Key clinical point: In patients with progressive multiple sclerosis (MS), impaired odor identification is associated with a greater clinical decline and higher risk for death.

Major finding: Impaired Brief-Smell Identification (B-SIT) was associated with higher risk for death (adjusted hazard ratio [aHR], 14.9; P less than .001). Among patients with progressive MS, impaired B-SIT vs normal B-SIT showed greater clinical change per month in terms of Multiple Sclerosis Severity scores (median, 0.62 vs. –0.08; P =.004) and Age-Related Multiple Sclerosis Severity scores (median, 0.54 vs. –0.07; P =.004).

Study details: Findings from a retrospective review on 149 patients with MS during a median follow-up of 121 months.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: da Silva AM et al. Mult Scler Relat Disord. 2020 Sep 3. doi: 10.1016/j.msard.2020.102486.

Key clinical point: In patients with progressive multiple sclerosis (MS), impaired odor identification is associated with a greater clinical decline and higher risk for death.

Major finding: Impaired Brief-Smell Identification (B-SIT) was associated with higher risk for death (adjusted hazard ratio [aHR], 14.9; P less than .001). Among patients with progressive MS, impaired B-SIT vs normal B-SIT showed greater clinical change per month in terms of Multiple Sclerosis Severity scores (median, 0.62 vs. –0.08; P =.004) and Age-Related Multiple Sclerosis Severity scores (median, 0.54 vs. –0.07; P =.004).

Study details: Findings from a retrospective review on 149 patients with MS during a median follow-up of 121 months.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: da Silva AM et al. Mult Scler Relat Disord. 2020 Sep 3. doi: 10.1016/j.msard.2020.102486.

Key clinical point: In patients with progressive multiple sclerosis (MS), impaired odor identification is associated with a greater clinical decline and higher risk for death.

Major finding: Impaired Brief-Smell Identification (B-SIT) was associated with higher risk for death (adjusted hazard ratio [aHR], 14.9; P less than .001). Among patients with progressive MS, impaired B-SIT vs normal B-SIT showed greater clinical change per month in terms of Multiple Sclerosis Severity scores (median, 0.62 vs. –0.08; P =.004) and Age-Related Multiple Sclerosis Severity scores (median, 0.54 vs. –0.07; P =.004).

Study details: Findings from a retrospective review on 149 patients with MS during a median follow-up of 121 months.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: da Silva AM et al. Mult Scler Relat Disord. 2020 Sep 3. doi: 10.1016/j.msard.2020.102486.

Treatments in the pipeline may offer more options for rosacea sufferers, according to Linda Stein Gold, MD, director of clinical research, in the department of dermatology, Henry Ford Hospital in Detroit.

sruilk/shutterstock

In addition, topical minocycline has recently been approved by the Food and Drug Administration for the treatment of rosacea in a 1.5% foam formulation. “The reason it has taken so long to have a minocycline product is that it is challenging to deliver it topically,” she said in a presentation at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually. Studies of higher concentrations were not significantly better for rosacea, so development of the 1.5% foam was pursued, although a 4% foam is approved for the treatment of acne.

Dr. Stein Gold shared results from a pair of 12-week randomized trials in which significantly more patients treated with topical minocycline foam showed treatment success, compared with those on vehicle, based on Investigator’s Global Assessment (IGA) scores of clear or almost clear and a decrease of at least two grades from baseline: 52.1% versus 43.0% in one study and 49.1% versus 39.0% in the second, statistically significant differences. The product also was well tolerated, with most patients reporting no side effects or mild side effects.

Research on how to maximize effectiveness of available treatments such as ivermectin is ongoing, but several new treatments in the pipeline continue to show promising results, she noted.

An up-and-coming rosacea treatment is an old product used in a new way: Benzoyl peroxide in a microencapsulated form. “Benzoyl peroxide is encased in silica molecules that allow very slow release of the benzoyl peroxide into the skin and that leads to decreased irritation,” Dr. Stein Gold explained. The deposit of active ingredient on the skin appears to stay below the level of irritation.

Dr. Stein Gold and colleagues conducted two randomized, vehicle-controlled trials in which 733 adults with moderate to severe rosacea were treated with either the encapsulated benzoyl peroxide cream formulation or a vehicle applied once daily for 12 weeks.

At 12 weeks, IGA success increased over the course of the studies, and reached 43.5% in one and 50.1% in the other, compared with 16.1% and 25.9%, respectively, for the vehicle groups in those studies (P < .001 for both). Overall, she described this as “a nice improvement for a drug that we had not considered to be part of our treatment armamentarium for our rosacea patients.”

Dr. Stein Gold also shared data from a phase 2 study of low-dose oral minocycline in adults with papulopustular rosacea. A group of 200 patients used the drug or a placebo once daily for 16 weeks. The study examined 20-mg and 40-mg extended-release formulations, and found a significant improvement with the 40-mg dose over the 20-mg dose and over placebo, in terms of those who reached an IGA of 0 or 1, with a 2 grade improvement. While this is a phase 2 study, it may lead to oral minocycline as another treatment option, she said.

“It is an exciting time for the treatment of rosacea, with a variety of options and an active pipeline, so we can aim for clear skin for our patients,” she commented.

Dr. Stein Gold disclosed serving as an investigator and consultant for Galderma, Vyne, Sun, Sol Gel, and Almirall; she is a consultant and speaker for Ortho.

MedscapeLive and this news organization are owned by the same parent company.
 

Treatments in the pipeline may offer more options for rosacea sufferers, according to Linda Stein Gold, MD, director of clinical research, in the department of dermatology, Henry Ford Hospital in Detroit.

sruilk/shutterstock

In addition, topical minocycline has recently been approved by the Food and Drug Administration for the treatment of rosacea in a 1.5% foam formulation. “The reason it has taken so long to have a minocycline product is that it is challenging to deliver it topically,” she said in a presentation at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually. Studies of higher concentrations were not significantly better for rosacea, so development of the 1.5% foam was pursued, although a 4% foam is approved for the treatment of acne.

Dr. Stein Gold shared results from a pair of 12-week randomized trials in which significantly more patients treated with topical minocycline foam showed treatment success, compared with those on vehicle, based on Investigator’s Global Assessment (IGA) scores of clear or almost clear and a decrease of at least two grades from baseline: 52.1% versus 43.0% in one study and 49.1% versus 39.0% in the second, statistically significant differences. The product also was well tolerated, with most patients reporting no side effects or mild side effects.

Research on how to maximize effectiveness of available treatments such as ivermectin is ongoing, but several new treatments in the pipeline continue to show promising results, she noted.

An up-and-coming rosacea treatment is an old product used in a new way: Benzoyl peroxide in a microencapsulated form. “Benzoyl peroxide is encased in silica molecules that allow very slow release of the benzoyl peroxide into the skin and that leads to decreased irritation,” Dr. Stein Gold explained. The deposit of active ingredient on the skin appears to stay below the level of irritation.

Dr. Stein Gold and colleagues conducted two randomized, vehicle-controlled trials in which 733 adults with moderate to severe rosacea were treated with either the encapsulated benzoyl peroxide cream formulation or a vehicle applied once daily for 12 weeks.

At 12 weeks, IGA success increased over the course of the studies, and reached 43.5% in one and 50.1% in the other, compared with 16.1% and 25.9%, respectively, for the vehicle groups in those studies (P < .001 for both). Overall, she described this as “a nice improvement for a drug that we had not considered to be part of our treatment armamentarium for our rosacea patients.”

