Due to the high cost of newer chemotherapy agents, institutions search for strategies to minimize drug cost and drug waste. Programmed death-1 (PD-1) inhibitors, nivolumab and pembrolizumab, are commonly used in the treatment of solid tumors; however, the agents cost thousands of dollars per dose. Nivolumab and pembrolizumab were initially approved using weight-based dosing, but package labeling for both agents now includes fixed dosing.^1,2 A combination of these 2 dosing strategies could be used by institutions depending on individual patient’s weight to maximize cost savings, minimize drug waste, and maintain safety and efficacy of PD-1 inhibitors. Irrespective of dosing strategy, the development of immune-related adverse events (IrAEs) has been demonstrated with PD-1 inhibitors as a result of the mechanism of action.

PD-1 expression suppresses T cell activity to prevent the development of autoimmunity; however, this is also a mechanism in which tumor cells can evade the host immune system.^3-5 Binding of PD-1 and programmed death-ligand 1 (PD-L1) suppresses T cell activity, whereas the inhibition of PD-1 and PD-L1 results in T cell activation.^4,5 Increased T cell activity elicits the anticancer effect, but also contributes to the development of IrAEs^.4,5 Hypothyroidism is one of the most common IrAEs, with a reported incidence of 9% with nivolumab therapy and 8.5% with pembrolizumab.^1,2

Data from the US Department of Veterans Affairs (VA) medical centers is stored in the centralized Corporate Data Warehouse (CDW). VA researchers can obtain approval to use CDW data, which allows for large scale retrospective review of veterans who have received care at VA medical centers (VAMCs). This study aimed to describe the PD-1 inhibitor dosing used within VAMCs and identify actual and potential cost savings. Due to the frequency of immunemediated hypothyroidism and objective data that can be obtained from CDW reports, the study estimated the incidence of immune-mediated hypothyroidism within the veteran population as a safety outcome.

Background

The US Food and Drug Administration (FDA) initially approved dosing for IV nivolumab at 3 mg/kg of patient body weight every 2 weeks and for IV pembrolizumab 2 mg/kg of patient body weight every 3 weeks.^1,2 Subsequent pharmacokinetic studies found that these agents have similar exposure and efficacy with fixed doses of nivolumab 240 mg IV every 2 weeks and pembrolizumab 200 mg IV every 3 weeks; in 2016, FDA labeling shifted from weight-based dosing to fixed dosing for most solid tumor indications.^6-9 Depending on patient weight, a combination of weightbased and fixed dosing could be used by institutions to maximize cost-savings opportunities, minimize drug waste, and maintain clinical efficacy with PD-1 inhibitors. For example, a patient initiating nivolumab who weighs 80 kg would receive 240 mg for both weight-based (3 mg/kg x 80 kg = 240 mg) and fixed dosing; therefore, no cost-savings opportunities would be available. However, for a patient who weighs ≤ 73.3 kg, it would be more costeffective to use weight-based dosing vs the fixed dose. Since nivolumab is available in 40- mg, 100-mg, and 240-mg vials with similar unit prices, a combination of vial sizes could be used to minimize drug waste. Alternatively, for a patient who weighs ≥ 86.7 kg, it would be more cost-effective to administer the fixed, 240 mg dose when compared with the weightbased dose. Pembrolizumab is available only in a 100-mg vial; therefore, weight-based dosing may result in drug waste.

IrAEs can be seen with PD-1 inhibitors due to increased T cell activity, which is independent of dosing strategy and can affect any organ system. However, immune-mediated hypothyroidism has been commonly seen with PD-1 inhibitors. For patients with immunemediated hypothyroidism, levothyroxine can be considered for asymptomatic patients with thyroid- stimulating hormone (TSH) > 10 uIU/mL with normal thyroxine (T4), or patients with clinical primary hypothyroidism (TSH > 10 uIU/mL with low free T4 and clinical symptoms). Additionally, since hypothyroidism usually follows immunotherapy induced thyrotoxicosis, thyroid function tests should be monitored and levothyroxine initiated if TSH is > 10 uIU/mL for these patients.^10,11

Hypothyroidism also can be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events. Hypothyroidism is considered grade 1 when hypothyroidism is demonstrated through clinical or diagnostic observations only and the patient is asymptomatic and no intervention needed. Grade 2 occurs when the patient is symptomatic and limits instrumental activities of daily living (ADLs), prompting thyroid replacement therapy. In grade 3, patients experience severe symptoms that restrict self-care ADLs, and hospitalization is indicated. Grade 4 has life-threatening consequences, and urgent intervention is indicated. Grade 5 results in the death of the patient.¹²

Electronic health records (EHRs) of veterans who receive care at a VAMC are stored in CDW and available through the VA Informatics and Computing Infrastructure (VINCI), which provides access to data while ensuring veterans’ privacy and data security. This feature of the VA EHR allows for analysis of data across the VA health care system, and larger data sets can be used for retrospective chart reviews.

Using reports from CDW, the primary objective of this study was to describe the dosing strategy used for PD-1 inhibitors, and the primary safety outcome was to determine the incidence of immune-mediated hypothyroidism. The secondary objective was to estimate potential cost-savings opportunities using a combination of PD-1 inhibitor dosing strategies.

Methods

This was a retrospective study including data stored in CDW. The study was approved by the Durham VA Health Care System Institutional Review Board and VINCI/Data Access request tracker. Data were limited to nivolumab and pembrolizumab because they received earlier FDA approval, had multiple solid tumor indications, and 2 FDA-approved dosing strategies. The incidence of IrAEs was limited to hypothyroidism, which could be objectively verified with laboratory monitoring of thyroid function tests, including TSH, free or total T4, and triiodothyronine (T3), all of which were available in CDW data. Additionally, most patients with hypothyroidism initiate treatment with levothyroxine. Prescription refill history could also be retrieved using CDW reports.

Hypothyroidism was defined as T4 below lower limit of normal (LLN), TSH above upper limit of normal (ULN), or any increase in levothyroxine dosage. Patients were excluded if they received PD-1 inhibitor for an indication other than solid tumor treatment, such as hematologic malignancy, or if dosing did not follow weight-based or fixed-dosing strategies, such as nivolumab 1 mg/kg when used in combination with ipilimumab, or pembrolizumab 10 mg/kg. The primary endpoint was the percentage of orders for each dosing strategy, and the primary safety outcome was the incidence of immune-mediated hypothyroidism. Secondary endpoints included estimated cost savings and cost-savings opportunities through nivolumab dose rounding and incidence of levothyroxine initiation or dose change. Descriptive statistics were used for the primary and secondary endpoints.

A report in CDW identified patients who received a dose of nivolumab or pembrolizumab between January 1, 2015 and July 1, 2017 at any VAMC. The CDW report obtained weight at time of PD-1 inhibitor therapy initiation, dose of PD-1 inhibitor given, administration date of PD-1 inhibitor, and VA site. Depending on PD-1 inhibitor administered, weight in kg was multiplied by 3 mg/kg or 2 mg/kg to obtain patient’s anticipated weight-based nivolumab and pembrolizumab dose, respectively. The calculated weight-based dose, fixed dose, and administered dose were compared to infer dosing strategy used at the time of ordering. If the patient’s weight-based dose was within 10% of the fixed dose, the order was categorized as converging because the doses were too similar to determine which dosing strategy was intended.

After determination of dosing strategy, the nivolumab orders were evaluated for actual vs missed cost savings. The cost-savings evaluation included only nivolumab orders because nivolumab is available in a 40-mg, 100-mg, and 240-mg vials and, therefore, has more potential for dose-rounding opportunities with minimal drug waste compared with pembrolizumab, which is available only in a 100-mg vial. Actual cost savings included patients who weighed ≤ 73.3 kg and received nivolumab dose based on 3 mg/kg or patients who weighed ≥ 86.7 kg and received nivolumab 240 mg (fixed dose). Missed cost savings comprised patients who weighed ≤ 73.3 kg who received 240 mg nivolumab or patients who weighed ≥ 86.7 kg and received a nivolumab dose > 240 mg. The cost difference between the dose given and theoretical cost-effective dose was calculated to determine actual and potential cost savings. Converging orders were not included in the cost-savings analysis as the intended nivolumab dose could not be determined. An additional cost analysis of nivolumab orders prescribed between September 1, 2016 and July 1, 2017 was also performed because nivolumab fixed dosing was FDA-approved for most solid tumor indications in September 2016.

To determine the incidence of immunemediated hypothyroidism for patients who received a dose of a PD-1 inhibitor at a VAMC, a CDW report with thyroid function laboratory values (TSH, T4, or T3), including reference range values based on specific VA site, and levothyroxine prescriptions issued during PD-1 inhibitor therapy was obtained. A patient was considered to have experienced immune-mediated hypothyroidism if the patient’s laboratory values demonstrated T4 below the LLN, TSH above the ULN, or if the medication fill history demonstrated levothyroxine initiation or a levothyroxine dose increase.

Results 

The CDW report identified 32,769 total PD-1 inhibitor orders. There were 3982 orders that did not meet inclusion criteria or inadequate data were obtained with CDW report and were excluded (Figure). The remaining 28,787 PD-1 inhibitor orders were evaluated for actual or missed cost savings. The distribution of dosing strategies can be found in Table 1.

Nivolumab accounted for 81.5% of all PD-1 inhibitor orders. Using the most cost-effective nivolumab dosing, the actual cost savings was estimated to be $8,514,300 with potential additional $5,591,250 of missed cost-savings opportunities. There were 8013 nivolumab orders written between September 1, 2016 and July 1, 2017. Cost-effective dosing was used in 4687 of these orders, which accounted for a cost savings of $5,198,570. The remaining 3326 orders had a missed cost-savings opportunity, which accounted for an additional $2,907,180 potential cost savings (Table 2).

PD-1 inhibitors were used for the treatment of 3249 unique patients. Based on abnormal thyroid function tests and levothyroxine initiation or dose increase, it is estimated that 514 (15.8%) patients experienced hypothyroidism during PD-1 inhibitor therapy. However, prior to PD-1 inhibitor therapy, 274 patients were receiving levothyroxine, suggesting baseline thyroid dysfunction. Of these patients, 152 (55.5%) patients maintained the same levothyroxine dose during PD-1 inhibitor therapy, but 91 (33.2%) required a levothyroxine dose increase. There were 187 patients who initiated levothyroxine during PD-1 inhibitor therapy (Table 3).

Discussion

Changes in FDA-approved dosing for PD-1 inhibitors allowed a combination of dosing strategies. Depending on patient weight, a weight-based or fixed-dosing strategy can be used to reduce drug cost while maintaining equivalent efficacy. This study evaluated use of dose rounding for PD-1 inhibitors within the VA health care system to identify actual and potential cost savings. To our knowledge, this is the first study to demonstrate cost savings through use of a combination of PD-1 inhibitor dosing strategies. Using CDW, researchers were able to review PD-1 dosing from all VAMCs and include a larger number of orders in a single retrospective study.

Nivolumab was the primary agent used within VAMCs. Depending on the indication, pembrolizumab requires PD-1 expression testing prior to its use in several solid tumor indications. Consequently, additional testing and patient eligibility is needed prior to use. Both PD-1 inhibitors were primarily dosed based on patient weight since this was the first FDAapproved dosing strategy. Nivolumab had more orders categorized as converging, which may be due to the therapeutic weight-based dose of 3 mg/kg for nivolumab vs 2 mg/kg for pembrolizumab. The calculated weight-based dose of nivolumab for an 80-kg patient is 240 mg, which also is the fixed dose. A 80-kg patient on pembrolizumab at 2 mg/kg would receive a 160-mg dose, whereas the fixed dose of pembrolizumab is 200 mg. Pembrolizumab is available only in a 100-mg vial, which limits opportunities for dose rounding without drug waste and could explain the higher amount of pembrolizumab orders in the fixed-dose category.

In this review of PD-1 inhibitor orders over approximately a 2.5-year study period, we identified $8,514,300 estimated cost savings with $5,591,250 estimated missed cost savings. When looking at orders administered after FDA approval for nivolumab-fixed dosing in September 2016, there was substantial cost savings of $5,198,570 with the potential for an additional $2,907,180 missed cost savings. Due to lower drug acquisition costs within the VA health care system, there may be higher cost-savings opportunities within other health care systems.

Through review of abnormal thyroid laboratory values and levothyroxine initiation or dose changes, this study estimated the incidence of hypothyroidism in patients receiving PD-1 inhibitor therapy at the VA. The incidence of primary hypothyroidism identified in this study was slightly higher at 15.8% compared with the 8.5 to 9.0% incidence reported from clinical trials.^1,2 There are several reasons why the incidence of hypothyroidism appeared higher in this study. Abnormal laboratory values were not assessed for the degree of deviation from the reference range; any TSH above the ULN, T4 below the LLN, or levothyroxine dose increase was included as thyroid dysfunction in this review. There is also the potential for endogenous age-related thyroid fluctuation, and the development of hypothyroidism may not have been related to PD-1 inhibitor therapy. Within this patient population, 8.4% were receiving levothyroxine prior to PD-1 inhibitor initiation indicating baseline thyroid dysfunction, and it is unclear whether levothyroxine dose increases were due to PD-1 inhibitor or endogenous fluctuation.

