Hematology

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

Sickle cell disease (SCD) was associated with a greater than fourfold excess risk for COVID-19–related hospitalization and a greater than twofold risk for COVID-19–related death, according to a big-data analysis from the United Kingdom.

SCD was associated with an adjusted hazard ratio (HR) of 4.11 (95% confidence interval, 2.98-5.66) for admission to hospital and an HR of 2.55 (95% CI, 1.36-4.75) for death, report Ashley K. Clift, MBBS, a clinical research fellow at the University of Oxford, and colleagues. The results were published online July 20 in Annals of Internal Medicine.

Even those who carry just one copy of the sickle cell gene – the carrier status for sickle cell disease – appeared to be at heightened risk for these outcomes (HR for hospitalization, 1.38; 95% CI, 1.12-1.70; HR for death, 1.51; 95% CI, 1.13-2.00).

“Given the well-known ethnic patterning of sickle cell disorders, the predisposition they pose to other infections, and early evidence from smaller registries, we thought this would be an important analysis to run at the population level,” Dr. Clift said in an interview.

“Our data suggest that people living with sickle cell disorders are a group at higher risk from this infection, and this is important from a public health perspective in terms of vaccination strategies and advice on nonpharmacological interventions,” he said.

“The best course of action for managing risk in this group is vaccination,” said Enrico M. Novelli, MD, director of the adult sickle cell program at the University of Pittsburgh Medical Center. Dr. Novelli, who is also section chief of benign hematology in the university’s School of Medicine, was not involved in the study. “To date, there are no specific studies of the effect of COVID-19 vaccination in patients with SCD, but there is no reason to believe it would be less effective or more risky in this patient population,” he said.

In addition, common-sense measures, such as masking and physical distancing, particularly at large, indoor gatherings, should be encouraged, Dr. Novelli added. Keeping SCD under good control with available treatments is also important. “Any patient with SCD who contracts COVID-19 should undergo close, outpatient monitoring with pulse oxygen measurements. If sick, they should be hospitalized in a center familiar with the care of SCD patients.”

The U.K. results are in line with and expand on earlier evidence from specialist centers and registries, but the association with sickle cell trait has been unclear and is notable in these findings, Dr. Clift said.

“The finding of the association with sickle cell trait is somewhat unexpected,” pediatric hematologist/oncologist Rabi Hanna, MD, director of pediatric bone marrow transplantation at Cleveland Clinic Children’s, told this news organization. “But I would question the accuracy of the numbers, since not all people with the trait realize they have it. In other respects, the study confirms earlier hypotheses and data from single-center studies.” Dr. Hanna did not participate in the U.K. study.
 

Study details

The SCD cohort consisted of 5,059 persons with SCD and 25,682 carriers, those with just one copy of the trait. Data were drawn from the United Kingdom’s large primary-care QResearch database. Follow-up for hospitalizations was conducted from Jan. 24, 2020 to Sept. 30, 2020; follow-up for deaths was conducted from Jan. 24, 2020 to Jan. 18, 2021. Among adults with SCD, there were 40 hospitalizations and 10 deaths. Among those with sickle cell trait, there were 98 hospitalizations and 50 deaths. No children died, and only a few (<5) required hospitalization.

Previous registry research showed similarly elevated risks for severe disease and fatality among patients with SCD who were infected with SARS-CoV-2.

Because SCD affects 8 to 12 million people globally – 100,000 in the United States – the authors say their results are important for policymakers and for prioritizing vaccination. They also note that trait carriers may be underdiagnosed.

“While SCD is part of newborn screening, there may be undiagnosed older people with the trait in the general population, but it’s difficult to quantify how much this is undiagnosed,” Dr. Clift said. “But now we have these results, it’s not that surprising that sickle cell trait is also associated with increased risk, albeit to a lower extent. This could suggest an almost dose-like effect of the sickle mutations on COVID hospitalization risk.”

Neonatal screening for the most common form of SCD is currently mandatory in the United States, but the Centers for Disease Control and Prevention has no clear data on how many people are aware they are carriers, Dr. Hanna said. “The states didn’t all begin screening at the same time – some started in the 1990s, others started in the 2000s – so many young adults may be unaware they have the trait,” he said.

