively between PCPs and specialists is an important goal and potentially feasible despite prior disagreements. “There has to be room for collaboration,” he said, but also emphasized the need for developing policies based on a systematic evidence review and a focus on patient-centered outcomes.

“We’re certainly missing patients with PA, but there needs to be greater clarity and standardization about the most appropriate screening approach and cutoff level” for flagging patients who need specialized assessment, Dr. O’Gurek said in an interview.

The current endocrinology literature also shows that experts remain divided on how best to accomplish this.

And some hypertension specialists question whether existing evidence is conclusive enough to warrant revised guidelines.

Dr. Cohen, the nephrologist and hypertension researcher, said that, while the recent prevalence report in Annals of Internal Medicine is “intriguing, hypothesis-generating information that suggests we are missing many cases of hyperaldosteronism in routine care,” she nevertheless believes that “we need additional data to be able to truly understand the breadth and implications of the findings.”

William C. Cushman, MD, a hypertension management specialist at the University of Tennessee Health Science Center in Memphis, agrees.

Changing existing practice guidelines “really needs randomized, controlled trials demonstrating a difference in long-term outcomes, ideally major cardiovascular outcomes,” that result from broader PA screening, he said.

Dr. Carey concurs that more evidence is needed to confirm the Annals report, but is confident this evidence will be in hand by the time a guideline-revision panel meets in 2021.
 

Australian model of PCPs screening for PA could be implemented in United States

An example of what might be possible when PCPs, endocrinologists, and hypertension specialists work together to make PA screening more accessible can be found in Melbourne, at the Endocrine Hypertension Service of Monash Health, in association with the Hudson Institute of Medical Research.

This began operating in July 2016, cofounded by Dr. Yang, whose experiences with her own father made her sensitive to the issue.

The service’s aim is to “address the underdiagnosis of PA, and to offer a streamlined diagnostic service for patients with hypertension,” with an “extensive outreach program” targeted to regional PCPs that, among other messages, encourages them to screen patients for PA when blood pressures exceed 140/90 mm Hg.

During its first 3 years of operation, the service saw 267 patients, with PA diagnosed in 135 and ruled out in 73 patients.

Notably, the proportion of these patients referred from PCPs jumped from 21% of 70 patients during the first year of operation to 47% of 70 patients during year 2, and 52% of 127 patients during the third year, ending in July 2019, said Dr. Yang, who continues to help run the service.

During the first year, a scant 3% of referred patients had recently diagnosed hypertension, but this rose to 14% during the second year, and to 19% during the most recent year with data available.

The median duration of diagnosed hypertension among referred patients fell from 11 years during year 1, to 7 years during year 3.

Service clinicians diagnosed 37 patients with unilateral adenomas, and removed them from 23 patients with four more awaiting surgery and the remaining 10 opting instead for medical management. Another 95 patients went on therapy with a MRA, and during the most recent year studied all patients who began a MRA regimen had a partial or complete clinical response.

Dr. Carey said the “creative program represents a model for implementation in U.S. practice.

Dr. Funder, Dr. Carey, Dr. Feldman, Dr. Yang, Dr. Cohen, and Dr. O’Gurek had no relevant disclosures. Dr. Cushman has been a consultant to Novartis, received personal fees from Sanofi, and research funding from Eli Lilly.

[email protected]

Jun Yang, MBBS, had watched as her father, who had battled hypertension for decades, ended up on four medications that still couldn’t bring his blood pressure to a healthy level. The cardiovascular endocrinologist then ran some tests, and soon thereafter her father had his blood pressure optimized on just one targeted medication.

Courtesy Dr. Jun Yang

Dr. Yang’s father was found to have a hormonal condition known as primary aldosteronism (PA) as the cause of his hypertension.

It turns out that PA is not as rare as once thought.

An eye-catching report in Annals of Internal Medicine this spring of an unexpectedly high prevalence of primary aldosteronism among a diverse cross section of U.S. patients with hypertension has raised issues that could dramatically change the way doctors in America, and elsewhere, assess and manage high blood pressure.

Foremost is the question of whether primary care physicians – the clinicians at the front line for diagnosing and initially treating most patients with hypertension – will absorb and act on this new evidence. For them, aldosteronism doesn’t automatically come to mind when they see high numbers on a BP monitor, and yet this latest research found that up to a third of all 726 patients in the study who were diagnosed with hypertension and with high urinary salt levels had PA.

That translates to a roughly three- to fivefold increase over standard prevalence estimates, and is a ”game changer” for how clinicians should approach hypertension management and PA diagnosis going forward, said John W. Funder, MD, in an editorial accompanying the Annals study.

Long considered relatively uncommon, hypertension driven by an excess of the hormone aldosterone, often because of an adenoma on the adrenal gland, is not the same as conventional “essential” hypertension. The former benefits from early diagnosis because its treatment is completely different – close to half of all PA patients can be treated definitively and quickly with surgical removal of an adenoma from one side of the adrenal gland.

For other PA patients, who have bilateral adrenal hyperplasia that is impossible to resolve surgically, treatment with drugs called mineralocorticoid receptor antagonists (MRAs), such as spironolactone, is needed because they target the hormonal cause of the high BP.

But what usually happens is that a patient with PA is mistakenly diagnosed with essential hypertension, in which the classic approach to treatment is to start with one regular antihypertensive drug, and add on further ones from different drug classes if blood pressure is not adequately controlled. When patients are taking three drugs, without adequate control, they are labeled as having “resistant hypertension.”

But in the case of PA, none of these conventional antihypertensives work, and the process of continuing to monitor and add different drugs wastes time, during which patients deteriorate.

“We need to change the culture of waiting for hypertension to be resistant and have patients riddled with end-organ damage,” due to years of persistently high BP and excess aldosterone “before we look for a secondary cause” like PA, declared Dr. Yang, of Hudson Institute of Medical Research and Monash University in Melbourne, during an interview.