Limitations

There are several limitations to acknowledge. The dosing strategy and apparent dose rounding was determined by investigator inference and may not accurately represent the intended dosing strategy. This study did not address efficacy of PD-1 inhibitor and dosing strategy; however, clinical trials have demonstrated equivalent efficacy to generate the change in FDA-approved dosing. Additionally, FDA approval for nivolumab fixed dosing was indication specific. Starting in September 2016, many solid tumor indications had fixed dosing approved, but this approval was not necessarily all encompassing.

While the use of CDW allowed for a greater number of PD-1 inhibitor orders to be included in retrospective review, there also were limitations of the CDW report. The patient weight was limited to weight at time of therapy initiation. Due to the potential for weight changes, nivolumab dosing may have seemed inappropriate to investigators, and thereby excluded. Based on data available from CDW reports, hypothyroidism could not be graded according to NCI Common Terminology Criteria for Adverse Events, and the incidence of clinically significant hypothyroidism could not be determined.

Conclusions

With increasing drug acquisition costs, particularly among antineoplastic agents, health care systems frequently seek out cost-savings opportunities. Using a combination of weightbased and fixed-dosing strategies for PD-1 inhibitors can be a mechanism to achieve costsavings. Through the identification of the dosing strategy used for PD-1 inhibitors, we were able to identify and report instances for potential cost-savings opportunities among veterans treated within VA health care system. Use of CDW allows for data from all VAMCs to be evaluated in a single retrospective chart review, which allows for the inclusion of a larger sample size. This study identified a substantial cost savings for nivolumab through a combination of weight-based and fixed-dosing strategies. Due to the novel mechanism of action, ongoing realworld evaluation of adverse events and IrAEs is warranted.

Dosing strategies with nivolumab and pembrolizumab continue to evolve. In March 2018, nivolumab 480 mg IV every 4 weeks was FDA approved and in April 2020, pembrolizumab 400 mg IV every 6 weeks was FDA approved.^13,14 While the drug costs will remain the same, extended interval dosing strategies have cost avoidance such as fewer clinic appointments, resulting in decreased staffing costs and decreased patient travel. Additional studies will be needed to evaluate the cost and safety of the recently approved dosing strategies

Due to the high cost of newer chemotherapy agents, institutions search for strategies to minimize drug cost and drug waste. Programmed death-1 (PD-1) inhibitors, nivolumab and pembrolizumab, are commonly used in the treatment of solid tumors; however, the agents cost thousands of dollars per dose. Nivolumab and pembrolizumab were initially approved using weight-based dosing, but package labeling for both agents now includes fixed dosing.^1,2 A combination of these 2 dosing strategies could be used by institutions depending on individual patient’s weight to maximize cost savings, minimize drug waste, and maintain safety and efficacy of PD-1 inhibitors. Irrespective of dosing strategy, the development of immune-related adverse events (IrAEs) has been demonstrated with PD-1 inhibitors as a result of the mechanism of action.

PD-1 expression suppresses T cell activity to prevent the development of autoimmunity; however, this is also a mechanism in which tumor cells can evade the host immune system.^3-5 Binding of PD-1 and programmed death-ligand 1 (PD-L1) suppresses T cell activity, whereas the inhibition of PD-1 and PD-L1 results in T cell activation.^4,5 Increased T cell activity elicits the anticancer effect, but also contributes to the development of IrAEs^.4,5 Hypothyroidism is one of the most common IrAEs, with a reported incidence of 9% with nivolumab therapy and 8.5% with pembrolizumab.^1,2

Data from the US Department of Veterans Affairs (VA) medical centers is stored in the centralized Corporate Data Warehouse (CDW). VA researchers can obtain approval to use CDW data, which allows for large scale retrospective review of veterans who have received care at VA medical centers (VAMCs). This study aimed to describe the PD-1 inhibitor dosing used within VAMCs and identify actual and potential cost savings. Due to the frequency of immunemediated hypothyroidism and objective data that can be obtained from CDW reports, the study estimated the incidence of immune-mediated hypothyroidism within the veteran population as a safety outcome.

Background

The US Food and Drug Administration (FDA) initially approved dosing for IV nivolumab at 3 mg/kg of patient body weight every 2 weeks and for IV pembrolizumab 2 mg/kg of patient body weight every 3 weeks.^1,2 Subsequent pharmacokinetic studies found that these agents have similar exposure and efficacy with fixed doses of nivolumab 240 mg IV every 2 weeks and pembrolizumab 200 mg IV every 3 weeks; in 2016, FDA labeling shifted from weight-based dosing to fixed dosing for most solid tumor indications.^6-9 Depending on patient weight, a combination of weightbased and fixed dosing could be used by institutions to maximize cost-savings opportunities, minimize drug waste, and maintain clinical efficacy with PD-1 inhibitors. For example, a patient initiating nivolumab who weighs 80 kg would receive 240 mg for both weight-based (3 mg/kg x 80 kg = 240 mg) and fixed dosing; therefore, no cost-savings opportunities would be available. However, for a patient who weighs ≤ 73.3 kg, it would be more costeffective to use weight-based dosing vs the fixed dose. Since nivolumab is available in 40- mg, 100-mg, and 240-mg vials with similar unit prices, a combination of vial sizes could be used to minimize drug waste. Alternatively, for a patient who weighs ≥ 86.7 kg, it would be more cost-effective to administer the fixed, 240 mg dose when compared with the weightbased dose. Pembrolizumab is available only in a 100-mg vial; therefore, weight-based dosing may result in drug waste.

IrAEs can be seen with PD-1 inhibitors due to increased T cell activity, which is independent of dosing strategy and can affect any organ system. However, immune-mediated hypothyroidism has been commonly seen with PD-1 inhibitors. For patients with immunemediated hypothyroidism, levothyroxine can be considered for asymptomatic patients with thyroid- stimulating hormone (TSH) > 10 uIU/mL with normal thyroxine (T4), or patients with clinical primary hypothyroidism (TSH > 10 uIU/mL with low free T4 and clinical symptoms). Additionally, since hypothyroidism usually follows immunotherapy induced thyrotoxicosis, thyroid function tests should be monitored and levothyroxine initiated if TSH is > 10 uIU/mL for these patients.^10,11

Hypothyroidism also can be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events. Hypothyroidism is considered grade 1 when hypothyroidism is demonstrated through clinical or diagnostic observations only and the patient is asymptomatic and no intervention needed. Grade 2 occurs when the patient is symptomatic and limits instrumental activities of daily living (ADLs), prompting thyroid replacement therapy. In grade 3, patients experience severe symptoms that restrict self-care ADLs, and hospitalization is indicated. Grade 4 has life-threatening consequences, and urgent intervention is indicated. Grade 5 results in the death of the patient.¹²

Electronic health records (EHRs) of veterans who receive care at a VAMC are stored in CDW and available through the VA Informatics and Computing Infrastructure (VINCI), which provides access to data while ensuring veterans’ privacy and data security. This feature of the VA EHR allows for analysis of data across the VA health care system, and larger data sets can be used for retrospective chart reviews.

Using reports from CDW, the primary objective of this study was to describe the dosing strategy used for PD-1 inhibitors, and the primary safety outcome was to determine the incidence of immune-mediated hypothyroidism. The secondary objective was to estimate potential cost-savings opportunities using a combination of PD-1 inhibitor dosing strategies.

Methods

This was a retrospective study including data stored in CDW. The study was approved by the Durham VA Health Care System Institutional Review Board and VINCI/Data Access request tracker. Data were limited to nivolumab and pembrolizumab because they received earlier FDA approval, had multiple solid tumor indications, and 2 FDA-approved dosing strategies. The incidence of IrAEs was limited to hypothyroidism, which could be objectively verified with laboratory monitoring of thyroid function tests, including TSH, free or total T4, and triiodothyronine (T3), all of which were available in CDW data. Additionally, most patients with hypothyroidism initiate treatment with levothyroxine. Prescription refill history could also be retrieved using CDW reports.

Hypothyroidism was defined as T4 below lower limit of normal (LLN), TSH above upper limit of normal (ULN), or any increase in levothyroxine dosage. Patients were excluded if they received PD-1 inhibitor for an indication other than solid tumor treatment, such as hematologic malignancy, or if dosing did not follow weight-based or fixed-dosing strategies, such as nivolumab 1 mg/kg when used in combination with ipilimumab, or pembrolizumab 10 mg/kg. The primary endpoint was the percentage of orders for each dosing strategy, and the primary safety outcome was the incidence of immune-mediated hypothyroidism. Secondary endpoints included estimated cost savings and cost-savings opportunities through nivolumab dose rounding and incidence of levothyroxine initiation or dose change. Descriptive statistics were used for the primary and secondary endpoints.

A report in CDW identified patients who received a dose of nivolumab or pembrolizumab between January 1, 2015 and July 1, 2017 at any VAMC. The CDW report obtained weight at time of PD-1 inhibitor therapy initiation, dose of PD-1 inhibitor given, administration date of PD-1 inhibitor, and VA site. Depending on PD-1 inhibitor administered, weight in kg was multiplied by 3 mg/kg or 2 mg/kg to obtain patient’s anticipated weight-based nivolumab and pembrolizumab dose, respectively. The calculated weight-based dose, fixed dose, and administered dose were compared to infer dosing strategy used at the time of ordering. If the patient’s weight-based dose was within 10% of the fixed dose, the order was categorized as converging because the doses were too similar to determine which dosing strategy was intended.

After determination of dosing strategy, the nivolumab orders were evaluated for actual vs missed cost savings. The cost-savings evaluation included only nivolumab orders because nivolumab is available in a 40-mg, 100-mg, and 240-mg vials and, therefore, has more potential for dose-rounding opportunities with minimal drug waste compared with pembrolizumab, which is available only in a 100-mg vial. Actual cost savings included patients who weighed ≤ 73.3 kg and received nivolumab dose based on 3 mg/kg or patients who weighed ≥ 86.7 kg and received nivolumab 240 mg (fixed dose). Missed cost savings comprised patients who weighed ≤ 73.3 kg who received 240 mg nivolumab or patients who weighed ≥ 86.7 kg and received a nivolumab dose > 240 mg. The cost difference between the dose given and theoretical cost-effective dose was calculated to determine actual and potential cost savings. Converging orders were not included in the cost-savings analysis as the intended nivolumab dose could not be determined. An additional cost analysis of nivolumab orders prescribed between September 1, 2016 and July 1, 2017 was also performed because nivolumab fixed dosing was FDA-approved for most solid tumor indications in September 2016.

To determine the incidence of immunemediated hypothyroidism for patients who received a dose of a PD-1 inhibitor at a VAMC, a CDW report with thyroid function laboratory values (TSH, T4, or T3), including reference range values based on specific VA site, and levothyroxine prescriptions issued during PD-1 inhibitor therapy was obtained. A patient was considered to have experienced immune-mediated hypothyroidism if the patient’s laboratory values demonstrated T4 below the LLN, TSH above the ULN, or if the medication fill history demonstrated levothyroxine initiation or a levothyroxine dose increase.

Results 

The CDW report identified 32,769 total PD-1 inhibitor orders. There were 3982 orders that did not meet inclusion criteria or inadequate data were obtained with CDW report and were excluded (Figure). The remaining 28,787 PD-1 inhibitor orders were evaluated for actual or missed cost savings. The distribution of dosing strategies can be found in Table 1.

Nivolumab accounted for 81.5% of all PD-1 inhibitor orders. Using the most cost-effective nivolumab dosing, the actual cost savings was estimated to be $8,514,300 with potential additional $5,591,250 of missed cost-savings opportunities. There were 8013 nivolumab orders written between September 1, 2016 and July 1, 2017. Cost-effective dosing was used in 4687 of these orders, which accounted for a cost savings of $5,198,570. The remaining 3326 orders had a missed cost-savings opportunity, which accounted for an additional $2,907,180 potential cost savings (Table 2).

PD-1 inhibitors were used for the treatment of 3249 unique patients. Based on abnormal thyroid function tests and levothyroxine initiation or dose increase, it is estimated that 514 (15.8%) patients experienced hypothyroidism during PD-1 inhibitor therapy. However, prior to PD-1 inhibitor therapy, 274 patients were receiving levothyroxine, suggesting baseline thyroid dysfunction. Of these patients, 152 (55.5%) patients maintained the same levothyroxine dose during PD-1 inhibitor therapy, but 91 (33.2%) required a levothyroxine dose increase. There were 187 patients who initiated levothyroxine during PD-1 inhibitor therapy (Table 3).

Discussion

Changes in FDA-approved dosing for PD-1 inhibitors allowed a combination of dosing strategies. Depending on patient weight, a weight-based or fixed-dosing strategy can be used to reduce drug cost while maintaining equivalent efficacy. This study evaluated use of dose rounding for PD-1 inhibitors within the VA health care system to identify actual and potential cost savings. To our knowledge, this is the first study to demonstrate cost savings through use of a combination of PD-1 inhibitor dosing strategies. Using CDW, researchers were able to review PD-1 dosing from all VAMCs and include a larger number of orders in a single retrospective study.