Dr. Stein Gold also shared data from a phase 2 study of low-dose oral minocycline in adults with papulopustular rosacea. A group of 200 patients used the drug or a placebo once daily for 16 weeks. The study examined 20-mg and 40-mg extended-release formulations, and found a significant improvement with the 40-mg dose over the 20-mg dose and over placebo, in terms of those who reached an IGA of 0 or 1, with a 2 grade improvement. While this is a phase 2 study, it may lead to oral minocycline as another treatment option, she said.

“It is an exciting time for the treatment of rosacea, with a variety of options and an active pipeline, so we can aim for clear skin for our patients,” she commented.

Dr. Stein Gold disclosed serving as an investigator and consultant for Galderma, Vyne, Sun, Sol Gel, and Almirall; she is a consultant and speaker for Ortho.

MedscapeLive and this news organization are owned by the same parent company.
 

Treatments in the pipeline may offer more options for rosacea sufferers, according to Linda Stein Gold, MD, director of clinical research, in the department of dermatology, Henry Ford Hospital in Detroit.

sruilk/shutterstock

In addition, topical minocycline has recently been approved by the Food and Drug Administration for the treatment of rosacea in a 1.5% foam formulation. “The reason it has taken so long to have a minocycline product is that it is challenging to deliver it topically,” she said in a presentation at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually. Studies of higher concentrations were not significantly better for rosacea, so development of the 1.5% foam was pursued, although a 4% foam is approved for the treatment of acne.

Dr. Stein Gold shared results from a pair of 12-week randomized trials in which significantly more patients treated with topical minocycline foam showed treatment success, compared with those on vehicle, based on Investigator’s Global Assessment (IGA) scores of clear or almost clear and a decrease of at least two grades from baseline: 52.1% versus 43.0% in one study and 49.1% versus 39.0% in the second, statistically significant differences. The product also was well tolerated, with most patients reporting no side effects or mild side effects.

Research on how to maximize effectiveness of available treatments such as ivermectin is ongoing, but several new treatments in the pipeline continue to show promising results, she noted.

An up-and-coming rosacea treatment is an old product used in a new way: Benzoyl peroxide in a microencapsulated form. “Benzoyl peroxide is encased in silica molecules that allow very slow release of the benzoyl peroxide into the skin and that leads to decreased irritation,” Dr. Stein Gold explained. The deposit of active ingredient on the skin appears to stay below the level of irritation.

Dr. Stein Gold and colleagues conducted two randomized, vehicle-controlled trials in which 733 adults with moderate to severe rosacea were treated with either the encapsulated benzoyl peroxide cream formulation or a vehicle applied once daily for 12 weeks.

At 12 weeks, IGA success increased over the course of the studies, and reached 43.5% in one and 50.1% in the other, compared with 16.1% and 25.9%, respectively, for the vehicle groups in those studies (P < .001 for both). Overall, she described this as “a nice improvement for a drug that we had not considered to be part of our treatment armamentarium for our rosacea patients.”

Dr. Stein Gold also shared data from a phase 2 study of low-dose oral minocycline in adults with papulopustular rosacea. A group of 200 patients used the drug or a placebo once daily for 16 weeks. The study examined 20-mg and 40-mg extended-release formulations, and found a significant improvement with the 40-mg dose over the 20-mg dose and over placebo, in terms of those who reached an IGA of 0 or 1, with a 2 grade improvement. While this is a phase 2 study, it may lead to oral minocycline as another treatment option, she said.

“It is an exciting time for the treatment of rosacea, with a variety of options and an active pipeline, so we can aim for clear skin for our patients,” she commented.

Dr. Stein Gold disclosed serving as an investigator and consultant for Galderma, Vyne, Sun, Sol Gel, and Almirall; she is a consultant and speaker for Ortho.

MedscapeLive and this news organization are owned by the same parent company.
 

Key clinical point: Impaired respiratory muscle functions are linked to sleep disturbance and cognitive impairment in patients with multiple sclerosis (MS), warranting early evaluation of respiratory muscle strength.

Major finding: The respiratory muscle function test negatively correlated with the scores of Epworth Sleepiness Scale (ESS) and Perceived Deficits Questionnaire (PDQ) and showed a positive correlation with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scale score (P less than .001 for all).

Study details: The study assessed 146 MS patients with a mean age of 29.3 years and a mean Expanded Disability Status Scale (EDSS) score of 4.11.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interests.

Citation: Hashim NA et al. Mult Scler Relat Dis. 2020 Sep 16. doi: 10.1016/j.msard.2020.102514.

Key clinical point: Impaired respiratory muscle functions are linked to sleep disturbance and cognitive impairment in patients with multiple sclerosis (MS), warranting early evaluation of respiratory muscle strength.

Major finding: The respiratory muscle function test negatively correlated with the scores of Epworth Sleepiness Scale (ESS) and Perceived Deficits Questionnaire (PDQ) and showed a positive correlation with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scale score (P less than .001 for all).

Study details: The study assessed 146 MS patients with a mean age of 29.3 years and a mean Expanded Disability Status Scale (EDSS) score of 4.11.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interests.

Citation: Hashim NA et al. Mult Scler Relat Dis. 2020 Sep 16. doi: 10.1016/j.msard.2020.102514.

Key clinical point: Impaired respiratory muscle functions are linked to sleep disturbance and cognitive impairment in patients with multiple sclerosis (MS), warranting early evaluation of respiratory muscle strength.

Major finding: The respiratory muscle function test negatively correlated with the scores of Epworth Sleepiness Scale (ESS) and Perceived Deficits Questionnaire (PDQ) and showed a positive correlation with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scale score (P less than .001 for all).

Study details: The study assessed 146 MS patients with a mean age of 29.3 years and a mean Expanded Disability Status Scale (EDSS) score of 4.11.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interests.

Citation: Hashim NA et al. Mult Scler Relat Dis. 2020 Sep 16. doi: 10.1016/j.msard.2020.102514.

Key clinical point: Teriflunomide as a long-term immunomodulatory therapy in patients with relapsing multiple sclerosis (MS) has a favorable benefit-risk profile.

Major finding: The safety profile of teriflunomide 14 mg in the extension study was consistent with that in the core study, with similar incidences of adverse events (AEs) and serious AEs. There were differences in serious AE incidences between the placebo and teriflunomide 14 mg groups (6.4% vs. 12.4%). Teriflunomide was associated with reduction in annualized relapse rates in all treatment groups, irrespective of when treatment was initiated.

Study details: Long-term extension of the phase 3 TOWER study: Patients who received teriflunomide 14 mg in the core study were assigned to their original dose (14 mg/14 mg group); patients who received placebo or teriflunomide 7 mg in the core study were reassigned to teriflunomide 14 mg (placebo/14 mg and 7 mg/14 mg groups, respectively).

Disclosures: Development of the manuscript was supported by Sanofi. AL Lublin, P Truffinet, J Chavin, J Delhay, and A Purvis are employees of Sanofi, with ownership interest. M Benamor is an employee of Sanofi. The remaining authors reported ties with various pharmaceutical companies, including Sanofi.

Citation: Miller AE et al. Mult Scler Relat Disord. 2020 Aug 1. doi: 10.1016/j.msard.2020.102438.