Dr. Clift said the multiorgan complications of SCD, such as cardiac and immune problems, may be contributing to the heightened risk in individuals infected with SARS-CoV-2. “For example, we know that people with sickle cell disease are more susceptible to other viral infections. There is also some pathophysiological overlap between SCD disease and severe COVID, such as clotting dysfunction, so that may be worth further exploration,” he said.

The overlapping clotting problems associated with both COVID-19 and SCD could increase the risk for severe venous thromboembolism. In addition, experts noted that patients with SCD often have pre-COVID endothelial damage and baseline inflammation and are very sensitive to hypoxia; as well, a sizable proportion have lung disease.

The message to patients and physicians counseling patients is twofold, said Dr. Hanna: “SCD patients are at higher risk of COVID complications, and these are preventable with vaccination.”

The study was supported by the UK Medical Research Council. Dr. Clift is supported by Cancer Research UK. Coauthor Dr. Hippisley-Cox has received fees from ClinRisk and nonfinancial support from QResearch outside of the submitted work. Dr. Hanna has disclosed no relevant financial relationships. Dr. Novelli is a consultant for Novartis.

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

Sickle cell disease (SCD) was associated with a greater than fourfold excess risk for COVID-19–related hospitalization and a greater than twofold risk for COVID-19–related death, according to a big-data analysis from the United Kingdom.

SCD was associated with an adjusted hazard ratio (HR) of 4.11 (95% confidence interval, 2.98-5.66) for admission to hospital and an HR of 2.55 (95% CI, 1.36-4.75) for death, report Ashley K. Clift, MBBS, a clinical research fellow at the University of Oxford, and colleagues. The results were published online July 20 in Annals of Internal Medicine.

Even those who carry just one copy of the sickle cell gene – the carrier status for sickle cell disease – appeared to be at heightened risk for these outcomes (HR for hospitalization, 1.38; 95% CI, 1.12-1.70; HR for death, 1.51; 95% CI, 1.13-2.00).

“Given the well-known ethnic patterning of sickle cell disorders, the predisposition they pose to other infections, and early evidence from smaller registries, we thought this would be an important analysis to run at the population level,” Dr. Clift said in an interview.

“Our data suggest that people living with sickle cell disorders are a group at higher risk from this infection, and this is important from a public health perspective in terms of vaccination strategies and advice on nonpharmacological interventions,” he said.

“The best course of action for managing risk in this group is vaccination,” said Enrico M. Novelli, MD, director of the adult sickle cell program at the University of Pittsburgh Medical Center. Dr. Novelli, who is also section chief of benign hematology in the university’s School of Medicine, was not involved in the study. “To date, there are no specific studies of the effect of COVID-19 vaccination in patients with SCD, but there is no reason to believe it would be less effective or more risky in this patient population,” he said.

In addition, common-sense measures, such as masking and physical distancing, particularly at large, indoor gatherings, should be encouraged, Dr. Novelli added. Keeping SCD under good control with available treatments is also important. “Any patient with SCD who contracts COVID-19 should undergo close, outpatient monitoring with pulse oxygen measurements. If sick, they should be hospitalized in a center familiar with the care of SCD patients.”

The U.K. results are in line with and expand on earlier evidence from specialist centers and registries, but the association with sickle cell trait has been unclear and is notable in these findings, Dr. Clift said.

“The finding of the association with sickle cell trait is somewhat unexpected,” pediatric hematologist/oncologist Rabi Hanna, MD, director of pediatric bone marrow transplantation at Cleveland Clinic Children’s, told this news organization. “But I would question the accuracy of the numbers, since not all people with the trait realize they have it. In other respects, the study confirms earlier hypotheses and data from single-center studies.” Dr. Hanna did not participate in the U.K. study.
 

Study details

The SCD cohort consisted of 5,059 persons with SCD and 25,682 carriers, those with just one copy of the trait. Data were drawn from the United Kingdom’s large primary-care QResearch database. Follow-up for hospitalizations was conducted from Jan. 24, 2020 to Sept. 30, 2020; follow-up for deaths was conducted from Jan. 24, 2020 to Jan. 18, 2021. Among adults with SCD, there were 40 hospitalizations and 10 deaths. Among those with sickle cell trait, there were 98 hospitalizations and 50 deaths. No children died, and only a few (<5) required hospitalization.