Nivolumab was the primary agent used within VAMCs. Depending on the indication, pembrolizumab requires PD-1 expression testing prior to its use in several solid tumor indications. Consequently, additional testing and patient eligibility is needed prior to use. Both PD-1 inhibitors were primarily dosed based on patient weight since this was the first FDAapproved dosing strategy. Nivolumab had more orders categorized as converging, which may be due to the therapeutic weight-based dose of 3 mg/kg for nivolumab vs 2 mg/kg for pembrolizumab. The calculated weight-based dose of nivolumab for an 80-kg patient is 240 mg, which also is the fixed dose. A 80-kg patient on pembrolizumab at 2 mg/kg would receive a 160-mg dose, whereas the fixed dose of pembrolizumab is 200 mg. Pembrolizumab is available only in a 100-mg vial, which limits opportunities for dose rounding without drug waste and could explain the higher amount of pembrolizumab orders in the fixed-dose category.

In this review of PD-1 inhibitor orders over approximately a 2.5-year study period, we identified $8,514,300 estimated cost savings with $5,591,250 estimated missed cost savings. When looking at orders administered after FDA approval for nivolumab-fixed dosing in September 2016, there was substantial cost savings of $5,198,570 with the potential for an additional $2,907,180 missed cost savings. Due to lower drug acquisition costs within the VA health care system, there may be higher cost-savings opportunities within other health care systems.

Through review of abnormal thyroid laboratory values and levothyroxine initiation or dose changes, this study estimated the incidence of hypothyroidism in patients receiving PD-1 inhibitor therapy at the VA. The incidence of primary hypothyroidism identified in this study was slightly higher at 15.8% compared with the 8.5 to 9.0% incidence reported from clinical trials.^1,2 There are several reasons why the incidence of hypothyroidism appeared higher in this study. Abnormal laboratory values were not assessed for the degree of deviation from the reference range; any TSH above the ULN, T4 below the LLN, or levothyroxine dose increase was included as thyroid dysfunction in this review. There is also the potential for endogenous age-related thyroid fluctuation, and the development of hypothyroidism may not have been related to PD-1 inhibitor therapy. Within this patient population, 8.4% were receiving levothyroxine prior to PD-1 inhibitor initiation indicating baseline thyroid dysfunction, and it is unclear whether levothyroxine dose increases were due to PD-1 inhibitor or endogenous fluctuation.

Limitations

There are several limitations to acknowledge. The dosing strategy and apparent dose rounding was determined by investigator inference and may not accurately represent the intended dosing strategy. This study did not address efficacy of PD-1 inhibitor and dosing strategy; however, clinical trials have demonstrated equivalent efficacy to generate the change in FDA-approved dosing. Additionally, FDA approval for nivolumab fixed dosing was indication specific. Starting in September 2016, many solid tumor indications had fixed dosing approved, but this approval was not necessarily all encompassing.

While the use of CDW allowed for a greater number of PD-1 inhibitor orders to be included in retrospective review, there also were limitations of the CDW report. The patient weight was limited to weight at time of therapy initiation. Due to the potential for weight changes, nivolumab dosing may have seemed inappropriate to investigators, and thereby excluded. Based on data available from CDW reports, hypothyroidism could not be graded according to NCI Common Terminology Criteria for Adverse Events, and the incidence of clinically significant hypothyroidism could not be determined.

Conclusions

With increasing drug acquisition costs, particularly among antineoplastic agents, health care systems frequently seek out cost-savings opportunities. Using a combination of weightbased and fixed-dosing strategies for PD-1 inhibitors can be a mechanism to achieve costsavings. Through the identification of the dosing strategy used for PD-1 inhibitors, we were able to identify and report instances for potential cost-savings opportunities among veterans treated within VA health care system. Use of CDW allows for data from all VAMCs to be evaluated in a single retrospective chart review, which allows for the inclusion of a larger sample size. This study identified a substantial cost savings for nivolumab through a combination of weight-based and fixed-dosing strategies. Due to the novel mechanism of action, ongoing realworld evaluation of adverse events and IrAEs is warranted.

Dosing strategies with nivolumab and pembrolizumab continue to evolve. In March 2018, nivolumab 480 mg IV every 4 weeks was FDA approved and in April 2020, pembrolizumab 400 mg IV every 6 weeks was FDA approved.^13,14 While the drug costs will remain the same, extended interval dosing strategies have cost avoidance such as fewer clinic appointments, resulting in decreased staffing costs and decreased patient travel. Additional studies will be needed to evaluate the cost and safety of the recently approved dosing strategies

Due to the high cost of newer chemotherapy agents, institutions search for strategies to minimize drug cost and drug waste. Programmed death-1 (PD-1) inhibitors, nivolumab and pembrolizumab, are commonly used in the treatment of solid tumors; however, the agents cost thousands of dollars per dose. Nivolumab and pembrolizumab were initially approved using weight-based dosing, but package labeling for both agents now includes fixed dosing.^1,2 A combination of these 2 dosing strategies could be used by institutions depending on individual patient’s weight to maximize cost savings, minimize drug waste, and maintain safety and efficacy of PD-1 inhibitors. Irrespective of dosing strategy, the development of immune-related adverse events (IrAEs) has been demonstrated with PD-1 inhibitors as a result of the mechanism of action.

PD-1 expression suppresses T cell activity to prevent the development of autoimmunity; however, this is also a mechanism in which tumor cells can evade the host immune system.^3-5 Binding of PD-1 and programmed death-ligand 1 (PD-L1) suppresses T cell activity, whereas the inhibition of PD-1 and PD-L1 results in T cell activation.^4,5 Increased T cell activity elicits the anticancer effect, but also contributes to the development of IrAEs^.4,5 Hypothyroidism is one of the most common IrAEs, with a reported incidence of 9% with nivolumab therapy and 8.5% with pembrolizumab.^1,2

Data from the US Department of Veterans Affairs (VA) medical centers is stored in the centralized Corporate Data Warehouse (CDW). VA researchers can obtain approval to use CDW data, which allows for large scale retrospective review of veterans who have received care at VA medical centers (VAMCs). This study aimed to describe the PD-1 inhibitor dosing used within VAMCs and identify actual and potential cost savings. Due to the frequency of immunemediated hypothyroidism and objective data that can be obtained from CDW reports, the study estimated the incidence of immune-mediated hypothyroidism within the veteran population as a safety outcome.

Background

The US Food and Drug Administration (FDA) initially approved dosing for IV nivolumab at 3 mg/kg of patient body weight every 2 weeks and for IV pembrolizumab 2 mg/kg of patient body weight every 3 weeks.^1,2 Subsequent pharmacokinetic studies found that these agents have similar exposure and efficacy with fixed doses of nivolumab 240 mg IV every 2 weeks and pembrolizumab 200 mg IV every 3 weeks; in 2016, FDA labeling shifted from weight-based dosing to fixed dosing for most solid tumor indications.^6-9 Depending on patient weight, a combination of weightbased and fixed dosing could be used by institutions to maximize cost-savings opportunities, minimize drug waste, and maintain clinical efficacy with PD-1 inhibitors. For example, a patient initiating nivolumab who weighs 80 kg would receive 240 mg for both weight-based (3 mg/kg x 80 kg = 240 mg) and fixed dosing; therefore, no cost-savings opportunities would be available. However, for a patient who weighs ≤ 73.3 kg, it would be more costeffective to use weight-based dosing vs the fixed dose. Since nivolumab is available in 40- mg, 100-mg, and 240-mg vials with similar unit prices, a combination of vial sizes could be used to minimize drug waste. Alternatively, for a patient who weighs ≥ 86.7 kg, it would be more cost-effective to administer the fixed, 240 mg dose when compared with the weightbased dose. Pembrolizumab is available only in a 100-mg vial; therefore, weight-based dosing may result in drug waste.

IrAEs can be seen with PD-1 inhibitors due to increased T cell activity, which is independent of dosing strategy and can affect any organ system. However, immune-mediated hypothyroidism has been commonly seen with PD-1 inhibitors. For patients with immunemediated hypothyroidism, levothyroxine can be considered for asymptomatic patients with thyroid- stimulating hormone (TSH) > 10 uIU/mL with normal thyroxine (T4), or patients with clinical primary hypothyroidism (TSH > 10 uIU/mL with low free T4 and clinical symptoms). Additionally, since hypothyroidism usually follows immunotherapy induced thyrotoxicosis, thyroid function tests should be monitored and levothyroxine initiated if TSH is > 10 uIU/mL for these patients.^10,11

Hypothyroidism also can be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events. Hypothyroidism is considered grade 1 when hypothyroidism is demonstrated through clinical or diagnostic observations only and the patient is asymptomatic and no intervention needed. Grade 2 occurs when the patient is symptomatic and limits instrumental activities of daily living (ADLs), prompting thyroid replacement therapy. In grade 3, patients experience severe symptoms that restrict self-care ADLs, and hospitalization is indicated. Grade 4 has life-threatening consequences, and urgent intervention is indicated. Grade 5 results in the death of the patient.¹²

Electronic health records (EHRs) of veterans who receive care at a VAMC are stored in CDW and available through the VA Informatics and Computing Infrastructure (VINCI), which provides access to data while ensuring veterans’ privacy and data security. This feature of the VA EHR allows for analysis of data across the VA health care system, and larger data sets can be used for retrospective chart reviews.

Using reports from CDW, the primary objective of this study was to describe the dosing strategy used for PD-1 inhibitors, and the primary safety outcome was to determine the incidence of immune-mediated hypothyroidism. The secondary objective was to estimate potential cost-savings opportunities using a combination of PD-1 inhibitor dosing strategies.

Methods

This was a retrospective study including data stored in CDW. The study was approved by the Durham VA Health Care System Institutional Review Board and VINCI/Data Access request tracker. Data were limited to nivolumab and pembrolizumab because they received earlier FDA approval, had multiple solid tumor indications, and 2 FDA-approved dosing strategies. The incidence of IrAEs was limited to hypothyroidism, which could be objectively verified with laboratory monitoring of thyroid function tests, including TSH, free or total T4, and triiodothyronine (T3), all of which were available in CDW data. Additionally, most patients with hypothyroidism initiate treatment with levothyroxine. Prescription refill history could also be retrieved using CDW reports.

Hypothyroidism was defined as T4 below lower limit of normal (LLN), TSH above upper limit of normal (ULN), or any increase in levothyroxine dosage. Patients were excluded if they received PD-1 inhibitor for an indication other than solid tumor treatment, such as hematologic malignancy, or if dosing did not follow weight-based or fixed-dosing strategies, such as nivolumab 1 mg/kg when used in combination with ipilimumab, or pembrolizumab 10 mg/kg. The primary endpoint was the percentage of orders for each dosing strategy, and the primary safety outcome was the incidence of immune-mediated hypothyroidism. Secondary endpoints included estimated cost savings and cost-savings opportunities through nivolumab dose rounding and incidence of levothyroxine initiation or dose change. Descriptive statistics were used for the primary and secondary endpoints.

A report in CDW identified patients who received a dose of nivolumab or pembrolizumab between January 1, 2015 and July 1, 2017 at any VAMC. The CDW report obtained weight at time of PD-1 inhibitor therapy initiation, dose of PD-1 inhibitor given, administration date of PD-1 inhibitor, and VA site. Depending on PD-1 inhibitor administered, weight in kg was multiplied by 3 mg/kg or 2 mg/kg to obtain patient’s anticipated weight-based nivolumab and pembrolizumab dose, respectively. The calculated weight-based dose, fixed dose, and administered dose were compared to infer dosing strategy used at the time of ordering. If the patient’s weight-based dose was within 10% of the fixed dose, the order was categorized as converging because the doses were too similar to determine which dosing strategy was intended.

After determination of dosing strategy, the nivolumab orders were evaluated for actual vs missed cost savings. The cost-savings evaluation included only nivolumab orders because nivolumab is available in a 40-mg, 100-mg, and 240-mg vials and, therefore, has more potential for dose-rounding opportunities with minimal drug waste compared with pembrolizumab, which is available only in a 100-mg vial. Actual cost savings included patients who weighed ≤ 73.3 kg and received nivolumab dose based on 3 mg/kg or patients who weighed ≥ 86.7 kg and received nivolumab 240 mg (fixed dose). Missed cost savings comprised patients who weighed ≤ 73.3 kg who received 240 mg nivolumab or patients who weighed ≥ 86.7 kg and received a nivolumab dose > 240 mg. The cost difference between the dose given and theoretical cost-effective dose was calculated to determine actual and potential cost savings. Converging orders were not included in the cost-savings analysis as the intended nivolumab dose could not be determined. An additional cost analysis of nivolumab orders prescribed between September 1, 2016 and July 1, 2017 was also performed because nivolumab fixed dosing was FDA-approved for most solid tumor indications in September 2016.

To determine the incidence of immunemediated hypothyroidism for patients who received a dose of a PD-1 inhibitor at a VAMC, a CDW report with thyroid function laboratory values (TSH, T4, or T3), including reference range values based on specific VA site, and levothyroxine prescriptions issued during PD-1 inhibitor therapy was obtained. A patient was considered to have experienced immune-mediated hypothyroidism if the patient’s laboratory values demonstrated T4 below the LLN, TSH above the ULN, or if the medication fill history demonstrated levothyroxine initiation or a levothyroxine dose increase.

Results 

The CDW report identified 32,769 total PD-1 inhibitor orders. There were 3982 orders that did not meet inclusion criteria or inadequate data were obtained with CDW report and were excluded (Figure). The remaining 28,787 PD-1 inhibitor orders were evaluated for actual or missed cost savings. The distribution of dosing strategies can be found in Table 1.