So early diagnosis and prompt treatment of PA is key.

In addition to boosting the public health importance of early PA detection in hypertensive patients, the new up-sized PA prevalence numbers throw a spotlight on primary care physicians (PCPs) as key players who will need to apply the findings to practice on a public health scale.

These novel results create a need for “new guidelines, and a radically revised game plan with the key role of PCPs” emphasized in future management of patients with hypertension, said Dr. Funder, a professor of medicine at Monash University, in a second recent editorial in Hypertension.

“Buy-in by PCPs is essential,” agrees Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville, and a coauthor of the new study.

But he too acknowledges that this presents a major challenge. PCPs and internists, who diagnose a lot of hypertension, are “not used to thinking about aldosterone,” he said in an interview, encapsulating the key problem faced by proponents of earlier and more widespread PA assessment.

This dilemma looms as a “huge public health issue,” Dr. Carey warned.
 

‘We’re a long way from getting’ PCPs to buy in to PA screening

Will PCPs grow more comfortable with screening patients for PA themselves, or might they become more willing to refer hypertensive individuals for assessment at an expert center?

One skeptic is Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg. The finding about high PA prevalence in patients with hypertension “is brand new, [and] the message needs to get to PCPs,” he said. But, “We’re a long way from getting it” to them. “I don’t know how to do that. It will be a tough sell.”

In addition, repositioning MRAs as an earlier option for many hypertensive patients won’t be easy either, because “we’ll never have outcome-trial data for MRAs,” given that they are now generic drugs, he noted.

“No clinical trial data show [MRAs] are first-line drugs,” said Dr. Feldman, who explained that, instead, MRAs are considered “go-to drugs” for patients with treatment-resistant hypertension, a niche therapeutic area. Results from the PATHWAY-2 trial published 5 years ago in Lancet showed “spironolactone was clearly the most effective treatment for the condition,” according to the report authors.

But even among patients with resistant hypertension, screening for PA dramatically lags despite being enshrined in guidelines.

“PCPs should start checking aldosterone-to-renin ratios [a widely used PA screen] in all patients with resistant hypertension or hypertension with hypokalemia, and then refer patients to specialists for testing and management,” said Jordana B. Cohen, MD, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia.

But recent studies of U.S. patient populations with clinical characteristics that meet existing criteria for PA screening showed that just 1%-2% of these individuals underwent an initial PA assessment, she noted, citing reports in the journals Surgery and Hypertension.

“We need to prioritize improving screening in these high-risk patients,” she stressed in an interview.

This illustrates that, in some respects, the new prevalence numbers are beside the point, because PA has been going unscreened and overlooked far too often even in the context of historical, lower prevalence rates, said Dr. Yang.

“The key point is that approximately 1 in 10 people with hypertension, and even more with resistant hypertension, have a form of the disease that is worse than essential hypertension but is routinely missed at present” and is also highly treatable.

“Evidence for the need for increased awareness of PA has been building for 2 decades,” stressed Dr. Yang, who has coauthored several commentaries and reviews that have bemoaned PA’s underappreciated status.
 

Interest in partnering with PCPs on guidance grows

One potential solution is to have endocrinologists and hypertension specialists’ partner with PCPs to come up with diagnostic and management recommendations. Both Dr. Funder and Dr. Carey are opinion leaders regarding the role of aldosterone in hypertension, and both were coauthors of the 2016 Endocrine Society guideline for PA assessment and management published in the Journal of Clinical Endocrinology & Metabolism , with Dr. Funder chairing the writing panel.

Now approaching its fifth year in effect, this guideline is “due for revision,” and “my hope is that we’ll be able to partner with one or more PCP organizations to come up with a version of the guideline targeted to PCPs,” Dr. Carey said.

He voiced interest in working on this with the American College of Physicians, which represents U.S. internal medicine physicians, and the American Academy of Family Physicians.

“We definitely need a partnership and educational efforts to get the word out from these organizations and not from a specialty society,” said Dr. Carey.

Dr. Funder said he has submitted a proposal to the Endocrine Society for a guidelines update he would chair with Dr. Carey’s assistance and with a diverse writing group that includes PCPs. Dr. Carey said that ideally this panel would write and release a revised guideline in 2021.

“Several of us are chomping at the bit to get this done,” he noted.

But participation by the ACP and AAFP remain uncertain as of September 2020. When approached about this, an ACP spokesperson said the organization had no comment. A spokesperson for the AAFP said, “It’s too early to tell if we will partner with any other organizations to develop guidelines specific to excess aldosterone, and how such guidelines might be received by our members.”

Recent history shows little cooperation between ACP, AAFP, and what might be termed the U.S. hypertension “establishment.” For example, when the American College of Cardiology and the American Heart Association released their most recent essential hypertension management guidelines in Hypertension in 2018, it was never adopted by ACP or AAFP.

The latter two organizations continue to endorse a higher BP threshold for diagnosing hypertension, and higher treatment targets set by alternative expert panels to those of the AHA/ACC.
 

Collaboration feasible, although PCPs overworked

Dr. Carey hopes that this episode will not preclude agreement over PA screening.

“I think it is still possible to partner with [the ACP and AAFP],” he observed, adding that he believes high PA prevalence among hypertensive patients and its consequences when unrecognized is “noncontentious.”

But he acknowledges that other, substantial hurdles also exist, notably the “overwhelming workload” that American PCPs already face.

David O’Gurek, MD, a family and community medicine physician at the Lewis Katz School of Medicine of Temple University in Philadelphia, agrees that a revamped approach to PA screening developed cooperatively between PCPs and specialists is an important goal and potentially feasible despite prior disagreements. “There has to be room for collaboration,” he said, but also emphasized the need for developing policies based on a systematic evidence review and a focus on patient-centered outcomes.