Key clinical point: Teriflunomide as a long-term immunomodulatory therapy in patients with relapsing multiple sclerosis (MS) has a favorable benefit-risk profile.

Major finding: The safety profile of teriflunomide 14 mg in the extension study was consistent with that in the core study, with similar incidences of adverse events (AEs) and serious AEs. There were differences in serious AE incidences between the placebo and teriflunomide 14 mg groups (6.4% vs. 12.4%). Teriflunomide was associated with reduction in annualized relapse rates in all treatment groups, irrespective of when treatment was initiated.

Study details: Long-term extension of the phase 3 TOWER study: Patients who received teriflunomide 14 mg in the core study were assigned to their original dose (14 mg/14 mg group); patients who received placebo or teriflunomide 7 mg in the core study were reassigned to teriflunomide 14 mg (placebo/14 mg and 7 mg/14 mg groups, respectively).

Disclosures: Development of the manuscript was supported by Sanofi. AL Lublin, P Truffinet, J Chavin, J Delhay, and A Purvis are employees of Sanofi, with ownership interest. M Benamor is an employee of Sanofi. The remaining authors reported ties with various pharmaceutical companies, including Sanofi.

Citation: Miller AE et al. Mult Scler Relat Disord. 2020 Aug 1. doi: 10.1016/j.msard.2020.102438.

Key clinical point: Teriflunomide as a long-term immunomodulatory therapy in patients with relapsing multiple sclerosis (MS) has a favorable benefit-risk profile.

Major finding: The safety profile of teriflunomide 14 mg in the extension study was consistent with that in the core study, with similar incidences of adverse events (AEs) and serious AEs. There were differences in serious AE incidences between the placebo and teriflunomide 14 mg groups (6.4% vs. 12.4%). Teriflunomide was associated with reduction in annualized relapse rates in all treatment groups, irrespective of when treatment was initiated.

Study details: Long-term extension of the phase 3 TOWER study: Patients who received teriflunomide 14 mg in the core study were assigned to their original dose (14 mg/14 mg group); patients who received placebo or teriflunomide 7 mg in the core study were reassigned to teriflunomide 14 mg (placebo/14 mg and 7 mg/14 mg groups, respectively).

Disclosures: Development of the manuscript was supported by Sanofi. AL Lublin, P Truffinet, J Chavin, J Delhay, and A Purvis are employees of Sanofi, with ownership interest. M Benamor is an employee of Sanofi. The remaining authors reported ties with various pharmaceutical companies, including Sanofi.

Citation: Miller AE et al. Mult Scler Relat Disord. 2020 Aug 1. doi: 10.1016/j.msard.2020.102438.

Study Overview

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

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

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

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

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

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

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

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

Commentary

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

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

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

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

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

Applications for Clinical Practice

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

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

Study Overview

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

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

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

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

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

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

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

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

Commentary

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

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

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

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

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

Applications for Clinical Practice

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

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

Study Overview

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

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

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

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

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

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

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

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

Commentary

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

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

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

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

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

Applications for Clinical Practice

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

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

Conventional wisdom holds that patients with atopic dermatitis (AD) should shun wool clothing in favor of cotton or silk, because wool is said to be irritating and promote itching. But not so when the garments are made of fine-diameter fibers of merino wool, Joseph F. Fowler, Jr., MD, said at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually.

“We’ve always though that wool is bad in atopics, right? Indeed, rough wool might be. But fine wool garments can actually improve atopic dermatitis, probably because wool is the most breathable fabric and has the best temperature regulation qualities of any fabric we can wear,” said Dr. Fowler, a dermatologist at the University of Louisville (Ky).

He was first author of a randomized, 12-week, crossover, assessor-blinded clinical trial which showed precisely that. And a second, similarly designed study, this one conducted in Australia, also concluded that fine merino wool assists in the management of AD.

The study by Dr. Fowler and coinvestigators included 50 children and adults with mild or moderate AD who either wore top-and-bottom base layer merino wool ensembles for 6 weeks and then switched to their regular nonwoolen clothing, or vice versa. The mean Eczema Area and Severity Index (EASI) score in those initially randomized to merino wool improved from a mean baseline of 4.5 to 1.7 at week 6, a significantly greater improvement than in the group wearing their regular clothing. Similarly, those who switched to merino wool after 6 weeks experienced a significant decrease in EASI scores from that point on to week 12, while those who switched from merino wool to their regular clothing did not.

Mean Dermatology Life Quality Index (DLQI) scores in patients who wore merino wool first improved from 6.9 at baseline to 3.4 at week 6. Those who wore their regular clothing first went from a mean baseline DLQI of 6.7 to 6.2 at week 6 – a nonsignificant change – but then improved to a week 12 mean DLQI of 3.7 while wearing wool. There was no improvement in DLQI scores while participants were wearing their regular clothing.

Static Investigator’s Global Assessment scores showed significantly greater improvement while patients wore merino wool garments than their regular clothing.

The Australian study included 39 patients with mild to moderate AD aged between 4 weeks and 3 years. This, too, was a 12-week, randomized, crossover, assessor-blinded clinical trial. Participating children wore merino wool for 6 weeks and cotton ensembles chosen by their parents for an equal time. The primary endpoint was change in the SCORing Atopic Dermatitis (SCORAD) index after each 6-week period. The mean 7.6-point greater SCORAD reduction at 6 weeks while wearing merino wool, compared with cotton, was “a pretty impressive reduction,” Dr. Fowler observed.

Reductions in the secondary endpoints of Atopic Dermatitis Severity Index and Infants’ Dermatitis Quality of Life Index while wearing merino wool followed suit. In contrast, switching from wool to cotton resulted in an increase in both scores. Also, use of topical corticosteroids was significantly reduced while patients wore merino wool.

Wool harvested from merino sheep is characterized by fine-diameter fibers. In Dr. Fowler’s study the mean fiber diameter was 17.5 mcm. This makes for a soft fabric with outstanding moisture absorbance capacity, a quality that’s beneficial in patients with AD, since their lesional skin loses the ability to regulate moisture, the dermatologist explained.

Both randomized trials were funded by Australian Wool Innovation and the Australian government.

MedscapeLive and this news organization are owned by the same parent company.
 

[email protected]

Conventional wisdom holds that patients with atopic dermatitis (AD) should shun wool clothing in favor of cotton or silk, because wool is said to be irritating and promote itching. But not so when the garments are made of fine-diameter fibers of merino wool, Joseph F. Fowler, Jr., MD, said at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually.

“We’ve always though that wool is bad in atopics, right? Indeed, rough wool might be. But fine wool garments can actually improve atopic dermatitis, probably because wool is the most breathable fabric and has the best temperature regulation qualities of any fabric we can wear,” said Dr. Fowler, a dermatologist at the University of Louisville (Ky).

He was first author of a randomized, 12-week, crossover, assessor-blinded clinical trial which showed precisely that. And a second, similarly designed study, this one conducted in Australia, also concluded that fine merino wool assists in the management of AD.

The study by Dr. Fowler and coinvestigators included 50 children and adults with mild or moderate AD who either wore top-and-bottom base layer merino wool ensembles for 6 weeks and then switched to their regular nonwoolen clothing, or vice versa. The mean Eczema Area and Severity Index (EASI) score in those initially randomized to merino wool improved from a mean baseline of 4.5 to 1.7 at week 6, a significantly greater improvement than in the group wearing their regular clothing. Similarly, those who switched to merino wool after 6 weeks experienced a significant decrease in EASI scores from that point on to week 12, while those who switched from merino wool to their regular clothing did not.