Nivolumab accounted for 81.5% of all PD-1 inhibitor orders. Using the most cost-effective nivolumab dosing, the actual cost savings was estimated to be $8,514,300 with potential additional $5,591,250 of missed cost-savings opportunities. There were 8013 nivolumab orders written between September 1, 2016 and July 1, 2017. Cost-effective dosing was used in 4687 of these orders, which accounted for a cost savings of $5,198,570. The remaining 3326 orders had a missed cost-savings opportunity, which accounted for an additional $2,907,180 potential cost savings (Table 2).

PD-1 inhibitors were used for the treatment of 3249 unique patients. Based on abnormal thyroid function tests and levothyroxine initiation or dose increase, it is estimated that 514 (15.8%) patients experienced hypothyroidism during PD-1 inhibitor therapy. However, prior to PD-1 inhibitor therapy, 274 patients were receiving levothyroxine, suggesting baseline thyroid dysfunction. Of these patients, 152 (55.5%) patients maintained the same levothyroxine dose during PD-1 inhibitor therapy, but 91 (33.2%) required a levothyroxine dose increase. There were 187 patients who initiated levothyroxine during PD-1 inhibitor therapy (Table 3).

Discussion

Changes in FDA-approved dosing for PD-1 inhibitors allowed a combination of dosing strategies. Depending on patient weight, a weight-based or fixed-dosing strategy can be used to reduce drug cost while maintaining equivalent efficacy. This study evaluated use of dose rounding for PD-1 inhibitors within the VA health care system to identify actual and potential cost savings. To our knowledge, this is the first study to demonstrate cost savings through use of a combination of PD-1 inhibitor dosing strategies. Using CDW, researchers were able to review PD-1 dosing from all VAMCs and include a larger number of orders in a single retrospective study.

Nivolumab was the primary agent used within VAMCs. Depending on the indication, pembrolizumab requires PD-1 expression testing prior to its use in several solid tumor indications. Consequently, additional testing and patient eligibility is needed prior to use. Both PD-1 inhibitors were primarily dosed based on patient weight since this was the first FDAapproved dosing strategy. Nivolumab had more orders categorized as converging, which may be due to the therapeutic weight-based dose of 3 mg/kg for nivolumab vs 2 mg/kg for pembrolizumab. The calculated weight-based dose of nivolumab for an 80-kg patient is 240 mg, which also is the fixed dose. A 80-kg patient on pembrolizumab at 2 mg/kg would receive a 160-mg dose, whereas the fixed dose of pembrolizumab is 200 mg. Pembrolizumab is available only in a 100-mg vial, which limits opportunities for dose rounding without drug waste and could explain the higher amount of pembrolizumab orders in the fixed-dose category.

In this review of PD-1 inhibitor orders over approximately a 2.5-year study period, we identified $8,514,300 estimated cost savings with $5,591,250 estimated missed cost savings. When looking at orders administered after FDA approval for nivolumab-fixed dosing in September 2016, there was substantial cost savings of $5,198,570 with the potential for an additional $2,907,180 missed cost savings. Due to lower drug acquisition costs within the VA health care system, there may be higher cost-savings opportunities within other health care systems.

Through review of abnormal thyroid laboratory values and levothyroxine initiation or dose changes, this study estimated the incidence of hypothyroidism in patients receiving PD-1 inhibitor therapy at the VA. The incidence of primary hypothyroidism identified in this study was slightly higher at 15.8% compared with the 8.5 to 9.0% incidence reported from clinical trials.^1,2 There are several reasons why the incidence of hypothyroidism appeared higher in this study. Abnormal laboratory values were not assessed for the degree of deviation from the reference range; any TSH above the ULN, T4 below the LLN, or levothyroxine dose increase was included as thyroid dysfunction in this review. There is also the potential for endogenous age-related thyroid fluctuation, and the development of hypothyroidism may not have been related to PD-1 inhibitor therapy. Within this patient population, 8.4% were receiving levothyroxine prior to PD-1 inhibitor initiation indicating baseline thyroid dysfunction, and it is unclear whether levothyroxine dose increases were due to PD-1 inhibitor or endogenous fluctuation.

Limitations

There are several limitations to acknowledge. The dosing strategy and apparent dose rounding was determined by investigator inference and may not accurately represent the intended dosing strategy. This study did not address efficacy of PD-1 inhibitor and dosing strategy; however, clinical trials have demonstrated equivalent efficacy to generate the change in FDA-approved dosing. Additionally, FDA approval for nivolumab fixed dosing was indication specific. Starting in September 2016, many solid tumor indications had fixed dosing approved, but this approval was not necessarily all encompassing.

While the use of CDW allowed for a greater number of PD-1 inhibitor orders to be included in retrospective review, there also were limitations of the CDW report. The patient weight was limited to weight at time of therapy initiation. Due to the potential for weight changes, nivolumab dosing may have seemed inappropriate to investigators, and thereby excluded. Based on data available from CDW reports, hypothyroidism could not be graded according to NCI Common Terminology Criteria for Adverse Events, and the incidence of clinically significant hypothyroidism could not be determined.

Conclusions

With increasing drug acquisition costs, particularly among antineoplastic agents, health care systems frequently seek out cost-savings opportunities. Using a combination of weightbased and fixed-dosing strategies for PD-1 inhibitors can be a mechanism to achieve costsavings. Through the identification of the dosing strategy used for PD-1 inhibitors, we were able to identify and report instances for potential cost-savings opportunities among veterans treated within VA health care system. Use of CDW allows for data from all VAMCs to be evaluated in a single retrospective chart review, which allows for the inclusion of a larger sample size. This study identified a substantial cost savings for nivolumab through a combination of weight-based and fixed-dosing strategies. Due to the novel mechanism of action, ongoing realworld evaluation of adverse events and IrAEs is warranted.

Dosing strategies with nivolumab and pembrolizumab continue to evolve. In March 2018, nivolumab 480 mg IV every 4 weeks was FDA approved and in April 2020, pembrolizumab 400 mg IV every 6 weeks was FDA approved.^13,14 While the drug costs will remain the same, extended interval dosing strategies have cost avoidance such as fewer clinic appointments, resulting in decreased staffing costs and decreased patient travel. Additional studies will be needed to evaluate the cost and safety of the recently approved dosing strategies

Steeve Verdieu was at his workstation in his bedroom when the shaking started the morning of Aug. 14. He jumped under his desk and held on as a 7.2-magnitude earthquake tore through his childhood home in southern Haiti.

Mr. Verdieu, 25, said all he could think about was 2010, when a strong earthquake hit the country and left more than 200,000 people dead.

“Most of these adults that are in their mid-20s and 30s have vivid memories,” according to John Fitts, assistant director of Sent To Serve. He started working in the nonprofit sector in Haiti after the 2010 earthquake.

“I can’t even relate to it,” Mr. Fitts said. “If you didn’t live through it, you cannot relate.”

Mr. Verdieu emerged to find his family alive and his home in crumbles.

“In the neighborhood, we have only one child who died the day of the earthquake, but mentally, everybody feels bad,” he said. “Also, we are really frustrated right now because it tends to rain, and everybody is outside right now. So, we are a little bit afraid.”

Mr. Verdieu said that his community has not seen or heard of government authorities coming to offer guidance on next steps.

So, he started posting photos and videos to his Twitter account to seek help.
 

Surviving to heal

Many Haitians are forced to quickly turn the page after major crises, said Mr. Fitts.

“Survival overrides emotional shock,” he said. “They’re not going to have time. They’re not going to think emotional wellness at this point. It’s not addressed because they don’t have the opportunity to address it. So, it gets buried.”

More rural areas of Haiti were hit hardest by the recent earthquake, which killed over 2,000 people.

Many people were left without shelter and had limited access to food, clean drinking water, and medical help for those severely injured.

But current problems in Haiti, like shaky leadership after the recent assassination of the country’s president, left many people with no direction on what to do next.

With no information coming in, many, like Mr. Verdieu, took to social media or tried calling family and friends to find help on their own.

Having access to basic needs, like food and water, lessens the emotional trauma after these types of disasters, according to Betty Jean, a licensed professional counselor and global mental health and trauma consultant.

“When there is a crisis like an earthquake, the number one thing people need is a sense of safety and that there are entities that are concerned about their overall well-being,” said Ms. Jean, who is Haitian. “The emotional and mental support that we have to provide to people begins first with attending to those primary needs.”

But that’s not always possible in Haiti, mostly because of poor infrastructure, according to Caleb Lucien, founder of Hosean International Ministries.

“For example, the earthquake took place in the south of Haiti,” said Mr. Lucien, who is Haitian. “There has been some gang violence blocking passage from Port-au-Prince [the capital] to the south. Because of the gang fighting, it has been difficult to take the risk of traveling by road. So, airplanes from the capital city have been trying to get supplies there.”
 

More than resilient

Haitians are usually applauded for their inner strength to keep pushing amid crises. But it’s important to understand that there is often grief behind their resiliency, according to Ms. Jean.

“Sometimes I struggle with that word,” she said. “When I say resilient, I mean they will survive. But we are talking about a traumatized people. I definitely believe the people of Haiti are a people that have PTSD. The Haitian people have not yet fully healed from the first earthquake. I don’t think there was time. And many Haitians are suffering silently right now.”

The trauma shows itself in various ways, said Wilford Marous, entrepreneur and founder of the Haitian Chamber of Commerce in Great Britain.

“I went traveling in Europe with some colleagues of mine to attend some conferences, and one of them, who is Haitian, refused to sleep in a building because he believed it was too high,” he said. “He still had this fear of the earthquake.”

Children are often most affected, Mr. Fitts said.

“They don’t know what to do with it,” he said. “Their parents are not there necessarily to give them the emotional support that they need because they’re just trying to survive when things like this happen. So, a lot of things don’t get addressed and they’re taught early on to move on.”

Hosean International Ministries evacuated 1,500 people after the earthquake in 2010, and 750 of them were kids. The group stayed on the charity’s campground, and children had the chance to continue their education through its school system.

“Kids had issues sleeping,” Mr. Lucien said. “They are dealing with the loss of their loved ones. Some of them lost their moms. Some lost their brothers and sisters. So, we had to work with them and try to get them through that process.”

The charity offered children and their parents counseling sessions to lessen some of the emotional impact after the earthquake.
 

Common trauma responses

But keep in mind that symptoms like depression and sleeplessness would be common for most people going through mental health crises, such as major natural disasters or war, said Guglielmo Schininà, head of mental health and psychosocial support at the International Organization for Migration.

“It’s important not to jump to conclusions with diagnoses for mental illness or disorders,” Mr. Schininà said. “Suffering exists and suffering is not a mental disorder and shouldn’t be treated as such. In other situations, psychological effects like these could be symptoms of mental disorders. But in this situation, these are just normal reactions.”

Alongside trauma from natural disasters, many Haitians are angry about the chaos in the country, given the number of resources brought to Haiti over the past decade, according to Ms. Jean.

“We should have had better infrastructure, better roads, lights, emergency plans, trauma hospitals,” she said. “The resources were there.”

The constant lack of safety and security within the country can have ugly outcomes, she said.

“A lot of the political instability, rebels, gang activity, and war within those in politics has been because oppositions feel that those who are in power have not done a very good job of upgrading the Haitian lifestyle,” Ms. Jean said.

Unity and public togetherness are key in times like these, Mr. Marous said. He suggests finding creative ways to promote widespread healing.

“Even if it’s trying to start some sort of healing process through the media,” he said. “Having someone talk to the population, even on TV, 1 hour in the morning. That might be a way to offer some sort of help to the population at large.”
 

Strategic rebuilding

Haitians across the world are rallying together to keep spirits high, while also helping with recovery efforts, Ms. Jean said.

“We have to step in for the morale of the young people,” she said. “They’re tired. They’re hungry. They want to be cared for. So, our role in the diaspora is really critical in helping Haitians come out of this very traumatic time.”

Hosean International Ministries is organizing and sending supplies to parts of Haiti hardest hit by the earthquake. The ministry is also helping to rebuild some of the homes destroyed by the earthquake.

It’s important to keep in mind lessons learned from past recovery efforts, said Mr. Lucien.

“What we need to do is work with local leaders, asking them exactly what it is that they need,” he said. “The tendency is to rush and say what you’re going to bring. People brought things in 2010 that were not needed. Look for people on the ground, and work with them to provide the help.”

“My call to the international community is how can we come alongside of this resilient nation to alleviate some of the pressure,” Jean said. “But whether or not the help comes, I do believe the Haitian people, yet again, will rise day to day, until we restore and rebuild again.”

This is certainly true for Mr. Verdieu.

He has already launched an online campaign to rebuild his home.

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

Steeve Verdieu was at his workstation in his bedroom when the shaking started the morning of Aug. 14. He jumped under his desk and held on as a 7.2-magnitude earthquake tore through his childhood home in southern Haiti.

Mr. Verdieu, 25, said all he could think about was 2010, when a strong earthquake hit the country and left more than 200,000 people dead.

“Most of these adults that are in their mid-20s and 30s have vivid memories,” according to John Fitts, assistant director of Sent To Serve. He started working in the nonprofit sector in Haiti after the 2010 earthquake.

“I can’t even relate to it,” Mr. Fitts said. “If you didn’t live through it, you cannot relate.”

Mr. Verdieu emerged to find his family alive and his home in crumbles.

“In the neighborhood, we have only one child who died the day of the earthquake, but mentally, everybody feels bad,” he said. “Also, we are really frustrated right now because it tends to rain, and everybody is outside right now. So, we are a little bit afraid.”