“We’re certainly missing patients with PA, but there needs to be greater clarity and standardization about the most appropriate screening approach and cutoff level” for flagging patients who need specialized assessment, Dr. O’Gurek said in an interview.

The current endocrinology literature also shows that experts remain divided on how best to accomplish this.

And some hypertension specialists question whether existing evidence is conclusive enough to warrant revised guidelines.

Dr. Cohen, the nephrologist and hypertension researcher, said that, while the recent prevalence report in Annals of Internal Medicine is “intriguing, hypothesis-generating information that suggests we are missing many cases of hyperaldosteronism in routine care,” she nevertheless believes that “we need additional data to be able to truly understand the breadth and implications of the findings.”

William C. Cushman, MD, a hypertension management specialist at the University of Tennessee Health Science Center in Memphis, agrees.

Changing existing practice guidelines “really needs randomized, controlled trials demonstrating a difference in long-term outcomes, ideally major cardiovascular outcomes,” that result from broader PA screening, he said.

Dr. Carey concurs that more evidence is needed to confirm the Annals report, but is confident this evidence will be in hand by the time a guideline-revision panel meets in 2021.
 

Australian model of PCPs screening for PA could be implemented in United States

An example of what might be possible when PCPs, endocrinologists, and hypertension specialists work together to make PA screening more accessible can be found in Melbourne, at the Endocrine Hypertension Service of Monash Health, in association with the Hudson Institute of Medical Research.

This began operating in July 2016, cofounded by Dr. Yang, whose experiences with her own father made her sensitive to the issue.

The service’s aim is to “address the underdiagnosis of PA, and to offer a streamlined diagnostic service for patients with hypertension,” with an “extensive outreach program” targeted to regional PCPs that, among other messages, encourages them to screen patients for PA when blood pressures exceed 140/90 mm Hg.

During its first 3 years of operation, the service saw 267 patients, with PA diagnosed in 135 and ruled out in 73 patients.

Notably, the proportion of these patients referred from PCPs jumped from 21% of 70 patients during the first year of operation to 47% of 70 patients during year 2, and 52% of 127 patients during the third year, ending in July 2019, said Dr. Yang, who continues to help run the service.

During the first year, a scant 3% of referred patients had recently diagnosed hypertension, but this rose to 14% during the second year, and to 19% during the most recent year with data available.

The median duration of diagnosed hypertension among referred patients fell from 11 years during year 1, to 7 years during year 3.

Service clinicians diagnosed 37 patients with unilateral adenomas, and removed them from 23 patients with four more awaiting surgery and the remaining 10 opting instead for medical management. Another 95 patients went on therapy with a MRA, and during the most recent year studied all patients who began a MRA regimen had a partial or complete clinical response.

Dr. Carey said the “creative program represents a model for implementation in U.S. practice.

Dr. Funder, Dr. Carey, Dr. Feldman, Dr. Yang, Dr. Cohen, and Dr. O’Gurek had no relevant disclosures. Dr. Cushman has been a consultant to Novartis, received personal fees from Sanofi, and research funding from Eli Lilly.

[email protected]

Jun Yang, MBBS, had watched as her father, who had battled hypertension for decades, ended up on four medications that still couldn’t bring his blood pressure to a healthy level. The cardiovascular endocrinologist then ran some tests, and soon thereafter her father had his blood pressure optimized on just one targeted medication.

Courtesy Dr. Jun Yang

Dr. Yang’s father was found to have a hormonal condition known as primary aldosteronism (PA) as the cause of his hypertension.

It turns out that PA is not as rare as once thought.

An eye-catching report in Annals of Internal Medicine this spring of an unexpectedly high prevalence of primary aldosteronism among a diverse cross section of U.S. patients with hypertension has raised issues that could dramatically change the way doctors in America, and elsewhere, assess and manage high blood pressure.

Foremost is the question of whether primary care physicians – the clinicians at the front line for diagnosing and initially treating most patients with hypertension – will absorb and act on this new evidence. For them, aldosteronism doesn’t automatically come to mind when they see high numbers on a BP monitor, and yet this latest research found that up to a third of all 726 patients in the study who were diagnosed with hypertension and with high urinary salt levels had PA.

That translates to a roughly three- to fivefold increase over standard prevalence estimates, and is a ”game changer” for how clinicians should approach hypertension management and PA diagnosis going forward, said John W. Funder, MD, in an editorial accompanying the Annals study.

Long considered relatively uncommon, hypertension driven by an excess of the hormone aldosterone, often because of an adenoma on the adrenal gland, is not the same as conventional “essential” hypertension. The former benefits from early diagnosis because its treatment is completely different – close to half of all PA patients can be treated definitively and quickly with surgical removal of an adenoma from one side of the adrenal gland.

For other PA patients, who have bilateral adrenal hyperplasia that is impossible to resolve surgically, treatment with drugs called mineralocorticoid receptor antagonists (MRAs), such as spironolactone, is needed because they target the hormonal cause of the high BP.

But what usually happens is that a patient with PA is mistakenly diagnosed with essential hypertension, in which the classic approach to treatment is to start with one regular antihypertensive drug, and add on further ones from different drug classes if blood pressure is not adequately controlled. When patients are taking three drugs, without adequate control, they are labeled as having “resistant hypertension.”

But in the case of PA, none of these conventional antihypertensives work, and the process of continuing to monitor and add different drugs wastes time, during which patients deteriorate.

“We need to change the culture of waiting for hypertension to be resistant and have patients riddled with end-organ damage,” due to years of persistently high BP and excess aldosterone “before we look for a secondary cause” like PA, declared Dr. Yang, of Hudson Institute of Medical Research and Monash University in Melbourne, during an interview.