Previous registry research showed similarly elevated risks for severe disease and fatality among patients with SCD who were infected with SARS-CoV-2.

Because SCD affects 8 to 12 million people globally – 100,000 in the United States – the authors say their results are important for policymakers and for prioritizing vaccination. They also note that trait carriers may be underdiagnosed.

“While SCD is part of newborn screening, there may be undiagnosed older people with the trait in the general population, but it’s difficult to quantify how much this is undiagnosed,” Dr. Clift said. “But now we have these results, it’s not that surprising that sickle cell trait is also associated with increased risk, albeit to a lower extent. This could suggest an almost dose-like effect of the sickle mutations on COVID hospitalization risk.”

Neonatal screening for the most common form of SCD is currently mandatory in the United States, but the Centers for Disease Control and Prevention has no clear data on how many people are aware they are carriers, Dr. Hanna said. “The states didn’t all begin screening at the same time – some started in the 1990s, others started in the 2000s – so many young adults may be unaware they have the trait,” he said.

Dr. Clift said the multiorgan complications of SCD, such as cardiac and immune problems, may be contributing to the heightened risk in individuals infected with SARS-CoV-2. “For example, we know that people with sickle cell disease are more susceptible to other viral infections. There is also some pathophysiological overlap between SCD disease and severe COVID, such as clotting dysfunction, so that may be worth further exploration,” he said.

The overlapping clotting problems associated with both COVID-19 and SCD could increase the risk for severe venous thromboembolism. In addition, experts noted that patients with SCD often have pre-COVID endothelial damage and baseline inflammation and are very sensitive to hypoxia; as well, a sizable proportion have lung disease.

The message to patients and physicians counseling patients is twofold, said Dr. Hanna: “SCD patients are at higher risk of COVID complications, and these are preventable with vaccination.”

The study was supported by the UK Medical Research Council. Dr. Clift is supported by Cancer Research UK. Coauthor Dr. Hippisley-Cox has received fees from ClinRisk and nonfinancial support from QResearch outside of the submitted work. Dr. Hanna has disclosed no relevant financial relationships. Dr. Novelli is a consultant for Novartis.

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

Sickle cell disease (SCD) was associated with a greater than fourfold excess risk for COVID-19–related hospitalization and a greater than twofold risk for COVID-19–related death, according to a big-data analysis from the United Kingdom.

SCD was associated with an adjusted hazard ratio (HR) of 4.11 (95% confidence interval, 2.98-5.66) for admission to hospital and an HR of 2.55 (95% CI, 1.36-4.75) for death, report Ashley K. Clift, MBBS, a clinical research fellow at the University of Oxford, and colleagues. The results were published online July 20 in Annals of Internal Medicine.

Even those who carry just one copy of the sickle cell gene – the carrier status for sickle cell disease – appeared to be at heightened risk for these outcomes (HR for hospitalization, 1.38; 95% CI, 1.12-1.70; HR for death, 1.51; 95% CI, 1.13-2.00).

“Given the well-known ethnic patterning of sickle cell disorders, the predisposition they pose to other infections, and early evidence from smaller registries, we thought this would be an important analysis to run at the population level,” Dr. Clift said in an interview.

“Our data suggest that people living with sickle cell disorders are a group at higher risk from this infection, and this is important from a public health perspective in terms of vaccination strategies and advice on nonpharmacological interventions,” he said.

“The best course of action for managing risk in this group is vaccination,” said Enrico M. Novelli, MD, director of the adult sickle cell program at the University of Pittsburgh Medical Center. Dr. Novelli, who is also section chief of benign hematology in the university’s School of Medicine, was not involved in the study. “To date, there are no specific studies of the effect of COVID-19 vaccination in patients with SCD, but there is no reason to believe it would be less effective or more risky in this patient population,” he said.

In addition, common-sense measures, such as masking and physical distancing, particularly at large, indoor gatherings, should be encouraged, Dr. Novelli added. Keeping SCD under good control with available treatments is also important. “Any patient with SCD who contracts COVID-19 should undergo close, outpatient monitoring with pulse oxygen measurements. If sick, they should be hospitalized in a center familiar with the care of SCD patients.”

The U.K. results are in line with and expand on earlier evidence from specialist centers and registries, but the association with sickle cell trait has been unclear and is notable in these findings, Dr. Clift said.