Mr. Verdieu said that his community has not seen or heard of government authorities coming to offer guidance on next steps.

So, he started posting photos and videos to his Twitter account to seek help.
 

Surviving to heal

Many Haitians are forced to quickly turn the page after major crises, said Mr. Fitts.

“Survival overrides emotional shock,” he said. “They’re not going to have time. They’re not going to think emotional wellness at this point. It’s not addressed because they don’t have the opportunity to address it. So, it gets buried.”

More rural areas of Haiti were hit hardest by the recent earthquake, which killed over 2,000 people.

Many people were left without shelter and had limited access to food, clean drinking water, and medical help for those severely injured.

But current problems in Haiti, like shaky leadership after the recent assassination of the country’s president, left many people with no direction on what to do next.

With no information coming in, many, like Mr. Verdieu, took to social media or tried calling family and friends to find help on their own.

Having access to basic needs, like food and water, lessens the emotional trauma after these types of disasters, according to Betty Jean, a licensed professional counselor and global mental health and trauma consultant.

“When there is a crisis like an earthquake, the number one thing people need is a sense of safety and that there are entities that are concerned about their overall well-being,” said Ms. Jean, who is Haitian. “The emotional and mental support that we have to provide to people begins first with attending to those primary needs.”

But that’s not always possible in Haiti, mostly because of poor infrastructure, according to Caleb Lucien, founder of Hosean International Ministries.

“For example, the earthquake took place in the south of Haiti,” said Mr. Lucien, who is Haitian. “There has been some gang violence blocking passage from Port-au-Prince [the capital] to the south. Because of the gang fighting, it has been difficult to take the risk of traveling by road. So, airplanes from the capital city have been trying to get supplies there.”
 

More than resilient

Haitians are usually applauded for their inner strength to keep pushing amid crises. But it’s important to understand that there is often grief behind their resiliency, according to Ms. Jean.

“Sometimes I struggle with that word,” she said. “When I say resilient, I mean they will survive. But we are talking about a traumatized people. I definitely believe the people of Haiti are a people that have PTSD. The Haitian people have not yet fully healed from the first earthquake. I don’t think there was time. And many Haitians are suffering silently right now.”

The trauma shows itself in various ways, said Wilford Marous, entrepreneur and founder of the Haitian Chamber of Commerce in Great Britain.

“I went traveling in Europe with some colleagues of mine to attend some conferences, and one of them, who is Haitian, refused to sleep in a building because he believed it was too high,” he said. “He still had this fear of the earthquake.”

Children are often most affected, Mr. Fitts said.

“They don’t know what to do with it,” he said. “Their parents are not there necessarily to give them the emotional support that they need because they’re just trying to survive when things like this happen. So, a lot of things don’t get addressed and they’re taught early on to move on.”

Hosean International Ministries evacuated 1,500 people after the earthquake in 2010, and 750 of them were kids. The group stayed on the charity’s campground, and children had the chance to continue their education through its school system.

“Kids had issues sleeping,” Mr. Lucien said. “They are dealing with the loss of their loved ones. Some of them lost their moms. Some lost their brothers and sisters. So, we had to work with them and try to get them through that process.”

The charity offered children and their parents counseling sessions to lessen some of the emotional impact after the earthquake.
 

Common trauma responses

But keep in mind that symptoms like depression and sleeplessness would be common for most people going through mental health crises, such as major natural disasters or war, said Guglielmo Schininà, head of mental health and psychosocial support at the International Organization for Migration.

“It’s important not to jump to conclusions with diagnoses for mental illness or disorders,” Mr. Schininà said. “Suffering exists and suffering is not a mental disorder and shouldn’t be treated as such. In other situations, psychological effects like these could be symptoms of mental disorders. But in this situation, these are just normal reactions.”

Alongside trauma from natural disasters, many Haitians are angry about the chaos in the country, given the number of resources brought to Haiti over the past decade, according to Ms. Jean.

“We should have had better infrastructure, better roads, lights, emergency plans, trauma hospitals,” she said. “The resources were there.”

The constant lack of safety and security within the country can have ugly outcomes, she said.

“A lot of the political instability, rebels, gang activity, and war within those in politics has been because oppositions feel that those who are in power have not done a very good job of upgrading the Haitian lifestyle,” Ms. Jean said.

Unity and public togetherness are key in times like these, Mr. Marous said. He suggests finding creative ways to promote widespread healing.

“Even if it’s trying to start some sort of healing process through the media,” he said. “Having someone talk to the population, even on TV, 1 hour in the morning. That might be a way to offer some sort of help to the population at large.”
 

Strategic rebuilding

Haitians across the world are rallying together to keep spirits high, while also helping with recovery efforts, Ms. Jean said.

“We have to step in for the morale of the young people,” she said. “They’re tired. They’re hungry. They want to be cared for. So, our role in the diaspora is really critical in helping Haitians come out of this very traumatic time.”

Hosean International Ministries is organizing and sending supplies to parts of Haiti hardest hit by the earthquake. The ministry is also helping to rebuild some of the homes destroyed by the earthquake.

It’s important to keep in mind lessons learned from past recovery efforts, said Mr. Lucien.

“What we need to do is work with local leaders, asking them exactly what it is that they need,” he said. “The tendency is to rush and say what you’re going to bring. People brought things in 2010 that were not needed. Look for people on the ground, and work with them to provide the help.”

“My call to the international community is how can we come alongside of this resilient nation to alleviate some of the pressure,” Jean said. “But whether or not the help comes, I do believe the Haitian people, yet again, will rise day to day, until we restore and rebuild again.”

This is certainly true for Mr. Verdieu.

He has already launched an online campaign to rebuild his home.

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

Steeve Verdieu was at his workstation in his bedroom when the shaking started the morning of Aug. 14. He jumped under his desk and held on as a 7.2-magnitude earthquake tore through his childhood home in southern Haiti.

Mr. Verdieu, 25, said all he could think about was 2010, when a strong earthquake hit the country and left more than 200,000 people dead.

“Most of these adults that are in their mid-20s and 30s have vivid memories,” according to John Fitts, assistant director of Sent To Serve. He started working in the nonprofit sector in Haiti after the 2010 earthquake.

“I can’t even relate to it,” Mr. Fitts said. “If you didn’t live through it, you cannot relate.”

Mr. Verdieu emerged to find his family alive and his home in crumbles.

“In the neighborhood, we have only one child who died the day of the earthquake, but mentally, everybody feels bad,” he said. “Also, we are really frustrated right now because it tends to rain, and everybody is outside right now. So, we are a little bit afraid.”

Mr. Verdieu said that his community has not seen or heard of government authorities coming to offer guidance on next steps.

So, he started posting photos and videos to his Twitter account to seek help.
 

Surviving to heal

Many Haitians are forced to quickly turn the page after major crises, said Mr. Fitts.

“Survival overrides emotional shock,” he said. “They’re not going to have time. They’re not going to think emotional wellness at this point. It’s not addressed because they don’t have the opportunity to address it. So, it gets buried.”

More rural areas of Haiti were hit hardest by the recent earthquake, which killed over 2,000 people.

Many people were left without shelter and had limited access to food, clean drinking water, and medical help for those severely injured.

But current problems in Haiti, like shaky leadership after the recent assassination of the country’s president, left many people with no direction on what to do next.

With no information coming in, many, like Mr. Verdieu, took to social media or tried calling family and friends to find help on their own.

Having access to basic needs, like food and water, lessens the emotional trauma after these types of disasters, according to Betty Jean, a licensed professional counselor and global mental health and trauma consultant.

“When there is a crisis like an earthquake, the number one thing people need is a sense of safety and that there are entities that are concerned about their overall well-being,” said Ms. Jean, who is Haitian. “The emotional and mental support that we have to provide to people begins first with attending to those primary needs.”

But that’s not always possible in Haiti, mostly because of poor infrastructure, according to Caleb Lucien, founder of Hosean International Ministries.

“For example, the earthquake took place in the south of Haiti,” said Mr. Lucien, who is Haitian. “There has been some gang violence blocking passage from Port-au-Prince [the capital] to the south. Because of the gang fighting, it has been difficult to take the risk of traveling by road. So, airplanes from the capital city have been trying to get supplies there.”
 

More than resilient

Haitians are usually applauded for their inner strength to keep pushing amid crises. But it’s important to understand that there is often grief behind their resiliency, according to Ms. Jean.

“Sometimes I struggle with that word,” she said. “When I say resilient, I mean they will survive. But we are talking about a traumatized people. I definitely believe the people of Haiti are a people that have PTSD. The Haitian people have not yet fully healed from the first earthquake. I don’t think there was time. And many Haitians are suffering silently right now.”

The trauma shows itself in various ways, said Wilford Marous, entrepreneur and founder of the Haitian Chamber of Commerce in Great Britain.

“I went traveling in Europe with some colleagues of mine to attend some conferences, and one of them, who is Haitian, refused to sleep in a building because he believed it was too high,” he said. “He still had this fear of the earthquake.”

Children are often most affected, Mr. Fitts said.

“They don’t know what to do with it,” he said. “Their parents are not there necessarily to give them the emotional support that they need because they’re just trying to survive when things like this happen. So, a lot of things don’t get addressed and they’re taught early on to move on.”

Hosean International Ministries evacuated 1,500 people after the earthquake in 2010, and 750 of them were kids. The group stayed on the charity’s campground, and children had the chance to continue their education through its school system.

“Kids had issues sleeping,” Mr. Lucien said. “They are dealing with the loss of their loved ones. Some of them lost their moms. Some lost their brothers and sisters. So, we had to work with them and try to get them through that process.”

The charity offered children and their parents counseling sessions to lessen some of the emotional impact after the earthquake.
 

Common trauma responses

But keep in mind that symptoms like depression and sleeplessness would be common for most people going through mental health crises, such as major natural disasters or war, said Guglielmo Schininà, head of mental health and psychosocial support at the International Organization for Migration.

“It’s important not to jump to conclusions with diagnoses for mental illness or disorders,” Mr. Schininà said. “Suffering exists and suffering is not a mental disorder and shouldn’t be treated as such. In other situations, psychological effects like these could be symptoms of mental disorders. But in this situation, these are just normal reactions.”

Alongside trauma from natural disasters, many Haitians are angry about the chaos in the country, given the number of resources brought to Haiti over the past decade, according to Ms. Jean.

“We should have had better infrastructure, better roads, lights, emergency plans, trauma hospitals,” she said. “The resources were there.”

The constant lack of safety and security within the country can have ugly outcomes, she said.

“A lot of the political instability, rebels, gang activity, and war within those in politics has been because oppositions feel that those who are in power have not done a very good job of upgrading the Haitian lifestyle,” Ms. Jean said.

Unity and public togetherness are key in times like these, Mr. Marous said. He suggests finding creative ways to promote widespread healing.

“Even if it’s trying to start some sort of healing process through the media,” he said. “Having someone talk to the population, even on TV, 1 hour in the morning. That might be a way to offer some sort of help to the population at large.”
 

Strategic rebuilding

Haitians across the world are rallying together to keep spirits high, while also helping with recovery efforts, Ms. Jean said.

“We have to step in for the morale of the young people,” she said. “They’re tired. They’re hungry. They want to be cared for. So, our role in the diaspora is really critical in helping Haitians come out of this very traumatic time.”

Hosean International Ministries is organizing and sending supplies to parts of Haiti hardest hit by the earthquake. The ministry is also helping to rebuild some of the homes destroyed by the earthquake.

It’s important to keep in mind lessons learned from past recovery efforts, said Mr. Lucien.

“What we need to do is work with local leaders, asking them exactly what it is that they need,” he said. “The tendency is to rush and say what you’re going to bring. People brought things in 2010 that were not needed. Look for people on the ground, and work with them to provide the help.”

“My call to the international community is how can we come alongside of this resilient nation to alleviate some of the pressure,” Jean said. “But whether or not the help comes, I do believe the Haitian people, yet again, will rise day to day, until we restore and rebuild again.”

This is certainly true for Mr. Verdieu.

He has already launched an online campaign to rebuild his home.

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

The United States could get the COVID-19 pandemic under control by the spring of 2022 if enough Americans become vaccinated, Anthony S. Fauci, MD, said.

Speaking to Anderson Cooper on CNN, Dr. Fauci corrected the timeline he gave in an interview earlier with Mary Louise Kelly of NPR.

In the NPR interview, he had said that if “the overwhelming majority of the people vaccinated, I think as we get into the fall and the winter, we could start to really get some good control over this as we get into 2022.”

Dr. Fauci told Mr. Cooper that he listened to a recording of the NPR interview later and realized his mistake.

“I meant to say the spring of 2022,” Dr. Fauci told CNN. “I misspoke. My bad.”

Dr. Fauci, the head of the National Institute of Allergy and Infectious Diseases and the chief White House medical adviser, said the pandemic will be under control when the large majority of Americans have gotten vaccinated or been infected with COVID-19 and recovered, which offers some protection against the virus.

People who have been infected and recovered should still get vaccinated, he said.

“The degree of protection you could induce in someone who’s been infected and then recovered and then vaccinated is an enormous increase in the degree of protection,” Dr. Fauci said.

“I think we can get a degree of overall blanket protection of the community that as we get into the early part of 2022 ... we could start getting back to a degree of normality.”