So early diagnosis and prompt treatment of PA is key.

In addition to boosting the public health importance of early PA detection in hypertensive patients, the new up-sized PA prevalence numbers throw a spotlight on primary care physicians (PCPs) as key players who will need to apply the findings to practice on a public health scale.

These novel results create a need for “new guidelines, and a radically revised game plan with the key role of PCPs” emphasized in future management of patients with hypertension, said Dr. Funder, a professor of medicine at Monash University, in a second recent editorial in Hypertension.

“Buy-in by PCPs is essential,” agrees Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville, and a coauthor of the new study.

But he too acknowledges that this presents a major challenge. PCPs and internists, who diagnose a lot of hypertension, are “not used to thinking about aldosterone,” he said in an interview, encapsulating the key problem faced by proponents of earlier and more widespread PA assessment.

This dilemma looms as a “huge public health issue,” Dr. Carey warned.
 

‘We’re a long way from getting’ PCPs to buy in to PA screening

Will PCPs grow more comfortable with screening patients for PA themselves, or might they become more willing to refer hypertensive individuals for assessment at an expert center?

One skeptic is Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg. The finding about high PA prevalence in patients with hypertension “is brand new, [and] the message needs to get to PCPs,” he said. But, “We’re a long way from getting it” to them. “I don’t know how to do that. It will be a tough sell.”

In addition, repositioning MRAs as an earlier option for many hypertensive patients won’t be easy either, because “we’ll never have outcome-trial data for MRAs,” given that they are now generic drugs, he noted.

“No clinical trial data show [MRAs] are first-line drugs,” said Dr. Feldman, who explained that, instead, MRAs are considered “go-to drugs” for patients with treatment-resistant hypertension, a niche therapeutic area. Results from the PATHWAY-2 trial published 5 years ago in Lancet showed “spironolactone was clearly the most effective treatment for the condition,” according to the report authors.

But even among patients with resistant hypertension, screening for PA dramatically lags despite being enshrined in guidelines.

“PCPs should start checking aldosterone-to-renin ratios [a widely used PA screen] in all patients with resistant hypertension or hypertension with hypokalemia, and then refer patients to specialists for testing and management,” said Jordana B. Cohen, MD, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia.

But recent studies of U.S. patient populations with clinical characteristics that meet existing criteria for PA screening showed that just 1%-2% of these individuals underwent an initial PA assessment, she noted, citing reports in the journals Surgery and Hypertension.

“We need to prioritize improving screening in these high-risk patients,” she stressed in an interview.

This illustrates that, in some respects, the new prevalence numbers are beside the point, because PA has been going unscreened and overlooked far too often even in the context of historical, lower prevalence rates, said Dr. Yang.

“The key point is that approximately 1 in 10 people with hypertension, and even more with resistant hypertension, have a form of the disease that is worse than essential hypertension but is routinely missed at present” and is also highly treatable.

“Evidence for the need for increased awareness of PA has been building for 2 decades,” stressed Dr. Yang, who has coauthored several commentaries and reviews that have bemoaned PA’s underappreciated status.
 

Interest in partnering with PCPs on guidance grows

One potential solution is to have endocrinologists and hypertension specialists’ partner with PCPs to come up with diagnostic and management recommendations. Both Dr. Funder and Dr. Carey are opinion leaders regarding the role of aldosterone in hypertension, and both were coauthors of the 2016 Endocrine Society guideline for PA assessment and management published in the Journal of Clinical Endocrinology & Metabolism , with Dr. Funder chairing the writing panel.

Now approaching its fifth year in effect, this guideline is “due for revision,” and “my hope is that we’ll be able to partner with one or more PCP organizations to come up with a version of the guideline targeted to PCPs,” Dr. Carey said.

He voiced interest in working on this with the American College of Physicians, which represents U.S. internal medicine physicians, and the American Academy of Family Physicians.

“We definitely need a partnership and educational efforts to get the word out from these organizations and not from a specialty society,” said Dr. Carey.

Dr. Funder said he has submitted a proposal to the Endocrine Society for a guidelines update he would chair with Dr. Carey’s assistance and with a diverse writing group that includes PCPs. Dr. Carey said that ideally this panel would write and release a revised guideline in 2021.

“Several of us are chomping at the bit to get this done,” he noted.

But participation by the ACP and AAFP remain uncertain as of September 2020. When approached about this, an ACP spokesperson said the organization had no comment. A spokesperson for the AAFP said, “It’s too early to tell if we will partner with any other organizations to develop guidelines specific to excess aldosterone, and how such guidelines might be received by our members.”

Recent history shows little cooperation between ACP, AAFP, and what might be termed the U.S. hypertension “establishment.” For example, when the American College of Cardiology and the American Heart Association released their most recent essential hypertension management guidelines in Hypertension in 2018, it was never adopted by ACP or AAFP.

The latter two organizations continue to endorse a higher BP threshold for diagnosing hypertension, and higher treatment targets set by alternative expert panels to those of the AHA/ACC.
 

Collaboration feasible, although PCPs overworked

Dr. Carey hopes that this episode will not preclude agreement over PA screening.

“I think it is still possible to partner with [the ACP and AAFP],” he observed, adding that he believes high PA prevalence among hypertensive patients and its consequences when unrecognized is “noncontentious.”

But he acknowledges that other, substantial hurdles also exist, notably the “overwhelming workload” that American PCPs already face.

David O’Gurek, MD, a family and community medicine physician at the Lewis Katz School of Medicine of Temple University in Philadelphia, agrees that a revamped approach to PA screening developed cooperatively between PCPs and specialists is an important goal and potentially feasible despite prior disagreements. “There has to be room for collaboration,” he said, but also emphasized the need for developing policies based on a systematic evidence review and a focus on patient-centered outcomes.