Mean Dermatology Life Quality Index (DLQI) scores in patients who wore merino wool first improved from 6.9 at baseline to 3.4 at week 6. Those who wore their regular clothing first went from a mean baseline DLQI of 6.7 to 6.2 at week 6 – a nonsignificant change – but then improved to a week 12 mean DLQI of 3.7 while wearing wool. There was no improvement in DLQI scores while participants were wearing their regular clothing.

Static Investigator’s Global Assessment scores showed significantly greater improvement while patients wore merino wool garments than their regular clothing.

The Australian study included 39 patients with mild to moderate AD aged between 4 weeks and 3 years. This, too, was a 12-week, randomized, crossover, assessor-blinded clinical trial. Participating children wore merino wool for 6 weeks and cotton ensembles chosen by their parents for an equal time. The primary endpoint was change in the SCORing Atopic Dermatitis (SCORAD) index after each 6-week period. The mean 7.6-point greater SCORAD reduction at 6 weeks while wearing merino wool, compared with cotton, was “a pretty impressive reduction,” Dr. Fowler observed.

Reductions in the secondary endpoints of Atopic Dermatitis Severity Index and Infants’ Dermatitis Quality of Life Index while wearing merino wool followed suit. In contrast, switching from wool to cotton resulted in an increase in both scores. Also, use of topical corticosteroids was significantly reduced while patients wore merino wool.

Wool harvested from merino sheep is characterized by fine-diameter fibers. In Dr. Fowler’s study the mean fiber diameter was 17.5 mcm. This makes for a soft fabric with outstanding moisture absorbance capacity, a quality that’s beneficial in patients with AD, since their lesional skin loses the ability to regulate moisture, the dermatologist explained.

Both randomized trials were funded by Australian Wool Innovation and the Australian government.

MedscapeLive and this news organization are owned by the same parent company.
 

[email protected]

Conventional wisdom holds that patients with atopic dermatitis (AD) should shun wool clothing in favor of cotton or silk, because wool is said to be irritating and promote itching. But not so when the garments are made of fine-diameter fibers of merino wool, Joseph F. Fowler, Jr., MD, said at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually.

“We’ve always though that wool is bad in atopics, right? Indeed, rough wool might be. But fine wool garments can actually improve atopic dermatitis, probably because wool is the most breathable fabric and has the best temperature regulation qualities of any fabric we can wear,” said Dr. Fowler, a dermatologist at the University of Louisville (Ky).

He was first author of a randomized, 12-week, crossover, assessor-blinded clinical trial which showed precisely that. And a second, similarly designed study, this one conducted in Australia, also concluded that fine merino wool assists in the management of AD.

The study by Dr. Fowler and coinvestigators included 50 children and adults with mild or moderate AD who either wore top-and-bottom base layer merino wool ensembles for 6 weeks and then switched to their regular nonwoolen clothing, or vice versa. The mean Eczema Area and Severity Index (EASI) score in those initially randomized to merino wool improved from a mean baseline of 4.5 to 1.7 at week 6, a significantly greater improvement than in the group wearing their regular clothing. Similarly, those who switched to merino wool after 6 weeks experienced a significant decrease in EASI scores from that point on to week 12, while those who switched from merino wool to their regular clothing did not.

Mean Dermatology Life Quality Index (DLQI) scores in patients who wore merino wool first improved from 6.9 at baseline to 3.4 at week 6. Those who wore their regular clothing first went from a mean baseline DLQI of 6.7 to 6.2 at week 6 – a nonsignificant change – but then improved to a week 12 mean DLQI of 3.7 while wearing wool. There was no improvement in DLQI scores while participants were wearing their regular clothing.

Static Investigator’s Global Assessment scores showed significantly greater improvement while patients wore merino wool garments than their regular clothing.

The Australian study included 39 patients with mild to moderate AD aged between 4 weeks and 3 years. This, too, was a 12-week, randomized, crossover, assessor-blinded clinical trial. Participating children wore merino wool for 6 weeks and cotton ensembles chosen by their parents for an equal time. The primary endpoint was change in the SCORing Atopic Dermatitis (SCORAD) index after each 6-week period. The mean 7.6-point greater SCORAD reduction at 6 weeks while wearing merino wool, compared with cotton, was “a pretty impressive reduction,” Dr. Fowler observed.

Reductions in the secondary endpoints of Atopic Dermatitis Severity Index and Infants’ Dermatitis Quality of Life Index while wearing merino wool followed suit. In contrast, switching from wool to cotton resulted in an increase in both scores. Also, use of topical corticosteroids was significantly reduced while patients wore merino wool.

Wool harvested from merino sheep is characterized by fine-diameter fibers. In Dr. Fowler’s study the mean fiber diameter was 17.5 mcm. This makes for a soft fabric with outstanding moisture absorbance capacity, a quality that’s beneficial in patients with AD, since their lesional skin loses the ability to regulate moisture, the dermatologist explained.

Both randomized trials were funded by Australian Wool Innovation and the Australian government.

MedscapeLive and this news organization are owned by the same parent company.
 

[email protected]

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Early treatment with the antidepressant fluvoxamine (Luvox) may help prevent respiratory deterioration in patients with mild symptomatic COVID-19, results of a preliminary randomized controlled trial suggest.

In the trial, none of the patients who took fluvoxamine within 7 days of first symptoms developed serious breathing difficulties or required hospitalization for respiratory deterioration.

Antiviral effects?

The study included 152 nonhospitalized adults (mean age, 46 years; 72% women) with confirmed SARS-CoV-2 infection and mild COVID-19 symptoms starting within 7 days and oxygen saturation of 92% or greater.

Eighty were randomly assigned to 100 mg of fluvoxamine three times daily for 15 days and 72 to matching placebo.

The primary outcome was clinical deterioration within 15 days of randomization defined by meeting two criteria. These included shortness of breath or hospitalization for shortness of breath or pneumonia and oxygen saturation <92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater.

Clinical deterioration occurred in none of the 80 patients taking fluvoxamine compared with 6 of 72 (8.3%) patients taking placebo, an absolute difference of 8.7% (95% confidence interval, 1.8%-16.4%).

Clinical deterioration in the placebo group happened from 1 to 7 days after randomization and from 3 to 12 days after the onset of COVID-19 symptoms. Four of the 6 patients with clinical deterioration were admitted to the hospital for 4-21 days. One patient required mechanical ventilation for 10 days. No patients died.
 

Hypothesis generating

The authors cautioned that the study was small and with short follow-up and that the findings “need to be interpreted as hypothesis generating rather than as a demonstration of efficacy.”

However, they noted, if the drug turns out to be effective for COVID-19, the potential advantages of fluvoxamine for outpatient use include its safety, widespread availability, low cost, and oral administration.

Carolyn Machamer, PhD, member of the COVID-19 Early Treatment Fund (CETF) scientific advisory board, which funded the study, noted that there are several reasons fluvoxamine might be helpful in COVID-19.

“The preliminary data suggest the mechanism involves activation of the sigma-1 receptor, which has a number of documented activities. One strong possibility is that activation dampens cytokine release and thus the inflammatory response,” she said in an interview.