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

The United States could get the COVID-19 pandemic under control by the spring of 2022 if enough Americans become vaccinated, Anthony S. Fauci, MD, said.

Speaking to Anderson Cooper on CNN, Dr. Fauci corrected the timeline he gave in an interview earlier with Mary Louise Kelly of NPR.

In the NPR interview, he had said that if “the overwhelming majority of the people vaccinated, I think as we get into the fall and the winter, we could start to really get some good control over this as we get into 2022.”

Dr. Fauci told Mr. Cooper that he listened to a recording of the NPR interview later and realized his mistake.

“I meant to say the spring of 2022,” Dr. Fauci told CNN. “I misspoke. My bad.”

Dr. Fauci, the head of the National Institute of Allergy and Infectious Diseases and the chief White House medical adviser, said the pandemic will be under control when the large majority of Americans have gotten vaccinated or been infected with COVID-19 and recovered, which offers some protection against the virus.

People who have been infected and recovered should still get vaccinated, he said.

“The degree of protection you could induce in someone who’s been infected and then recovered and then vaccinated is an enormous increase in the degree of protection,” Dr. Fauci said.

“I think we can get a degree of overall blanket protection of the community that as we get into the early part of 2022 ... we could start getting back to a degree of normality.”

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

The United States could get the COVID-19 pandemic under control by the spring of 2022 if enough Americans become vaccinated, Anthony S. Fauci, MD, said.

Speaking to Anderson Cooper on CNN, Dr. Fauci corrected the timeline he gave in an interview earlier with Mary Louise Kelly of NPR.

In the NPR interview, he had said that if “the overwhelming majority of the people vaccinated, I think as we get into the fall and the winter, we could start to really get some good control over this as we get into 2022.”

Dr. Fauci told Mr. Cooper that he listened to a recording of the NPR interview later and realized his mistake.

“I meant to say the spring of 2022,” Dr. Fauci told CNN. “I misspoke. My bad.”

Dr. Fauci, the head of the National Institute of Allergy and Infectious Diseases and the chief White House medical adviser, said the pandemic will be under control when the large majority of Americans have gotten vaccinated or been infected with COVID-19 and recovered, which offers some protection against the virus.

People who have been infected and recovered should still get vaccinated, he said.

“The degree of protection you could induce in someone who’s been infected and then recovered and then vaccinated is an enormous increase in the degree of protection,” Dr. Fauci said.

“I think we can get a degree of overall blanket protection of the community that as we get into the early part of 2022 ... we could start getting back to a degree of normality.”

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

The novel calcitonin gene-related peptide (CGRP) antagonist atogepant is safe and effective for the preventive treatment of migraine, full results from a phase 3 trial suggest.

AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.

The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.

The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.

All doses effective

The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.

After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.

The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).

Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).

In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).

The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
 

Multidose flexibility

“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.

The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.

“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.

Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”

An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.

“You can easily identify patients who would do well on this medication,” she added.

In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
 

“Well-conducted study”

Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.

The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.

The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.

It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”

In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”

Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.

The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.

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

The novel calcitonin gene-related peptide (CGRP) antagonist atogepant is safe and effective for the preventive treatment of migraine, full results from a phase 3 trial suggest.

AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.

The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.

The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.

All doses effective

The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.

After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.

The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).

Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).

In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).

The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
 

Multidose flexibility

“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.

The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.

“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.

Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”

An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.

“You can easily identify patients who would do well on this medication,” she added.

In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
 

“Well-conducted study”

Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.

The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.

The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.

It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”

In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”

Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.

The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.

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

The novel calcitonin gene-related peptide (CGRP) antagonist atogepant is safe and effective for the preventive treatment of migraine, full results from a phase 3 trial suggest.

AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.

The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.

The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.

All doses effective

The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.

After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.

The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).

Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).

In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).

The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
 

Multidose flexibility

“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.

The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.

“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.

Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”

An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.

“You can easily identify patients who would do well on this medication,” she added.

In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
 

“Well-conducted study”

Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.

The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.

The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.

It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”

In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”

Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.

The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.

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

Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.

The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.

In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.

The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
 

Median time to flare: 219 days

Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).

In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.

Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.

Systemic JIA recapture rate at 6 months: 76%

At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.

About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.

The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.

Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.

“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”

JIA recurrence risk is unclear

In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.

“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.

“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.

Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.

For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.

“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.

Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.

Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.

The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.

In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.

The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
 

Median time to flare: 219 days

Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).

In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.

Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.

Systemic JIA recapture rate at 6 months: 76%

At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.

About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.

The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.

Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.

“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”

JIA recurrence risk is unclear

In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.

“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.

“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.

Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.

For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.

“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.

Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.

Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.

The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.

In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.

The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
 

Median time to flare: 219 days

Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).

In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.

Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.

Systemic JIA recapture rate at 6 months: 76%

At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.

About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.

The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.

Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.

“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”

JIA recurrence risk is unclear

In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.

“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.

“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.

Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.

For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.

“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.

Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.

The benefits of low-dose colchicine (Colcrys) are consistent if started months or years after acute coronary syndrome (ACS) in patients with stable coronary artery disease, a new LoDoCo2 subanalysis suggests.

As previously reported, the parent trial showed that adding colchicine 0.5 mg daily to standard care reduced the risk of the primary endpoint – a composite of cardiovascular (CV) death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization – by 31% compared with placebo.

In the new analysis, led by Tjerk S.J. Opstal, MD, the anti-inflammatory agent was equally effective in reducing the risk of the primary endpoint in patients with no prior ACS, a recent ACS (6-24 months), remote ACS (2-7 years), or very remote ACS (> 7 years), with no interaction found between groups (P = .59).

The incidence of the primary endpoint per 100 person-years and hazard ratios (HRs) for the four groups with colchicine and placebo are as follows:

• No prior ACS: 2.8 vs. 3.4; HR, 0.81 (95% confidence interval, 0.52-1.27).
• Recent ACS: 2.4 vs. 3.3; HR, 0.75 (95% CI, 0.51-1.10).
• Remote ACS: 1.8 vs. 3.2; HR, 0.55 (95% CI, 0.37-0.82)
• Very remote ACS: 3.0 vs. 4.3; HR, 0.70 (95% CI, 0.51-0.96).

The results were reported Aug. 23 in the Journal of the American College of Cardiology.

In contrast, however, a recent subgroup analysis from the COLCOT trial reported an even greater reduction in its primary composite CV endpoint when colchicine was started within 3 days of an MI.

“The result of COLCOT could imply that initiation of colchicine treatment would be best suited directly after myocardial infarction,” Dr. Opstal, from Radboud University Medical Center, Nijmegen, the Netherlands, said in an interview. “Our subanalysis shows that later initiation of colchicine therapy in patients visiting outpatient clinics years after their ACS events is equally effective. As such, colchicine therapy should not be limited to patients with recent ACS, and should be considered in all patients with coronary artery disease.”

Dr. Opstal pointed out that the two trials targeted different populations. COLCOT enrolled 4,765 patients within a month of MI, whereas LoDoCo2 enrolled 5,522 patients who were clinically stable for at least 6 months after an ACS or coronary revascularization.

Overall, 864 LoDoCo2 patients had no prior ACS and 86% had a history of ACS, of which 1,479 were recent, 1,582 were remote, and 1,597 were very remote.

Patients with a history of very remote ACS had a numerically higher event rate for the primary outcome, but the difference was not statistically significant and could be attributed to a play of chance, noted Dr. Opstal.

The team presumed patients with more recent prior ACS would remain at higher risk of ACS recurrence than would those with a more remote ACS that had proved to be clinically stable under standard medical therapy. But, he said, the data show they were at equal risk of the primary outcome.

“This implies that current optimal medical therapy does not result in an attenuation of residual risk over time regardless of whether patients are clinically stable, and that the ongoing process of atherosclerosis results in continuously elevated risk, which warrants new avenues of therapy, such as anti-inflammatory medication,” Dr. Opstal said.

In a binary analysis, there was no difference in composite cardiovascular events between patients with and without prior ACS (HR, 0.67 vs. HR, 0.81; P value for interaction, 0.43).

Dr. Opstal observed that a lack of statistical power precludes any definitive conclusions and that a large randomized controlled trial in patients with established coronary artery disease (CAD) but no prior ACS would elucidate whether early initiation of colchicine is “warranted at the moment CAD is established but before a first ACS event, as is common practice with acetylsalicylic acid and statins.”

In addition, the ongoing OASIS 9 trial will answer the question of whether patients with an estimated glomerular filtration rate of 30-60 mL/min can safely use low-dose colchicine. The gout medication is contraindicated in patients with severe renal or hepatic impairment and in patients on drugs that inhibit both CYP3A4 or the P-glycoprotein.

In an accompanying editorial, colchicine researchers Jean-Claude Tardif, MD, and Guillaume Marquis-Gravel, MD, of the Montreal Heart Institute, Quebec, Canada, suggest that study design features likely explain the discord between the LoDoCo2 and COLCOT subgroup analyses and the lack of difference in CV event rates between patients with and without prior ACS.

The editorialists say lingering questions remain, including the value of colchicine in patients with diabetes or peripheral artery disease without known CAD, but they also point out that three 2021 meta-analyses confirmed large reductions in the risk of CV events, MI, and coronary revascularization with low-dose colchicine.

“In light of the positive results from LoDoCo2, COLCOT, and meta-analyses; its good tolerability profile; and cost-effectiveness, inflammation reduction with low-dose colchicine should be considered to treat patients with coronary disease in the absence of severe renal dysfunction,” Dr. Tardif and Dr. Marquis-Gravel concluded.

The study was supported by the National Health Medical Research Council of Australia; a grant from the Sir Charles Gairdner Research Advisory Committee; the Withering Foundation; the Netherlands Heart Foundation; the Netherlands Organization for Health Research and Development; and a consortium of Teva, Disphar, and Tiofarma in the Netherlands. The funders had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript. Dr. Opstal reports no relevant financial relationships. Coauthor disclosures are listed in the original article.

Dr. Tardif has received grant support from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio, and Sanofi; has received honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Therapeutics, Pendopharm, and Sanofi; has minor equity interest in DalCor Pharmaceuticals; and is mentioned as an author on submitted patents on pharmacogenomics-guided CETP inhibition, use of colchicine after myocardial infarction, and use of colchicine in COVID-19 (he has waived his rights in the colchicine patents and does not stand to gain financially). Dr. Marquis-Gravel has received research grants from Bayer, has received speaker honoraria from Novartis, and has served on national advisory boards for Servier, JAMP, and Bayer.
 

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

The benefits of low-dose colchicine (Colcrys) are consistent if started months or years after acute coronary syndrome (ACS) in patients with stable coronary artery disease, a new LoDoCo2 subanalysis suggests.

As previously reported, the parent trial showed that adding colchicine 0.5 mg daily to standard care reduced the risk of the primary endpoint – a composite of cardiovascular (CV) death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization – by 31% compared with placebo.

In the new analysis, led by Tjerk S.J. Opstal, MD, the anti-inflammatory agent was equally effective in reducing the risk of the primary endpoint in patients with no prior ACS, a recent ACS (6-24 months), remote ACS (2-7 years), or very remote ACS (> 7 years), with no interaction found between groups (P = .59).

The incidence of the primary endpoint per 100 person-years and hazard ratios (HRs) for the four groups with colchicine and placebo are as follows:

• No prior ACS: 2.8 vs. 3.4; HR, 0.81 (95% confidence interval, 0.52-1.27).
• Recent ACS: 2.4 vs. 3.3; HR, 0.75 (95% CI, 0.51-1.10).
• Remote ACS: 1.8 vs. 3.2; HR, 0.55 (95% CI, 0.37-0.82)
• Very remote ACS: 3.0 vs. 4.3; HR, 0.70 (95% CI, 0.51-0.96).

The results were reported Aug. 23 in the Journal of the American College of Cardiology.

In contrast, however, a recent subgroup analysis from the COLCOT trial reported an even greater reduction in its primary composite CV endpoint when colchicine was started within 3 days of an MI.

“The result of COLCOT could imply that initiation of colchicine treatment would be best suited directly after myocardial infarction,” Dr. Opstal, from Radboud University Medical Center, Nijmegen, the Netherlands, said in an interview. “Our subanalysis shows that later initiation of colchicine therapy in patients visiting outpatient clinics years after their ACS events is equally effective. As such, colchicine therapy should not be limited to patients with recent ACS, and should be considered in all patients with coronary artery disease.”

Dr. Opstal pointed out that the two trials targeted different populations. COLCOT enrolled 4,765 patients within a month of MI, whereas LoDoCo2 enrolled 5,522 patients who were clinically stable for at least 6 months after an ACS or coronary revascularization.

Overall, 864 LoDoCo2 patients had no prior ACS and 86% had a history of ACS, of which 1,479 were recent, 1,582 were remote, and 1,597 were very remote.

Patients with a history of very remote ACS had a numerically higher event rate for the primary outcome, but the difference was not statistically significant and could be attributed to a play of chance, noted Dr. Opstal.

The team presumed patients with more recent prior ACS would remain at higher risk of ACS recurrence than would those with a more remote ACS that had proved to be clinically stable under standard medical therapy. But, he said, the data show they were at equal risk of the primary outcome.

“This implies that current optimal medical therapy does not result in an attenuation of residual risk over time regardless of whether patients are clinically stable, and that the ongoing process of atherosclerosis results in continuously elevated risk, which warrants new avenues of therapy, such as anti-inflammatory medication,” Dr. Opstal said.