“We’re certainly missing patients with PA, but there needs to be greater clarity and standardization about the most appropriate screening approach and cutoff level” for flagging patients who need specialized assessment, Dr. O’Gurek said in an interview.

The current endocrinology literature also shows that experts remain divided on how best to accomplish this.

And some hypertension specialists question whether existing evidence is conclusive enough to warrant revised guidelines.

Dr. Cohen, the nephrologist and hypertension researcher, said that, while the recent prevalence report in Annals of Internal Medicine is “intriguing, hypothesis-generating information that suggests we are missing many cases of hyperaldosteronism in routine care,” she nevertheless believes that “we need additional data to be able to truly understand the breadth and implications of the findings.”

William C. Cushman, MD, a hypertension management specialist at the University of Tennessee Health Science Center in Memphis, agrees.

Changing existing practice guidelines “really needs randomized, controlled trials demonstrating a difference in long-term outcomes, ideally major cardiovascular outcomes,” that result from broader PA screening, he said.

Dr. Carey concurs that more evidence is needed to confirm the Annals report, but is confident this evidence will be in hand by the time a guideline-revision panel meets in 2021.
 

Australian model of PCPs screening for PA could be implemented in United States

An example of what might be possible when PCPs, endocrinologists, and hypertension specialists work together to make PA screening more accessible can be found in Melbourne, at the Endocrine Hypertension Service of Monash Health, in association with the Hudson Institute of Medical Research.

This began operating in July 2016, cofounded by Dr. Yang, whose experiences with her own father made her sensitive to the issue.

The service’s aim is to “address the underdiagnosis of PA, and to offer a streamlined diagnostic service for patients with hypertension,” with an “extensive outreach program” targeted to regional PCPs that, among other messages, encourages them to screen patients for PA when blood pressures exceed 140/90 mm Hg.

During its first 3 years of operation, the service saw 267 patients, with PA diagnosed in 135 and ruled out in 73 patients.

Notably, the proportion of these patients referred from PCPs jumped from 21% of 70 patients during the first year of operation to 47% of 70 patients during year 2, and 52% of 127 patients during the third year, ending in July 2019, said Dr. Yang, who continues to help run the service.

During the first year, a scant 3% of referred patients had recently diagnosed hypertension, but this rose to 14% during the second year, and to 19% during the most recent year with data available.

The median duration of diagnosed hypertension among referred patients fell from 11 years during year 1, to 7 years during year 3.

Service clinicians diagnosed 37 patients with unilateral adenomas, and removed them from 23 patients with four more awaiting surgery and the remaining 10 opting instead for medical management. Another 95 patients went on therapy with a MRA, and during the most recent year studied all patients who began a MRA regimen had a partial or complete clinical response.

Dr. Carey said the “creative program represents a model for implementation in U.S. practice.

Dr. Funder, Dr. Carey, Dr. Feldman, Dr. Yang, Dr. Cohen, and Dr. O’Gurek had no relevant disclosures. Dr. Cushman has been a consultant to Novartis, received personal fees from Sanofi, and research funding from Eli Lilly.

[email protected]

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

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

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

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

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

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

During normal times, the U.K.-based charity No Panic offers itself as an easily accessible service to those with anxiety disorders and phobias. Visitors to the website who can receive immediate, remote support from trained volunteers. But this spring was anything but normal, as the reality of COVID-19’s worldwide spread became terrifyingly clear.

COVID-19 cases peaked in the United Kingdom in early April. Nationwide lockdown efforts contributed to a gradual but ultimately substantial decline in cases, yet, despite the favorable trend lines, No Panic has remained busier than ever.

Beyond the physical symptoms associated with COVID-19, the psychological outcomes are vast and, it seems, prolonged. Researchers have now formalized a definition of the long-term mental maladies associated with the pandemic, collectively deeming them “coronaphobia.”

The term is a catch-all phrase for the fear and the emotional and social strain experienced by the general public in response to COVID-19. Obsessive behaviors, distress, avoidance reaction, panic, anxiety, hoarding, paranoia, and depression are some of the responses associated with coronaphobia. On the surface, these appear to be normal, somewhat fitting reactions to this surreal and frightening moment in time. However, for those experiencing coronaphobia, they are distinctly maladaptive and harmful.

“We had a serious rise in the use of our services, notably the helpline and email enquiries,” explained Sarah Floyd, No Panic’s volunteer advisor and social media coordinator. “It has been up and down all along, but more of an up since lockdown is easing.”

The group’s experience offers yet more evidence that the anxieties and fears caused by this global pandemic don’t flatten alongside the curve but instead linger as chronic problems requiring ongoing care.

“Every week in my clinic, I’m seeing people who are experiencing more anxiety and hopelessness and having an emotional response that is perhaps out of proportion to what one would expect, which is directly related to what is going on in the world right now with coronavirus,” said Gregory Scott Brown, MD, founder and director of the Center for Green Psychiatry in West Lake Hills, Tex. “Simply put, I think what we are looking at is adjustment disorder. That is probably how the DSM would define it.”

Adjustment disorder is one of the most frequently diagnosed mental health conditions, although it is also relatively understudied. It is really a set of disorders that follow in the wake of a significant stressor, which can vary from serious illness or the death of a loved one to relocating or experiencing work problems. The resulting dysfunction and distress that the person experiences are considered out of proportion in duration or scale with what would normally be expected. Diagnosing an adjustment disorder is made difficult by the lack of a valid and reliable screening measure.

Recent literature suggests that coronaphobia may be likely to occur in those who feel vulnerable to disease, are predisposed to anxiety, or are intolerant of uncertainty. Preexisting mental health conditions can also be exacerbated by periods of quarantine, self-isolation, and lockdown, which can lead to panic attacks, chronophobia (fear of passing time), and suicidality.