“Other possible mechanisms can include inhibition of platelet activation and modulation of autophagy. Coronaviruses usurp some autophagy machinery to remodel membranes for replicating their genomes, so this last mechanism might actually be antiviral,” said Dr. Machamer.

She added that a much larger trial is “crucial to see if the initial striking results can be reproduced, and the Healthy Mind Lab and CETF are currently coordinating these next steps.”

The editors of JAMA published an “Editor’s Note” with the study. In it, they wrote the pilot study addresses a “critically important question during the pandemic of how to prevent individuals who acquire COVID-19 from deteriorating to serious illness. If an effective treatment is found for this key gap in treatment, it will affect the health of millions of people worldwide.”

However, the study has “important limitations, and the findings should be interpreted as only hypothesis generating; they should not be used as the basis for current treatment decisions,” cautioned authors Christopher Seymour, MD, Howard Bauchner, MD, and Robert Golub, MD.

This study was supported by the Taylor Family Institute for Innovative Psychiatric Treatment at Washington University and the CETF. Additional support was provided by the Center for Brain Research in Mood Disorders at Washington University, the Bantly Foundation, and the National Institutes of Health.

Dr. Lenze has received grants from the Patient-Centered Outcomes Research Institute, Takeda, Alkermes, Janssen, Acadia, and the Barnes Jewish Hospital Foundation and has received consulting fees from Janssen and Jazz Pharmaceuticals. Dr. Machamer has disclosed no relevant financial relationships. Dr. Seymour has received grants from the National Institutes of Health and personal fees from Beckman Coulter and Edwards Lifesciences.

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

Early treatment with the antidepressant fluvoxamine (Luvox) may help prevent respiratory deterioration in patients with mild symptomatic COVID-19, results of a preliminary randomized controlled trial suggest.

In the trial, none of the patients who took fluvoxamine within 7 days of first symptoms developed serious breathing difficulties or required hospitalization for respiratory deterioration.

Antiviral effects?

The study included 152 nonhospitalized adults (mean age, 46 years; 72% women) with confirmed SARS-CoV-2 infection and mild COVID-19 symptoms starting within 7 days and oxygen saturation of 92% or greater.

Eighty were randomly assigned to 100 mg of fluvoxamine three times daily for 15 days and 72 to matching placebo.

The primary outcome was clinical deterioration within 15 days of randomization defined by meeting two criteria. These included shortness of breath or hospitalization for shortness of breath or pneumonia and oxygen saturation <92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater.

Clinical deterioration occurred in none of the 80 patients taking fluvoxamine compared with 6 of 72 (8.3%) patients taking placebo, an absolute difference of 8.7% (95% confidence interval, 1.8%-16.4%).

Clinical deterioration in the placebo group happened from 1 to 7 days after randomization and from 3 to 12 days after the onset of COVID-19 symptoms. Four of the 6 patients with clinical deterioration were admitted to the hospital for 4-21 days. One patient required mechanical ventilation for 10 days. No patients died.
 

Hypothesis generating

The authors cautioned that the study was small and with short follow-up and that the findings “need to be interpreted as hypothesis generating rather than as a demonstration of efficacy.”

However, they noted, if the drug turns out to be effective for COVID-19, the potential advantages of fluvoxamine for outpatient use include its safety, widespread availability, low cost, and oral administration.

Carolyn Machamer, PhD, member of the COVID-19 Early Treatment Fund (CETF) scientific advisory board, which funded the study, noted that there are several reasons fluvoxamine might be helpful in COVID-19.

“The preliminary data suggest the mechanism involves activation of the sigma-1 receptor, which has a number of documented activities. One strong possibility is that activation dampens cytokine release and thus the inflammatory response,” she said in an interview.

“Other possible mechanisms can include inhibition of platelet activation and modulation of autophagy. Coronaviruses usurp some autophagy machinery to remodel membranes for replicating their genomes, so this last mechanism might actually be antiviral,” said Dr. Machamer.

She added that a much larger trial is “crucial to see if the initial striking results can be reproduced, and the Healthy Mind Lab and CETF are currently coordinating these next steps.”

The editors of JAMA published an “Editor’s Note” with the study. In it, they wrote the pilot study addresses a “critically important question during the pandemic of how to prevent individuals who acquire COVID-19 from deteriorating to serious illness. If an effective treatment is found for this key gap in treatment, it will affect the health of millions of people worldwide.”

However, the study has “important limitations, and the findings should be interpreted as only hypothesis generating; they should not be used as the basis for current treatment decisions,” cautioned authors Christopher Seymour, MD, Howard Bauchner, MD, and Robert Golub, MD.

This study was supported by the Taylor Family Institute for Innovative Psychiatric Treatment at Washington University and the CETF. Additional support was provided by the Center for Brain Research in Mood Disorders at Washington University, the Bantly Foundation, and the National Institutes of Health.

Dr. Lenze has received grants from the Patient-Centered Outcomes Research Institute, Takeda, Alkermes, Janssen, Acadia, and the Barnes Jewish Hospital Foundation and has received consulting fees from Janssen and Jazz Pharmaceuticals. Dr. Machamer has disclosed no relevant financial relationships. Dr. Seymour has received grants from the National Institutes of Health and personal fees from Beckman Coulter and Edwards Lifesciences.

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

Early treatment with the antidepressant fluvoxamine (Luvox) may help prevent respiratory deterioration in patients with mild symptomatic COVID-19, results of a preliminary randomized controlled trial suggest.

In the trial, none of the patients who took fluvoxamine within 7 days of first symptoms developed serious breathing difficulties or required hospitalization for respiratory deterioration.

Antiviral effects?

The study included 152 nonhospitalized adults (mean age, 46 years; 72% women) with confirmed SARS-CoV-2 infection and mild COVID-19 symptoms starting within 7 days and oxygen saturation of 92% or greater.

Eighty were randomly assigned to 100 mg of fluvoxamine three times daily for 15 days and 72 to matching placebo.

The primary outcome was clinical deterioration within 15 days of randomization defined by meeting two criteria. These included shortness of breath or hospitalization for shortness of breath or pneumonia and oxygen saturation <92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater.

Clinical deterioration occurred in none of the 80 patients taking fluvoxamine compared with 6 of 72 (8.3%) patients taking placebo, an absolute difference of 8.7% (95% confidence interval, 1.8%-16.4%).

Clinical deterioration in the placebo group happened from 1 to 7 days after randomization and from 3 to 12 days after the onset of COVID-19 symptoms. Four of the 6 patients with clinical deterioration were admitted to the hospital for 4-21 days. One patient required mechanical ventilation for 10 days. No patients died.
 

Hypothesis generating

The authors cautioned that the study was small and with short follow-up and that the findings “need to be interpreted as hypothesis generating rather than as a demonstration of efficacy.”

However, they noted, if the drug turns out to be effective for COVID-19, the potential advantages of fluvoxamine for outpatient use include its safety, widespread availability, low cost, and oral administration.

Carolyn Machamer, PhD, member of the COVID-19 Early Treatment Fund (CETF) scientific advisory board, which funded the study, noted that there are several reasons fluvoxamine might be helpful in COVID-19.

“The preliminary data suggest the mechanism involves activation of the sigma-1 receptor, which has a number of documented activities. One strong possibility is that activation dampens cytokine release and thus the inflammatory response,” she said in an interview.