In a binary analysis, there was no difference in composite cardiovascular events between patients with and without prior ACS (HR, 0.67 vs. HR, 0.81; P value for interaction, 0.43).

Dr. Opstal observed that a lack of statistical power precludes any definitive conclusions and that a large randomized controlled trial in patients with established coronary artery disease (CAD) but no prior ACS would elucidate whether early initiation of colchicine is “warranted at the moment CAD is established but before a first ACS event, as is common practice with acetylsalicylic acid and statins.”

In addition, the ongoing OASIS 9 trial will answer the question of whether patients with an estimated glomerular filtration rate of 30-60 mL/min can safely use low-dose colchicine. The gout medication is contraindicated in patients with severe renal or hepatic impairment and in patients on drugs that inhibit both CYP3A4 or the P-glycoprotein.

In an accompanying editorial, colchicine researchers Jean-Claude Tardif, MD, and Guillaume Marquis-Gravel, MD, of the Montreal Heart Institute, Quebec, Canada, suggest that study design features likely explain the discord between the LoDoCo2 and COLCOT subgroup analyses and the lack of difference in CV event rates between patients with and without prior ACS.

The editorialists say lingering questions remain, including the value of colchicine in patients with diabetes or peripheral artery disease without known CAD, but they also point out that three 2021 meta-analyses confirmed large reductions in the risk of CV events, MI, and coronary revascularization with low-dose colchicine.

“In light of the positive results from LoDoCo2, COLCOT, and meta-analyses; its good tolerability profile; and cost-effectiveness, inflammation reduction with low-dose colchicine should be considered to treat patients with coronary disease in the absence of severe renal dysfunction,” Dr. Tardif and Dr. Marquis-Gravel concluded.

The study was supported by the National Health Medical Research Council of Australia; a grant from the Sir Charles Gairdner Research Advisory Committee; the Withering Foundation; the Netherlands Heart Foundation; the Netherlands Organization for Health Research and Development; and a consortium of Teva, Disphar, and Tiofarma in the Netherlands. The funders had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript. Dr. Opstal reports no relevant financial relationships. Coauthor disclosures are listed in the original article.

Dr. Tardif has received grant support from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio, and Sanofi; has received honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Therapeutics, Pendopharm, and Sanofi; has minor equity interest in DalCor Pharmaceuticals; and is mentioned as an author on submitted patents on pharmacogenomics-guided CETP inhibition, use of colchicine after myocardial infarction, and use of colchicine in COVID-19 (he has waived his rights in the colchicine patents and does not stand to gain financially). Dr. Marquis-Gravel has received research grants from Bayer, has received speaker honoraria from Novartis, and has served on national advisory boards for Servier, JAMP, and Bayer.
 

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

The benefits of low-dose colchicine (Colcrys) are consistent if started months or years after acute coronary syndrome (ACS) in patients with stable coronary artery disease, a new LoDoCo2 subanalysis suggests.

As previously reported, the parent trial showed that adding colchicine 0.5 mg daily to standard care reduced the risk of the primary endpoint – a composite of cardiovascular (CV) death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization – by 31% compared with placebo.

In the new analysis, led by Tjerk S.J. Opstal, MD, the anti-inflammatory agent was equally effective in reducing the risk of the primary endpoint in patients with no prior ACS, a recent ACS (6-24 months), remote ACS (2-7 years), or very remote ACS (> 7 years), with no interaction found between groups (P = .59).

The incidence of the primary endpoint per 100 person-years and hazard ratios (HRs) for the four groups with colchicine and placebo are as follows:

• No prior ACS: 2.8 vs. 3.4; HR, 0.81 (95% confidence interval, 0.52-1.27).
• Recent ACS: 2.4 vs. 3.3; HR, 0.75 (95% CI, 0.51-1.10).
• Remote ACS: 1.8 vs. 3.2; HR, 0.55 (95% CI, 0.37-0.82)
• Very remote ACS: 3.0 vs. 4.3; HR, 0.70 (95% CI, 0.51-0.96).

The results were reported Aug. 23 in the Journal of the American College of Cardiology.

In contrast, however, a recent subgroup analysis from the COLCOT trial reported an even greater reduction in its primary composite CV endpoint when colchicine was started within 3 days of an MI.

“The result of COLCOT could imply that initiation of colchicine treatment would be best suited directly after myocardial infarction,” Dr. Opstal, from Radboud University Medical Center, Nijmegen, the Netherlands, said in an interview. “Our subanalysis shows that later initiation of colchicine therapy in patients visiting outpatient clinics years after their ACS events is equally effective. As such, colchicine therapy should not be limited to patients with recent ACS, and should be considered in all patients with coronary artery disease.”

Dr. Opstal pointed out that the two trials targeted different populations. COLCOT enrolled 4,765 patients within a month of MI, whereas LoDoCo2 enrolled 5,522 patients who were clinically stable for at least 6 months after an ACS or coronary revascularization.

Overall, 864 LoDoCo2 patients had no prior ACS and 86% had a history of ACS, of which 1,479 were recent, 1,582 were remote, and 1,597 were very remote.

Patients with a history of very remote ACS had a numerically higher event rate for the primary outcome, but the difference was not statistically significant and could be attributed to a play of chance, noted Dr. Opstal.

The team presumed patients with more recent prior ACS would remain at higher risk of ACS recurrence than would those with a more remote ACS that had proved to be clinically stable under standard medical therapy. But, he said, the data show they were at equal risk of the primary outcome.

“This implies that current optimal medical therapy does not result in an attenuation of residual risk over time regardless of whether patients are clinically stable, and that the ongoing process of atherosclerosis results in continuously elevated risk, which warrants new avenues of therapy, such as anti-inflammatory medication,” Dr. Opstal said.

In a binary analysis, there was no difference in composite cardiovascular events between patients with and without prior ACS (HR, 0.67 vs. HR, 0.81; P value for interaction, 0.43).

Dr. Opstal observed that a lack of statistical power precludes any definitive conclusions and that a large randomized controlled trial in patients with established coronary artery disease (CAD) but no prior ACS would elucidate whether early initiation of colchicine is “warranted at the moment CAD is established but before a first ACS event, as is common practice with acetylsalicylic acid and statins.”

In addition, the ongoing OASIS 9 trial will answer the question of whether patients with an estimated glomerular filtration rate of 30-60 mL/min can safely use low-dose colchicine. The gout medication is contraindicated in patients with severe renal or hepatic impairment and in patients on drugs that inhibit both CYP3A4 or the P-glycoprotein.

In an accompanying editorial, colchicine researchers Jean-Claude Tardif, MD, and Guillaume Marquis-Gravel, MD, of the Montreal Heart Institute, Quebec, Canada, suggest that study design features likely explain the discord between the LoDoCo2 and COLCOT subgroup analyses and the lack of difference in CV event rates between patients with and without prior ACS.

The editorialists say lingering questions remain, including the value of colchicine in patients with diabetes or peripheral artery disease without known CAD, but they also point out that three 2021 meta-analyses confirmed large reductions in the risk of CV events, MI, and coronary revascularization with low-dose colchicine.

“In light of the positive results from LoDoCo2, COLCOT, and meta-analyses; its good tolerability profile; and cost-effectiveness, inflammation reduction with low-dose colchicine should be considered to treat patients with coronary disease in the absence of severe renal dysfunction,” Dr. Tardif and Dr. Marquis-Gravel concluded.

The study was supported by the National Health Medical Research Council of Australia; a grant from the Sir Charles Gairdner Research Advisory Committee; the Withering Foundation; the Netherlands Heart Foundation; the Netherlands Organization for Health Research and Development; and a consortium of Teva, Disphar, and Tiofarma in the Netherlands. The funders had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript. Dr. Opstal reports no relevant financial relationships. Coauthor disclosures are listed in the original article.

Dr. Tardif has received grant support from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio, and Sanofi; has received honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Therapeutics, Pendopharm, and Sanofi; has minor equity interest in DalCor Pharmaceuticals; and is mentioned as an author on submitted patents on pharmacogenomics-guided CETP inhibition, use of colchicine after myocardial infarction, and use of colchicine in COVID-19 (he has waived his rights in the colchicine patents and does not stand to gain financially). Dr. Marquis-Gravel has received research grants from Bayer, has received speaker honoraria from Novartis, and has served on national advisory boards for Servier, JAMP, and Bayer.
 

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

Background: Up to 30 million people in the United States meet criteria for alcohol use disorder. Gabapentin addresses symptoms of protracted withdrawal such as insomnia, irritability, difficulty with attention, dysphoria, and anxiety. It does that by acting on voltage-gated calcium channels and, in turn, influencing GABA and glutamate tone and activity.

A couple of study limitations were a significant noncompletion rate (30% in gabapentin arm and 39% in the placebo arm) and self-reported alcohol withdrawal symptoms prior to entry into the study.

Bottom line: Gabapentin helps in reducing drinking and maintaining alcohol abstinence in individuals with alcohol use disorder, especially those with high–alcohol withdrawal symptoms.

Citation: Anton RF et al. Efficacy of gabapentin for the treatment of alcohol use disorder in patients with alcohol withdrawal symptoms: A randomized clinical trial. JAMA Intern Med. 2020 Mar 9;180(5):728-36.

Dr. Gaddam is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: Up to 30 million people in the United States meet criteria for alcohol use disorder. Gabapentin addresses symptoms of protracted withdrawal such as insomnia, irritability, difficulty with attention, dysphoria, and anxiety. It does that by acting on voltage-gated calcium channels and, in turn, influencing GABA and glutamate tone and activity.

A couple of study limitations were a significant noncompletion rate (30% in gabapentin arm and 39% in the placebo arm) and self-reported alcohol withdrawal symptoms prior to entry into the study.

Bottom line: Gabapentin helps in reducing drinking and maintaining alcohol abstinence in individuals with alcohol use disorder, especially those with high–alcohol withdrawal symptoms.

Citation: Anton RF et al. Efficacy of gabapentin for the treatment of alcohol use disorder in patients with alcohol withdrawal symptoms: A randomized clinical trial. JAMA Intern Med. 2020 Mar 9;180(5):728-36.

Dr. Gaddam is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: Up to 30 million people in the United States meet criteria for alcohol use disorder. Gabapentin addresses symptoms of protracted withdrawal such as insomnia, irritability, difficulty with attention, dysphoria, and anxiety. It does that by acting on voltage-gated calcium channels and, in turn, influencing GABA and glutamate tone and activity.

A couple of study limitations were a significant noncompletion rate (30% in gabapentin arm and 39% in the placebo arm) and self-reported alcohol withdrawal symptoms prior to entry into the study.

Bottom line: Gabapentin helps in reducing drinking and maintaining alcohol abstinence in individuals with alcohol use disorder, especially those with high–alcohol withdrawal symptoms.

Citation: Anton RF et al. Efficacy of gabapentin for the treatment of alcohol use disorder in patients with alcohol withdrawal symptoms: A randomized clinical trial. JAMA Intern Med. 2020 Mar 9;180(5):728-36.

Dr. Gaddam is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

New consensus recommendations address diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with advice that may also be helpful for patients with lingering symptoms following acute COVID-19 infection.

VioletaStoimenova/Getty Images

The document was published online Aug. 25, 2021, in the Mayo Clinic Proceedings by the 23-member U.S. ME/CFS Clinician Coalition, headed by Lucinda Bateman, MD, of the Bateman Horne Center of Excellence, Salt Lake City. The document is the culmination of work that began with a summit held at the center in March 2018.

The target audience is both generalist and specialist health care providers. While ME/CFS is estimated to affect up to 2.5 million Americans, more than 90% are either undiagnosed or misdiagnosed with other conditions such as depression. And those who are diagnosed often receive inappropriate, outdated treatments such as psychotherapy and exercise prescriptions.

“Despite myalgic encephalomyelitis/chronic fatigue syndrome affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful,” Dr. Bateman and colleagues wrote.

The urgency of appropriate recognition and management of ME/CFS has increased as growing numbers of people are exhibiting signs and symptoms of ME/CFS following acute COVID-19 infection. This isn’t surprising because the illness has long been linked to other infections, including Epstein-Barr virus, the authors noted.

The document covers the epidemiology, impact, and prognosis of ME/CFS, as well as etiology and pathophysiology. “Scientific studies demonstrate multiple dysfunctional organ systems, including neuro, immune, and metabolic, in ME/CFS. These findings are not explained merely by deconditioning,” document coauthor Lily Chu, MD, an independent consultant in Burlingame, Calif., said in an interview.

The document reviews the 2015 U.S. Institute of Medicine (now Academy of Medicine) diagnostic criteria that are now also recommended by the Centers for Disease Control and Prevention. They are based on four main symptoms: substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social or personal activities for longer than 6 months; postexertional malaise, a worsening of all current symptoms, that patients often describe as a “crash”; unrefreshing sleep; and cognitive impairment and/or orthostatic intolerance.

“The new diagnostic criteria focusing on the key symptom of postexertional malaise rather than chronic fatigue, which is common in many conditions, may make the diagnostic process quicker and more accurate. Diagnosis now is both an inclusionary and not just exclusionary process, so it’s not necessary to eliminate all causes of fatigue. Diagnose patients who fit the criteria and be alert for it in people with persistent symptoms post COVID,” Dr. Chu said.