Although imperfect comparisons, findings from earlier 21st century disease outbreaks, such as severe acute respiratory syndrome and the Ebola virus, signal that containment efforts themselves play a role in deteriorating mental health. A recent rapid review found that, in studies comparing persons who had previously undergone quarantines and those who had not, the former were significantly more likely to experience acute stress disorder, posttraumatic stress symptoms, and depression. Quarantine was found to result in long-term behavioral changes, such as avoiding crowds, among the general public and health care practitioners.

That tremendous psychological morbidity should accompany a global pandemic of this scale is not surprising, according to Amit Anand, MD, vice chair for research for the Center for Behavioral Health and director of the Mood and Emotional Disorders Across the Life Span program at the Cleveland Clinic.

“The technical definition of anxiety is an impending sense of doom, and I think all of us are living with that,” Dr. Anand said. “The basic question then becomes, what is normal and when does it become abnormal?”

He added that most classifications of psychiatric disorders are set during periods of relative stability, which the current moment is most certainly not.

“This is such an unusual situation, so I think it will depend on case-by-case basis, keeping the whole context in mind as whether the patient is thinking or behaving with an abnormal amount of anxiety,” Dr. Anand said.

Investigators are currently trying to give clinicians the tools to better make that determination. In the first scientific study of this clinical condition, Sherman Lee, MD, reported that five symptoms – dizziness, sleep disturbances, tonic immobility, appetite loss, and nausea/abdominal distress – were strong factors for distinguishing coronaphobia from otherwise normal concerns about COVID-19 that did not result in functional impairment. Dr. Lee and colleagues have since published further evidence that coronaphobia “is a unique predictor of psychological distress during the COVID-19 crisis.” They are working on validating a self-reported mental health screener for this condition.

Having the tools to identify patients struggling with coronaphobia may go some ways toward addressing another area of declining health. At the outset of the COVID-19 pandemic, there was a question as to whether doctors would be beset by a surge of the “worried well” – persons mistakenly believing themselves to be infected. Now months into the pandemic, the converse phenomenon – a fear of contracting COVID-19 that is driving patients away from practitioners – appears to be the more valid concern.

In early spring, the pandemic’s first surge was accompanied by reports of approximately 40% and 60% drops in visits to EDs and ambulatory centers, respectively. Stories of acute stroke patients avoiding treatment began to appear in the press. Major U.S. cities saw noteworthy declines in 911 calls, indicating a hesitancy to be taken to a hospital. That COVID-19 has been accompanied by mass unemployment and subsequent loss of insurance complicates the notion that fear alone is keeping people from treatment. In other countries, it has been explicitly linked. Investigators in Singapore noted that coronaphobia played a role in reducing willingness to attend in-person visits among adolescents with eating disorders. Similarly, case reports in Israel suggest that coronaphobia has contributed to delays in diagnoses of common pediatric diseases.

There is also a concern, colloquially termed “reentry anxiety,” that mental health problems caused by the pandemic, the accompanying lockdown, self-isolation, and quarantine practices will prove alarmingly durable. Even after this challenging moment in history draws to a close, many people may face substantial stress in returning to the normal activities of life – social, professional, familial – once taken for granted.

“We are in the beginning phase of that now,” said Dr. Anand. “Lots of people are decompensating, getting depressed, and needing treatment. I think the longer it goes on for, the more difficult it will be.”

In the United States, that day may seem far away. Nonetheless, it is important to begin laying the therapeutic groundwork now, according to Dr. Brown.

“I am recommending unconventional therapies like meet-up groups, online forums,” he said. “Everything has shifted online, and so there are a lot of support groups that patients can participate to learn coping skills and really hear what other people are going through.”

Before reaching that stage, Dr. Brown recommends that clinicians first simply discuss such anxieties with their patients in order to normalize them.

“Realize that everyone essentially is going through some degree of this right now. The coronavirus pandemic is literally impacting every person on the face of the planet. Sometimes just pointing that out to people can really help,” he said.

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

During normal times, the U.K.-based charity No Panic offers itself as an easily accessible service to those with anxiety disorders and phobias. Visitors to the website who can receive immediate, remote support from trained volunteers. But this spring was anything but normal, as the reality of COVID-19’s worldwide spread became terrifyingly clear.

COVID-19 cases peaked in the United Kingdom in early April. Nationwide lockdown efforts contributed to a gradual but ultimately substantial decline in cases, yet, despite the favorable trend lines, No Panic has remained busier than ever.

Beyond the physical symptoms associated with COVID-19, the psychological outcomes are vast and, it seems, prolonged. Researchers have now formalized a definition of the long-term mental maladies associated with the pandemic, collectively deeming them “coronaphobia.”

The term is a catch-all phrase for the fear and the emotional and social strain experienced by the general public in response to COVID-19. Obsessive behaviors, distress, avoidance reaction, panic, anxiety, hoarding, paranoia, and depression are some of the responses associated with coronaphobia. On the surface, these appear to be normal, somewhat fitting reactions to this surreal and frightening moment in time. However, for those experiencing coronaphobia, they are distinctly maladaptive and harmful.

“We had a serious rise in the use of our services, notably the helpline and email enquiries,” explained Sarah Floyd, No Panic’s volunteer advisor and social media coordinator. “It has been up and down all along, but more of an up since lockdown is easing.”

The group’s experience offers yet more evidence that the anxieties and fears caused by this global pandemic don’t flatten alongside the curve but instead linger as chronic problems requiring ongoing care.

“Every week in my clinic, I’m seeing people who are experiencing more anxiety and hopelessness and having an emotional response that is perhaps out of proportion to what one would expect, which is directly related to what is going on in the world right now with coronavirus,” said Gregory Scott Brown, MD, founder and director of the Center for Green Psychiatry in West Lake Hills, Tex. “Simply put, I think what we are looking at is adjustment disorder. That is probably how the DSM would define it.”