“Other possible mechanisms can include inhibition of platelet activation and modulation of autophagy. Coronaviruses usurp some autophagy machinery to remodel membranes for replicating their genomes, so this last mechanism might actually be antiviral,” said Dr. Machamer.

She added that a much larger trial is “crucial to see if the initial striking results can be reproduced, and the Healthy Mind Lab and CETF are currently coordinating these next steps.”

The editors of JAMA published an “Editor’s Note” with the study. In it, they wrote the pilot study addresses a “critically important question during the pandemic of how to prevent individuals who acquire COVID-19 from deteriorating to serious illness. If an effective treatment is found for this key gap in treatment, it will affect the health of millions of people worldwide.”

However, the study has “important limitations, and the findings should be interpreted as only hypothesis generating; they should not be used as the basis for current treatment decisions,” cautioned authors Christopher Seymour, MD, Howard Bauchner, MD, and Robert Golub, MD.

This study was supported by the Taylor Family Institute for Innovative Psychiatric Treatment at Washington University and the CETF. Additional support was provided by the Center for Brain Research in Mood Disorders at Washington University, the Bantly Foundation, and the National Institutes of Health.

Dr. Lenze has received grants from the Patient-Centered Outcomes Research Institute, Takeda, Alkermes, Janssen, Acadia, and the Barnes Jewish Hospital Foundation and has received consulting fees from Janssen and Jazz Pharmaceuticals. Dr. Machamer has disclosed no relevant financial relationships. Dr. Seymour has received grants from the National Institutes of Health and personal fees from Beckman Coulter and Edwards Lifesciences.

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

Esophagology was a term coined in 1948 to describe a medical specialty devoted to the study of the anatomy, physiology, and pathology of the esophagus. The term was born out of increased interest and evolution in esophagology and supported by development in esophagoscopy.¹ While still rooted in these basic tenets, the landscape of esophagology is dramatically different in 2020. The last decade alone has seen unprecedented technological advances in esophagology, from the transformation of line tracings to high-resolution esophageal pressure topography to more recent innovations such as the functional lumen imaging probe. Successful therapeutic developments have increased opportunities for effective and less invasive treatment approaches for achalasia and gastroesophageal reflux disease (GERD). With changing concepts in esophageal diseases such as eosinophilic esophagitis, successful management now incorporates findings from recent discoveries that have revolutionized care pathways. Esophagology is an evolving, dynamic subspecialty of gastroenterology, and esophagologists require comprehensive and unique training during gastroenterology fellowship and beyond (see Figure 1).

Figure 1

Optimizing esophagology training during fellowship

First, and most importantly, an esophagologist must have a foundation in the basic principles of esophageal anatomy, physiology, and pathology (see Figure 2). While newer digital learning resources exist, tried and true book-based resources – text books, chapters, and reviews – related to esophageal mechanics, the interplay between muscle function and neurogenics, and factors associated with nociception, remain the optimal learning strategy.

Once equipped with a foundation in esophageal physiology, one can readily engage with esophageal technologies, as there exists a vast array of testing to assess esophageal function. A comprehensive understanding of each, including device configuration, clinical protocol, and data storage, promotes a depth of knowledge every esophagologist should develop. Aspiring esophagologists should take time to observe and perform procedures in their motility labs, particularly esophageal high-resolution manometry and ambulatory reflux monitoring studies. If afforded the opportunity through a research study or a clinical indication, esophagologists should also undergo the tests themselves. Empathy regarding the discomfort and tolerability of motility tests, which are notoriously challenging for patients, can promote rapport and trust with patients, increase patient satisfaction, and enhance one’s own understanding of resource utilization and safety.

Perhaps most critical to becoming an esophagologist, is acquiring sufficient competency in interpretation of esophageal studies. Prior research highlights the limitations in achieving competency when trainees adhere to the minimum case volume of studies recommended by the GI core curriculum.^2,3 With the bar set higher for the burgeoning esophagologist, one must not only practice with a higher case volume, but also engage in competency-based assessments and performance feedback.⁴ Trainees should start by reviewing tracings for their own patients. Preliminary interpretation of pending studies and review with a mentor before the final sign-off, participation in research that requires study, or even teaching co-trainees basic tenets of motility are other creative approaches to learning. Esophagologists will be expected to know how to navigate the software to access studies, manually review tracings, and generate reports. Trainees should refer to the multitude of societal guidelines and classification scheme recommendations available when developing competency in diagnostic impression.⁵

Figure 2

While esophagology is a medical specialty, it is imperative that the esophagologist has a robust understanding of therapeutic options and surgical interventions for esophageal pathology. Scrubbing into the operating room during foregut surgeries is an eye-opening experience. This includes thoracic and abdominal approaches, robotic, laparoscopic, and open techniques, and interventions for GERD, achalasia, diverticular disease, and bariatric management. Equally important is working alongside advanced endoscopy faculty to understand utilities of endoscopic ultrasound, ablative methods for Barrett’s esophagus, and advanced techniques such as peroral endoscopic myotomy and transoral incisionless fundoplication. This exposure is critical as the role of the esophagologist is to speak knowledgably of therapeutic options and the risks and benefits of alternative approaches. Further, the patient’s journey rarely ends with the intervention, and an esophagologist must understand how to evaluate symptoms and manage complications following therapy.

Figure 3

Steep learning curve post fellowship

Regardless of the robust nature of clinical esophagology training, early career esophagologists will face challenges and learn on the job.

Many esophagologists are directors of a motility lab early in their careers. This is often uncharted territory in terms of managing a team of nurses, technicians, and other providers. The director of a motility lab will be called upon to troubleshoot various arenas of diagnostic workup, from study acquisition and interpretation to technical barriers with equipment or software. Keys to maintaining a successful motility lab further include optimizing schedules and protocols, delineating roles and responsibilities of team members, ensuring adequate training across staff and providers, communicating expectations, and cultivating an open relationship with the motility lab supervisor. Crucial, yet often neglected during fellowship training, are the economic considerations of operating and expanding the motility lab, and the financial implications for one’s own practice.⁶ Participating in professional development workshops can be especially valuable in cultivating leadership skills.

The care an esophagologist provides relies heavily on collaborative relationships within the organization and peer mentorship, cooperation, and feedback. It is essential to cultivate multidisciplinary relationships with surgical (e.g., foregut surgery, laryngology), medical (e.g., pulmonology, allergy), radiology, and pathology colleagues, as well as with integrated health specialists including psychologists, dietitians, and speech language pathologists. It is also important to have open industry partnerships to ensure appropriate technical support and access to advancements.

Often organizations will have only one esophageal specialist within the group. Fortunately, the national and global community of esophagologists is highly collaborative and collegial. All esophagologists should have a network of mentors and colleagues within and outside of their organization to review complex cases, discuss challenges in the workplace, and foster research and innovation. Along these lines, both aspiring and practicing esophagologists should engage with professional societies as opportunities are abundant. Esophageal-focused societies include the ANMS, American Foregut Society, and International Society of Diseases of Esophagus, and the overarching GI societies also have a strong esophageal focus.

The path to becoming an esophagologist does not mirror the structure of the organ itself. Development is neither confined, unidirectional, nor set in length, but gradual, each step thoughtfully built on the last. Esophageal pathology is diverse, complex, and fascinating. With the appropriate training, mentorship, engagement, and leadership, esophagologists have the privilege of making a great impact on the lives of patients we meet, a fulfilling journey worth the time and effort it takes.
 