The document provides advice for taking a clinical history to obtain the information necessary for making the diagnosis, including use of laboratory testing to rule out other conditions. Physical exams, while they may not reveal specific abnormalities, may help in identifying comorbidities and ruling out alternative diagnoses.

A long list of nonpharmacologic and pharmacologic treatment and management approaches is offered for each of the individual core and common ME/CFS symptoms, including postexertional malaise, orthostatic intolerance, sleep issues, cognitive dysfunction and fatigue, immune dysfunction, pain, and gastrointestinal issues.

The document recommends against using the “outdated standard of care” cognitive-behavioral therapy and graded exercise therapy as primary treatments for the illness. Instead, the authors recommend teaching patients “pacing,” an individualized approach to energy conservation aimed at minimizing the frequency, duration, and severity of postexertional malaise.

Clinicians are also advised to assess patients’ daily living needs and provide support, including acquiring handicap placards, work or school accommodations, and disability benefits.

“There are things clinicians can do now to help patients even without a disease-modifying treatment. These are actions they are already familiar with and carry out for people with other chronic diseases, which often have limited treatment options as well. Don’t underestimate the importance and value of supportive care for patients.” Dr. Chu said.

The recommendations are based primarily on clinical expertise because there are very few randomized trials, and much of the evidence from other types of trials has been flawed, document coauthor Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said in an interview.

“The sad reality is there aren’t very many large randomized clinical trials with this illness and so what a group of very experienced clinicians did was to gather their collective experience and report it as that. It’s largely uncontrolled experience, but from people who have seen a lot of patients, for what it’s worth to the medical community.”

Dr. Komaroff also advised that clinicians watch out for ME/CFS in patients with long COVID. “If we find that those called long COVID meet ME/CFS criteria, the reason for knowing that is that there are already some treatments that according to experienced clinicians are helpful for ME/CFS, and it would be perfectly appropriate to try some of them in long COVID, particularly the ones that have minimal adverse reactions.”

The guidelines project was supported by the Open Medicine Foundation. Dr. Komaroff reported receiving personal fees from Serimmune outside the submitted work. Dr. Chu has no disclosures.

New consensus recommendations address diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with advice that may also be helpful for patients with lingering symptoms following acute COVID-19 infection.

VioletaStoimenova/Getty Images

The document was published online Aug. 25, 2021, in the Mayo Clinic Proceedings by the 23-member U.S. ME/CFS Clinician Coalition, headed by Lucinda Bateman, MD, of the Bateman Horne Center of Excellence, Salt Lake City. The document is the culmination of work that began with a summit held at the center in March 2018.

The target audience is both generalist and specialist health care providers. While ME/CFS is estimated to affect up to 2.5 million Americans, more than 90% are either undiagnosed or misdiagnosed with other conditions such as depression. And those who are diagnosed often receive inappropriate, outdated treatments such as psychotherapy and exercise prescriptions.

“Despite myalgic encephalomyelitis/chronic fatigue syndrome affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful,” Dr. Bateman and colleagues wrote.

The urgency of appropriate recognition and management of ME/CFS has increased as growing numbers of people are exhibiting signs and symptoms of ME/CFS following acute COVID-19 infection. This isn’t surprising because the illness has long been linked to other infections, including Epstein-Barr virus, the authors noted.

The document covers the epidemiology, impact, and prognosis of ME/CFS, as well as etiology and pathophysiology. “Scientific studies demonstrate multiple dysfunctional organ systems, including neuro, immune, and metabolic, in ME/CFS. These findings are not explained merely by deconditioning,” document coauthor Lily Chu, MD, an independent consultant in Burlingame, Calif., said in an interview.

The document reviews the 2015 U.S. Institute of Medicine (now Academy of Medicine) diagnostic criteria that are now also recommended by the Centers for Disease Control and Prevention. They are based on four main symptoms: substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social or personal activities for longer than 6 months; postexertional malaise, a worsening of all current symptoms, that patients often describe as a “crash”; unrefreshing sleep; and cognitive impairment and/or orthostatic intolerance.

“The new diagnostic criteria focusing on the key symptom of postexertional malaise rather than chronic fatigue, which is common in many conditions, may make the diagnostic process quicker and more accurate. Diagnosis now is both an inclusionary and not just exclusionary process, so it’s not necessary to eliminate all causes of fatigue. Diagnose patients who fit the criteria and be alert for it in people with persistent symptoms post COVID,” Dr. Chu said.

The document provides advice for taking a clinical history to obtain the information necessary for making the diagnosis, including use of laboratory testing to rule out other conditions. Physical exams, while they may not reveal specific abnormalities, may help in identifying comorbidities and ruling out alternative diagnoses.

A long list of nonpharmacologic and pharmacologic treatment and management approaches is offered for each of the individual core and common ME/CFS symptoms, including postexertional malaise, orthostatic intolerance, sleep issues, cognitive dysfunction and fatigue, immune dysfunction, pain, and gastrointestinal issues.

The document recommends against using the “outdated standard of care” cognitive-behavioral therapy and graded exercise therapy as primary treatments for the illness. Instead, the authors recommend teaching patients “pacing,” an individualized approach to energy conservation aimed at minimizing the frequency, duration, and severity of postexertional malaise.

Clinicians are also advised to assess patients’ daily living needs and provide support, including acquiring handicap placards, work or school accommodations, and disability benefits.

“There are things clinicians can do now to help patients even without a disease-modifying treatment. These are actions they are already familiar with and carry out for people with other chronic diseases, which often have limited treatment options as well. Don’t underestimate the importance and value of supportive care for patients.” Dr. Chu said.

The recommendations are based primarily on clinical expertise because there are very few randomized trials, and much of the evidence from other types of trials has been flawed, document coauthor Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said in an interview.

“The sad reality is there aren’t very many large randomized clinical trials with this illness and so what a group of very experienced clinicians did was to gather their collective experience and report it as that. It’s largely uncontrolled experience, but from people who have seen a lot of patients, for what it’s worth to the medical community.”

Dr. Komaroff also advised that clinicians watch out for ME/CFS in patients with long COVID. “If we find that those called long COVID meet ME/CFS criteria, the reason for knowing that is that there are already some treatments that according to experienced clinicians are helpful for ME/CFS, and it would be perfectly appropriate to try some of them in long COVID, particularly the ones that have minimal adverse reactions.”

The guidelines project was supported by the Open Medicine Foundation. Dr. Komaroff reported receiving personal fees from Serimmune outside the submitted work. Dr. Chu has no disclosures.

New consensus recommendations address diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with advice that may also be helpful for patients with lingering symptoms following acute COVID-19 infection.

VioletaStoimenova/Getty Images

The document was published online Aug. 25, 2021, in the Mayo Clinic Proceedings by the 23-member U.S. ME/CFS Clinician Coalition, headed by Lucinda Bateman, MD, of the Bateman Horne Center of Excellence, Salt Lake City. The document is the culmination of work that began with a summit held at the center in March 2018.

The target audience is both generalist and specialist health care providers. While ME/CFS is estimated to affect up to 2.5 million Americans, more than 90% are either undiagnosed or misdiagnosed with other conditions such as depression. And those who are diagnosed often receive inappropriate, outdated treatments such as psychotherapy and exercise prescriptions.

“Despite myalgic encephalomyelitis/chronic fatigue syndrome affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful,” Dr. Bateman and colleagues wrote.

The urgency of appropriate recognition and management of ME/CFS has increased as growing numbers of people are exhibiting signs and symptoms of ME/CFS following acute COVID-19 infection. This isn’t surprising because the illness has long been linked to other infections, including Epstein-Barr virus, the authors noted.

The document covers the epidemiology, impact, and prognosis of ME/CFS, as well as etiology and pathophysiology. “Scientific studies demonstrate multiple dysfunctional organ systems, including neuro, immune, and metabolic, in ME/CFS. These findings are not explained merely by deconditioning,” document coauthor Lily Chu, MD, an independent consultant in Burlingame, Calif., said in an interview.

The document reviews the 2015 U.S. Institute of Medicine (now Academy of Medicine) diagnostic criteria that are now also recommended by the Centers for Disease Control and Prevention. They are based on four main symptoms: substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social or personal activities for longer than 6 months; postexertional malaise, a worsening of all current symptoms, that patients often describe as a “crash”; unrefreshing sleep; and cognitive impairment and/or orthostatic intolerance.

“The new diagnostic criteria focusing on the key symptom of postexertional malaise rather than chronic fatigue, which is common in many conditions, may make the diagnostic process quicker and more accurate. Diagnosis now is both an inclusionary and not just exclusionary process, so it’s not necessary to eliminate all causes of fatigue. Diagnose patients who fit the criteria and be alert for it in people with persistent symptoms post COVID,” Dr. Chu said.

The document provides advice for taking a clinical history to obtain the information necessary for making the diagnosis, including use of laboratory testing to rule out other conditions. Physical exams, while they may not reveal specific abnormalities, may help in identifying comorbidities and ruling out alternative diagnoses.

A long list of nonpharmacologic and pharmacologic treatment and management approaches is offered for each of the individual core and common ME/CFS symptoms, including postexertional malaise, orthostatic intolerance, sleep issues, cognitive dysfunction and fatigue, immune dysfunction, pain, and gastrointestinal issues.

The document recommends against using the “outdated standard of care” cognitive-behavioral therapy and graded exercise therapy as primary treatments for the illness. Instead, the authors recommend teaching patients “pacing,” an individualized approach to energy conservation aimed at minimizing the frequency, duration, and severity of postexertional malaise.

Clinicians are also advised to assess patients’ daily living needs and provide support, including acquiring handicap placards, work or school accommodations, and disability benefits.

“There are things clinicians can do now to help patients even without a disease-modifying treatment. These are actions they are already familiar with and carry out for people with other chronic diseases, which often have limited treatment options as well. Don’t underestimate the importance and value of supportive care for patients.” Dr. Chu said.

The recommendations are based primarily on clinical expertise because there are very few randomized trials, and much of the evidence from other types of trials has been flawed, document coauthor Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said in an interview.

“The sad reality is there aren’t very many large randomized clinical trials with this illness and so what a group of very experienced clinicians did was to gather their collective experience and report it as that. It’s largely uncontrolled experience, but from people who have seen a lot of patients, for what it’s worth to the medical community.”

Dr. Komaroff also advised that clinicians watch out for ME/CFS in patients with long COVID. “If we find that those called long COVID meet ME/CFS criteria, the reason for knowing that is that there are already some treatments that according to experienced clinicians are helpful for ME/CFS, and it would be perfectly appropriate to try some of them in long COVID, particularly the ones that have minimal adverse reactions.”

The guidelines project was supported by the Open Medicine Foundation. Dr. Komaroff reported receiving personal fees from Serimmune outside the submitted work. Dr. Chu has no disclosures.

There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.

Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.

There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.

The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
 

The virtues of virtual

That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.

“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”

But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.

“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.

“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.  
 

New and updated guidelines

Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).

Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.

“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”

A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?

As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
 

Spotlight on EMPEROR-Preserved

The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.

That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.

And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.

Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.

“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.

“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”

For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.

There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”

Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
 

Other offerings, Friday, Aug. 27

Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.

The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.

In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.

The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.

The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.

Saturday, Aug. 28

The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.

The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.

The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.

Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.

Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.

Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.

Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.

Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.

After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.

The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace. 

Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
 

Sunday, Aug. 29

The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.

Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.

Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.

The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.

The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.

On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.

As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.

Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.

Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.

The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.

COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.

The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.

Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
 

Monday, Aug. 30

The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.

Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.

Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.

The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.

Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.

They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.

Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.

Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.

The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.

The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
 

Program structure and format

A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.

Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.

Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.

The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.

Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.

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

There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.

Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.

There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.

The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
 

The virtues of virtual

That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.

“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”

But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.

“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.

“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.  
 

New and updated guidelines

Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).

Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.

“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”

A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?

As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
 

Spotlight on EMPEROR-Preserved

The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.

That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.

And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.

Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.

“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.

“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”

For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.

There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”

Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
 

Other offerings, Friday, Aug. 27

Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.

The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.

In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.

The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.

The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.

Saturday, Aug. 28

The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.

The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.

The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.

Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.

Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.

Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.

Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.

Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.

After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.

The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace. 

Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
 

Sunday, Aug. 29

The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.

Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.

Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.

The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.

The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.

On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.

As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.

Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.

Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.

The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.

COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.

The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.

Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
 

Monday, Aug. 30

The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.

Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.

Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.

The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.

Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.

They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.

Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.

Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.

The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.

The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
 

Program structure and format

A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.

Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.

Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.

The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.

Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.

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

There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.

Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.

There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.

The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
 

The virtues of virtual

That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.

“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”

But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.

“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.

“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.  
 

New and updated guidelines

Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).

Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.

“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”

A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?

As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
 

Spotlight on EMPEROR-Preserved

The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.

That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.

And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.

Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.

“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.

“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”

For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.

There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”

Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
 

Other offerings, Friday, Aug. 27

Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.

The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.

In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.

The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.

The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.

Saturday, Aug. 28

The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.

The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.

The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.

Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.

Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.

Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.

Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.

Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.

After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.

The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace. 

Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
 

Sunday, Aug. 29

The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.

Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.

Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.

The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.

The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.

On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.

As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.

Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.

Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.

The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.

COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.

The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.

Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
 

Monday, Aug. 30

The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.

Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.

Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.

The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.

Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.

They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.

Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.

Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.

The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.

The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
 

Program structure and format

A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.

Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.

Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.

The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.

Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.

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