Adjustment disorder is one of the most frequently diagnosed mental health conditions, although it is also relatively understudied. It is really a set of disorders that follow in the wake of a significant stressor, which can vary from serious illness or the death of a loved one to relocating or experiencing work problems. The resulting dysfunction and distress that the person experiences are considered out of proportion in duration or scale with what would normally be expected. Diagnosing an adjustment disorder is made difficult by the lack of a valid and reliable screening measure.

Recent literature suggests that coronaphobia may be likely to occur in those who feel vulnerable to disease, are predisposed to anxiety, or are intolerant of uncertainty. Preexisting mental health conditions can also be exacerbated by periods of quarantine, self-isolation, and lockdown, which can lead to panic attacks, chronophobia (fear of passing time), and suicidality.

Although imperfect comparisons, findings from earlier 21st century disease outbreaks, such as severe acute respiratory syndrome and the Ebola virus, signal that containment efforts themselves play a role in deteriorating mental health. A recent rapid review found that, in studies comparing persons who had previously undergone quarantines and those who had not, the former were significantly more likely to experience acute stress disorder, posttraumatic stress symptoms, and depression. Quarantine was found to result in long-term behavioral changes, such as avoiding crowds, among the general public and health care practitioners.

That tremendous psychological morbidity should accompany a global pandemic of this scale is not surprising, according to Amit Anand, MD, vice chair for research for the Center for Behavioral Health and director of the Mood and Emotional Disorders Across the Life Span program at the Cleveland Clinic.

“The technical definition of anxiety is an impending sense of doom, and I think all of us are living with that,” Dr. Anand said. “The basic question then becomes, what is normal and when does it become abnormal?”

He added that most classifications of psychiatric disorders are set during periods of relative stability, which the current moment is most certainly not.

“This is such an unusual situation, so I think it will depend on case-by-case basis, keeping the whole context in mind as whether the patient is thinking or behaving with an abnormal amount of anxiety,” Dr. Anand said.

Investigators are currently trying to give clinicians the tools to better make that determination. In the first scientific study of this clinical condition, Sherman Lee, MD, reported that five symptoms – dizziness, sleep disturbances, tonic immobility, appetite loss, and nausea/abdominal distress – were strong factors for distinguishing coronaphobia from otherwise normal concerns about COVID-19 that did not result in functional impairment. Dr. Lee and colleagues have since published further evidence that coronaphobia “is a unique predictor of psychological distress during the COVID-19 crisis.” They are working on validating a self-reported mental health screener for this condition.

Having the tools to identify patients struggling with coronaphobia may go some ways toward addressing another area of declining health. At the outset of the COVID-19 pandemic, there was a question as to whether doctors would be beset by a surge of the “worried well” – persons mistakenly believing themselves to be infected. Now months into the pandemic, the converse phenomenon – a fear of contracting COVID-19 that is driving patients away from practitioners – appears to be the more valid concern.

In early spring, the pandemic’s first surge was accompanied by reports of approximately 40% and 60% drops in visits to EDs and ambulatory centers, respectively. Stories of acute stroke patients avoiding treatment began to appear in the press. Major U.S. cities saw noteworthy declines in 911 calls, indicating a hesitancy to be taken to a hospital. That COVID-19 has been accompanied by mass unemployment and subsequent loss of insurance complicates the notion that fear alone is keeping people from treatment. In other countries, it has been explicitly linked. Investigators in Singapore noted that coronaphobia played a role in reducing willingness to attend in-person visits among adolescents with eating disorders. Similarly, case reports in Israel suggest that coronaphobia has contributed to delays in diagnoses of common pediatric diseases.

There is also a concern, colloquially termed “reentry anxiety,” that mental health problems caused by the pandemic, the accompanying lockdown, self-isolation, and quarantine practices will prove alarmingly durable. Even after this challenging moment in history draws to a close, many people may face substantial stress in returning to the normal activities of life – social, professional, familial – once taken for granted.

“We are in the beginning phase of that now,” said Dr. Anand. “Lots of people are decompensating, getting depressed, and needing treatment. I think the longer it goes on for, the more difficult it will be.”

In the United States, that day may seem far away. Nonetheless, it is important to begin laying the therapeutic groundwork now, according to Dr. Brown.

“I am recommending unconventional therapies like meet-up groups, online forums,” he said. “Everything has shifted online, and so there are a lot of support groups that patients can participate to learn coping skills and really hear what other people are going through.”

Before reaching that stage, Dr. Brown recommends that clinicians first simply discuss such anxieties with their patients in order to normalize them.

“Realize that everyone essentially is going through some degree of this right now. The coronavirus pandemic is literally impacting every person on the face of the planet. Sometimes just pointing that out to people can really help,” he said.

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

During normal times, the U.K.-based charity No Panic offers itself as an easily accessible service to those with anxiety disorders and phobias. Visitors to the website who can receive immediate, remote support from trained volunteers. But this spring was anything but normal, as the reality of COVID-19’s worldwide spread became terrifyingly clear.

COVID-19 cases peaked in the United Kingdom in early April. Nationwide lockdown efforts contributed to a gradual but ultimately substantial decline in cases, yet, despite the favorable trend lines, No Panic has remained busier than ever.

Beyond the physical symptoms associated with COVID-19, the psychological outcomes are vast and, it seems, prolonged. Researchers have now formalized a definition of the long-term mental maladies associated with the pandemic, collectively deeming them “coronaphobia.”