Dr. Delay is in the division of gastroenterology & hepatology, University of Colorado Anschutz Medical Campus, Aurora. Dr. Yadlapati is at the Center for Esophageal Diseases, division of gastroenterology, University of California San Diego, La Jolla. She is a consultant through institutional agreement to Medtronic, Ironwood Pharmaceuticals, and Diversatek; she has received research support from Ironwood Pharmaceuticals; and is on the advisory board of Phathom Pharmaceuticals.

References

1. Holinger PH. Arch Otolaryngol. 1948;47:119-26.

2. Yadlapati R et al. Clin Gastroenterol Hepatol. 2017;15:1708-14.e3.

3. Oversight Working Network et al. Gastrointest Endosc. 2014;80:16-27.

4. DeLay K et al. Am J Gastroenterol. 2020;115:1453-9.

5. Gyawali CP et al. Neurogastroenterol Motil. 2018;30(9):e13341.

6. Yadlapati R et al. Gastroenterology. 2020;158:1202-10.

Esophagology was a term coined in 1948 to describe a medical specialty devoted to the study of the anatomy, physiology, and pathology of the esophagus. The term was born out of increased interest and evolution in esophagology and supported by development in esophagoscopy.¹ While still rooted in these basic tenets, the landscape of esophagology is dramatically different in 2020. The last decade alone has seen unprecedented technological advances in esophagology, from the transformation of line tracings to high-resolution esophageal pressure topography to more recent innovations such as the functional lumen imaging probe. Successful therapeutic developments have increased opportunities for effective and less invasive treatment approaches for achalasia and gastroesophageal reflux disease (GERD). With changing concepts in esophageal diseases such as eosinophilic esophagitis, successful management now incorporates findings from recent discoveries that have revolutionized care pathways. Esophagology is an evolving, dynamic subspecialty of gastroenterology, and esophagologists require comprehensive and unique training during gastroenterology fellowship and beyond (see Figure 1).

Figure 1

Optimizing esophagology training during fellowship

First, and most importantly, an esophagologist must have a foundation in the basic principles of esophageal anatomy, physiology, and pathology (see Figure 2). While newer digital learning resources exist, tried and true book-based resources – text books, chapters, and reviews – related to esophageal mechanics, the interplay between muscle function and neurogenics, and factors associated with nociception, remain the optimal learning strategy.

Once equipped with a foundation in esophageal physiology, one can readily engage with esophageal technologies, as there exists a vast array of testing to assess esophageal function. A comprehensive understanding of each, including device configuration, clinical protocol, and data storage, promotes a depth of knowledge every esophagologist should develop. Aspiring esophagologists should take time to observe and perform procedures in their motility labs, particularly esophageal high-resolution manometry and ambulatory reflux monitoring studies. If afforded the opportunity through a research study or a clinical indication, esophagologists should also undergo the tests themselves. Empathy regarding the discomfort and tolerability of motility tests, which are notoriously challenging for patients, can promote rapport and trust with patients, increase patient satisfaction, and enhance one’s own understanding of resource utilization and safety.

Perhaps most critical to becoming an esophagologist, is acquiring sufficient competency in interpretation of esophageal studies. Prior research highlights the limitations in achieving competency when trainees adhere to the minimum case volume of studies recommended by the GI core curriculum.^2,3 With the bar set higher for the burgeoning esophagologist, one must not only practice with a higher case volume, but also engage in competency-based assessments and performance feedback.⁴ Trainees should start by reviewing tracings for their own patients. Preliminary interpretation of pending studies and review with a mentor before the final sign-off, participation in research that requires study, or even teaching co-trainees basic tenets of motility are other creative approaches to learning. Esophagologists will be expected to know how to navigate the software to access studies, manually review tracings, and generate reports. Trainees should refer to the multitude of societal guidelines and classification scheme recommendations available when developing competency in diagnostic impression.⁵

Figure 2

While esophagology is a medical specialty, it is imperative that the esophagologist has a robust understanding of therapeutic options and surgical interventions for esophageal pathology. Scrubbing into the operating room during foregut surgeries is an eye-opening experience. This includes thoracic and abdominal approaches, robotic, laparoscopic, and open techniques, and interventions for GERD, achalasia, diverticular disease, and bariatric management. Equally important is working alongside advanced endoscopy faculty to understand utilities of endoscopic ultrasound, ablative methods for Barrett’s esophagus, and advanced techniques such as peroral endoscopic myotomy and transoral incisionless fundoplication. This exposure is critical as the role of the esophagologist is to speak knowledgably of therapeutic options and the risks and benefits of alternative approaches. Further, the patient’s journey rarely ends with the intervention, and an esophagologist must understand how to evaluate symptoms and manage complications following therapy.

Figure 3

Steep learning curve post fellowship

Regardless of the robust nature of clinical esophagology training, early career esophagologists will face challenges and learn on the job.

Many esophagologists are directors of a motility lab early in their careers. This is often uncharted territory in terms of managing a team of nurses, technicians, and other providers. The director of a motility lab will be called upon to troubleshoot various arenas of diagnostic workup, from study acquisition and interpretation to technical barriers with equipment or software. Keys to maintaining a successful motility lab further include optimizing schedules and protocols, delineating roles and responsibilities of team members, ensuring adequate training across staff and providers, communicating expectations, and cultivating an open relationship with the motility lab supervisor. Crucial, yet often neglected during fellowship training, are the economic considerations of operating and expanding the motility lab, and the financial implications for one’s own practice.⁶ Participating in professional development workshops can be especially valuable in cultivating leadership skills.

The care an esophagologist provides relies heavily on collaborative relationships within the organization and peer mentorship, cooperation, and feedback. It is essential to cultivate multidisciplinary relationships with surgical (e.g., foregut surgery, laryngology), medical (e.g., pulmonology, allergy), radiology, and pathology colleagues, as well as with integrated health specialists including psychologists, dietitians, and speech language pathologists. It is also important to have open industry partnerships to ensure appropriate technical support and access to advancements.

Often organizations will have only one esophageal specialist within the group. Fortunately, the national and global community of esophagologists is highly collaborative and collegial. All esophagologists should have a network of mentors and colleagues within and outside of their organization to review complex cases, discuss challenges in the workplace, and foster research and innovation. Along these lines, both aspiring and practicing esophagologists should engage with professional societies as opportunities are abundant. Esophageal-focused societies include the ANMS, American Foregut Society, and International Society of Diseases of Esophagus, and the overarching GI societies also have a strong esophageal focus.

The path to becoming an esophagologist does not mirror the structure of the organ itself. Development is neither confined, unidirectional, nor set in length, but gradual, each step thoughtfully built on the last. Esophageal pathology is diverse, complex, and fascinating. With the appropriate training, mentorship, engagement, and leadership, esophagologists have the privilege of making a great impact on the lives of patients we meet, a fulfilling journey worth the time and effort it takes.
 

Dr. Delay is in the division of gastroenterology & hepatology, University of Colorado Anschutz Medical Campus, Aurora. Dr. Yadlapati is at the Center for Esophageal Diseases, division of gastroenterology, University of California San Diego, La Jolla. She is a consultant through institutional agreement to Medtronic, Ironwood Pharmaceuticals, and Diversatek; she has received research support from Ironwood Pharmaceuticals; and is on the advisory board of Phathom Pharmaceuticals.