The term is a catch-all phrase for the fear and the emotional and social strain experienced by the general public in response to COVID-19. Obsessive behaviors, distress, avoidance reaction, panic, anxiety, hoarding, paranoia, and depression are some of the responses associated with coronaphobia. On the surface, these appear to be normal, somewhat fitting reactions to this surreal and frightening moment in time. However, for those experiencing coronaphobia, they are distinctly maladaptive and harmful.

“We had a serious rise in the use of our services, notably the helpline and email enquiries,” explained Sarah Floyd, No Panic’s volunteer advisor and social media coordinator. “It has been up and down all along, but more of an up since lockdown is easing.”

The group’s experience offers yet more evidence that the anxieties and fears caused by this global pandemic don’t flatten alongside the curve but instead linger as chronic problems requiring ongoing care.

“Every week in my clinic, I’m seeing people who are experiencing more anxiety and hopelessness and having an emotional response that is perhaps out of proportion to what one would expect, which is directly related to what is going on in the world right now with coronavirus,” said Gregory Scott Brown, MD, founder and director of the Center for Green Psychiatry in West Lake Hills, Tex. “Simply put, I think what we are looking at is adjustment disorder. That is probably how the DSM would define it.”

Adjustment disorder is one of the most frequently diagnosed mental health conditions, although it is also relatively understudied. It is really a set of disorders that follow in the wake of a significant stressor, which can vary from serious illness or the death of a loved one to relocating or experiencing work problems. The resulting dysfunction and distress that the person experiences are considered out of proportion in duration or scale with what would normally be expected. Diagnosing an adjustment disorder is made difficult by the lack of a valid and reliable screening measure.

Recent literature suggests that coronaphobia may be likely to occur in those who feel vulnerable to disease, are predisposed to anxiety, or are intolerant of uncertainty. Preexisting mental health conditions can also be exacerbated by periods of quarantine, self-isolation, and lockdown, which can lead to panic attacks, chronophobia (fear of passing time), and suicidality.

Although imperfect comparisons, findings from earlier 21st century disease outbreaks, such as severe acute respiratory syndrome and the Ebola virus, signal that containment efforts themselves play a role in deteriorating mental health. A recent rapid review found that, in studies comparing persons who had previously undergone quarantines and those who had not, the former were significantly more likely to experience acute stress disorder, posttraumatic stress symptoms, and depression. Quarantine was found to result in long-term behavioral changes, such as avoiding crowds, among the general public and health care practitioners.

That tremendous psychological morbidity should accompany a global pandemic of this scale is not surprising, according to Amit Anand, MD, vice chair for research for the Center for Behavioral Health and director of the Mood and Emotional Disorders Across the Life Span program at the Cleveland Clinic.

“The technical definition of anxiety is an impending sense of doom, and I think all of us are living with that,” Dr. Anand said. “The basic question then becomes, what is normal and when does it become abnormal?”

He added that most classifications of psychiatric disorders are set during periods of relative stability, which the current moment is most certainly not.

“This is such an unusual situation, so I think it will depend on case-by-case basis, keeping the whole context in mind as whether the patient is thinking or behaving with an abnormal amount of anxiety,” Dr. Anand said.

Investigators are currently trying to give clinicians the tools to better make that determination. In the first scientific study of this clinical condition, Sherman Lee, MD, reported that five symptoms – dizziness, sleep disturbances, tonic immobility, appetite loss, and nausea/abdominal distress – were strong factors for distinguishing coronaphobia from otherwise normal concerns about COVID-19 that did not result in functional impairment. Dr. Lee and colleagues have since published further evidence that coronaphobia “is a unique predictor of psychological distress during the COVID-19 crisis.” They are working on validating a self-reported mental health screener for this condition.

Having the tools to identify patients struggling with coronaphobia may go some ways toward addressing another area of declining health. At the outset of the COVID-19 pandemic, there was a question as to whether doctors would be beset by a surge of the “worried well” – persons mistakenly believing themselves to be infected. Now months into the pandemic, the converse phenomenon – a fear of contracting COVID-19 that is driving patients away from practitioners – appears to be the more valid concern.

In early spring, the pandemic’s first surge was accompanied by reports of approximately 40% and 60% drops in visits to EDs and ambulatory centers, respectively. Stories of acute stroke patients avoiding treatment began to appear in the press. Major U.S. cities saw noteworthy declines in 911 calls, indicating a hesitancy to be taken to a hospital. That COVID-19 has been accompanied by mass unemployment and subsequent loss of insurance complicates the notion that fear alone is keeping people from treatment. In other countries, it has been explicitly linked. Investigators in Singapore noted that coronaphobia played a role in reducing willingness to attend in-person visits among adolescents with eating disorders. Similarly, case reports in Israel suggest that coronaphobia has contributed to delays in diagnoses of common pediatric diseases.

There is also a concern, colloquially termed “reentry anxiety,” that mental health problems caused by the pandemic, the accompanying lockdown, self-isolation, and quarantine practices will prove alarmingly durable. Even after this challenging moment in history draws to a close, many people may face substantial stress in returning to the normal activities of life – social, professional, familial – once taken for granted.

“We are in the beginning phase of that now,” said Dr. Anand. “Lots of people are decompensating, getting depressed, and needing treatment. I think the longer it goes on for, the more difficult it will be.”

In the United States, that day may seem far away. Nonetheless, it is important to begin laying the therapeutic groundwork now, according to Dr. Brown.

“I am recommending unconventional therapies like meet-up groups, online forums,” he said. “Everything has shifted online, and so there are a lot of support groups that patients can participate to learn coping skills and really hear what other people are going through.”

Before reaching that stage, Dr. Brown recommends that clinicians first simply discuss such anxieties with their patients in order to normalize them.

“Realize that everyone essentially is going through some degree of this right now. The coronavirus pandemic is literally impacting every person on the face of the planet. Sometimes just pointing that out to people can really help,” he said.