References

1. Holinger PH. Arch Otolaryngol. 1948;47:119-26.

2. Yadlapati R et al. Clin Gastroenterol Hepatol. 2017;15:1708-14.e3.

3. Oversight Working Network et al. Gastrointest Endosc. 2014;80:16-27.

4. DeLay K et al. Am J Gastroenterol. 2020;115:1453-9.

5. Gyawali CP et al. Neurogastroenterol Motil. 2018;30(9):e13341.

6. Yadlapati R et al. Gastroenterology. 2020;158:1202-10.

Esophagology was a term coined in 1948 to describe a medical specialty devoted to the study of the anatomy, physiology, and pathology of the esophagus. The term was born out of increased interest and evolution in esophagology and supported by development in esophagoscopy.¹ While still rooted in these basic tenets, the landscape of esophagology is dramatically different in 2020. The last decade alone has seen unprecedented technological advances in esophagology, from the transformation of line tracings to high-resolution esophageal pressure topography to more recent innovations such as the functional lumen imaging probe. Successful therapeutic developments have increased opportunities for effective and less invasive treatment approaches for achalasia and gastroesophageal reflux disease (GERD). With changing concepts in esophageal diseases such as eosinophilic esophagitis, successful management now incorporates findings from recent discoveries that have revolutionized care pathways. Esophagology is an evolving, dynamic subspecialty of gastroenterology, and esophagologists require comprehensive and unique training during gastroenterology fellowship and beyond (see Figure 1).

Figure 1

Optimizing esophagology training during fellowship

First, and most importantly, an esophagologist must have a foundation in the basic principles of esophageal anatomy, physiology, and pathology (see Figure 2). While newer digital learning resources exist, tried and true book-based resources – text books, chapters, and reviews – related to esophageal mechanics, the interplay between muscle function and neurogenics, and factors associated with nociception, remain the optimal learning strategy.

Once equipped with a foundation in esophageal physiology, one can readily engage with esophageal technologies, as there exists a vast array of testing to assess esophageal function. A comprehensive understanding of each, including device configuration, clinical protocol, and data storage, promotes a depth of knowledge every esophagologist should develop. Aspiring esophagologists should take time to observe and perform procedures in their motility labs, particularly esophageal high-resolution manometry and ambulatory reflux monitoring studies. If afforded the opportunity through a research study or a clinical indication, esophagologists should also undergo the tests themselves. Empathy regarding the discomfort and tolerability of motility tests, which are notoriously challenging for patients, can promote rapport and trust with patients, increase patient satisfaction, and enhance one’s own understanding of resource utilization and safety.

Perhaps most critical to becoming an esophagologist, is acquiring sufficient competency in interpretation of esophageal studies. Prior research highlights the limitations in achieving competency when trainees adhere to the minimum case volume of studies recommended by the GI core curriculum.^2,3 With the bar set higher for the burgeoning esophagologist, one must not only practice with a higher case volume, but also engage in competency-based assessments and performance feedback.⁴ Trainees should start by reviewing tracings for their own patients. Preliminary interpretation of pending studies and review with a mentor before the final sign-off, participation in research that requires study, or even teaching co-trainees basic tenets of motility are other creative approaches to learning. Esophagologists will be expected to know how to navigate the software to access studies, manually review tracings, and generate reports. Trainees should refer to the multitude of societal guidelines and classification scheme recommendations available when developing competency in diagnostic impression.⁵

Figure 2

While esophagology is a medical specialty, it is imperative that the esophagologist has a robust understanding of therapeutic options and surgical interventions for esophageal pathology. Scrubbing into the operating room during foregut surgeries is an eye-opening experience. This includes thoracic and abdominal approaches, robotic, laparoscopic, and open techniques, and interventions for GERD, achalasia, diverticular disease, and bariatric management. Equally important is working alongside advanced endoscopy faculty to understand utilities of endoscopic ultrasound, ablative methods for Barrett’s esophagus, and advanced techniques such as peroral endoscopic myotomy and transoral incisionless fundoplication. This exposure is critical as the role of the esophagologist is to speak knowledgably of therapeutic options and the risks and benefits of alternative approaches. Further, the patient’s journey rarely ends with the intervention, and an esophagologist must understand how to evaluate symptoms and manage complications following therapy.

Figure 3

Steep learning curve post fellowship

Regardless of the robust nature of clinical esophagology training, early career esophagologists will face challenges and learn on the job.

Many esophagologists are directors of a motility lab early in their careers. This is often uncharted territory in terms of managing a team of nurses, technicians, and other providers. The director of a motility lab will be called upon to troubleshoot various arenas of diagnostic workup, from study acquisition and interpretation to technical barriers with equipment or software. Keys to maintaining a successful motility lab further include optimizing schedules and protocols, delineating roles and responsibilities of team members, ensuring adequate training across staff and providers, communicating expectations, and cultivating an open relationship with the motility lab supervisor. Crucial, yet often neglected during fellowship training, are the economic considerations of operating and expanding the motility lab, and the financial implications for one’s own practice.⁶ Participating in professional development workshops can be especially valuable in cultivating leadership skills.

The care an esophagologist provides relies heavily on collaborative relationships within the organization and peer mentorship, cooperation, and feedback. It is essential to cultivate multidisciplinary relationships with surgical (e.g., foregut surgery, laryngology), medical (e.g., pulmonology, allergy), radiology, and pathology colleagues, as well as with integrated health specialists including psychologists, dietitians, and speech language pathologists. It is also important to have open industry partnerships to ensure appropriate technical support and access to advancements.

Often organizations will have only one esophageal specialist within the group. Fortunately, the national and global community of esophagologists is highly collaborative and collegial. All esophagologists should have a network of mentors and colleagues within and outside of their organization to review complex cases, discuss challenges in the workplace, and foster research and innovation. Along these lines, both aspiring and practicing esophagologists should engage with professional societies as opportunities are abundant. Esophageal-focused societies include the ANMS, American Foregut Society, and International Society of Diseases of Esophagus, and the overarching GI societies also have a strong esophageal focus.

The path to becoming an esophagologist does not mirror the structure of the organ itself. Development is neither confined, unidirectional, nor set in length, but gradual, each step thoughtfully built on the last. Esophageal pathology is diverse, complex, and fascinating. With the appropriate training, mentorship, engagement, and leadership, esophagologists have the privilege of making a great impact on the lives of patients we meet, a fulfilling journey worth the time and effort it takes.
 

Dr. Delay is in the division of gastroenterology & hepatology, University of Colorado Anschutz Medical Campus, Aurora. Dr. Yadlapati is at the Center for Esophageal Diseases, division of gastroenterology, University of California San Diego, La Jolla. She is a consultant through institutional agreement to Medtronic, Ironwood Pharmaceuticals, and Diversatek; she has received research support from Ironwood Pharmaceuticals; and is on the advisory board of Phathom Pharmaceuticals.

References

1. Holinger PH. Arch Otolaryngol. 1948;47:119-26.

2. Yadlapati R et al. Clin Gastroenterol Hepatol. 2017;15:1708-14.e3.

3. Oversight Working Network et al. Gastrointest Endosc. 2014;80:16-27.

4. DeLay K et al. Am J Gastroenterol. 2020;115:1453-9.

5. Gyawali CP et al. Neurogastroenterol Motil. 2018;30(9):e13341.

6. Yadlapati R et al. Gastroenterology. 2020;158:1202-10.