“The finding of the association with sickle cell trait is somewhat unexpected,” pediatric hematologist/oncologist Rabi Hanna, MD, director of pediatric bone marrow transplantation at Cleveland Clinic Children’s, told this news organization. “But I would question the accuracy of the numbers, since not all people with the trait realize they have it. In other respects, the study confirms earlier hypotheses and data from single-center studies.” Dr. Hanna did not participate in the U.K. study.
 

Study details

The SCD cohort consisted of 5,059 persons with SCD and 25,682 carriers, those with just one copy of the trait. Data were drawn from the United Kingdom’s large primary-care QResearch database. Follow-up for hospitalizations was conducted from Jan. 24, 2020 to Sept. 30, 2020; follow-up for deaths was conducted from Jan. 24, 2020 to Jan. 18, 2021. Among adults with SCD, there were 40 hospitalizations and 10 deaths. Among those with sickle cell trait, there were 98 hospitalizations and 50 deaths. No children died, and only a few (<5) required hospitalization.

Previous registry research showed similarly elevated risks for severe disease and fatality among patients with SCD who were infected with SARS-CoV-2.

Because SCD affects 8 to 12 million people globally – 100,000 in the United States – the authors say their results are important for policymakers and for prioritizing vaccination. They also note that trait carriers may be underdiagnosed.

“While SCD is part of newborn screening, there may be undiagnosed older people with the trait in the general population, but it’s difficult to quantify how much this is undiagnosed,” Dr. Clift said. “But now we have these results, it’s not that surprising that sickle cell trait is also associated with increased risk, albeit to a lower extent. This could suggest an almost dose-like effect of the sickle mutations on COVID hospitalization risk.”

Neonatal screening for the most common form of SCD is currently mandatory in the United States, but the Centers for Disease Control and Prevention has no clear data on how many people are aware they are carriers, Dr. Hanna said. “The states didn’t all begin screening at the same time – some started in the 1990s, others started in the 2000s – so many young adults may be unaware they have the trait,” he said.

Dr. Clift said the multiorgan complications of SCD, such as cardiac and immune problems, may be contributing to the heightened risk in individuals infected with SARS-CoV-2. “For example, we know that people with sickle cell disease are more susceptible to other viral infections. There is also some pathophysiological overlap between SCD disease and severe COVID, such as clotting dysfunction, so that may be worth further exploration,” he said.

The overlapping clotting problems associated with both COVID-19 and SCD could increase the risk for severe venous thromboembolism. In addition, experts noted that patients with SCD often have pre-COVID endothelial damage and baseline inflammation and are very sensitive to hypoxia; as well, a sizable proportion have lung disease.

The message to patients and physicians counseling patients is twofold, said Dr. Hanna: “SCD patients are at higher risk of COVID complications, and these are preventable with vaccination.”

The study was supported by the UK Medical Research Council. Dr. Clift is supported by Cancer Research UK. Coauthor Dr. Hippisley-Cox has received fees from ClinRisk and nonfinancial support from QResearch outside of the submitted work. Dr. Hanna has disclosed no relevant financial relationships. Dr. Novelli is a consultant for Novartis.

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

Early treatment with low-molecular-weight heparin (LMWH) reduces the risk for death in patients with COVID-19, a retrospective cohort study shows.

Heparin could reduce the risk for blood clots, Andrea De Vito, MD, of the unit of infectious diseases at the University of Sassari, Italy, said during his online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.

“Several studies try to describe the role played by coagulopathies in COVID-19 death,” but the mechanism causing them is still unclear, Dr. De Vito explained.

Some guidelines have suggested heparin as a treatment for hospitalized COVID-19 patients, but few have looked at nonhospitalized patients. In fact, the National Institutes of Health discourages the use of heparin in nonhospitalized COVID-19 patients, and guidance for the home care of COVID-19 patients from the World Health Organization doesn’t mention heparin treatment at all, he said.

To examine the benefits of early heparin – whether administered at home or in the hospital – Dr. De Vito and colleagues looked at a cohort of older adults with COVID-19 who were evaluated or treated at an Italian university hospital.

“Some patients were hospitalized immediately after symptoms onset; other people preferred to call their general practitioner and started the treatment at home,” Dr. De Vito said in an interview. “Other people were hospitalized for worsening of symptoms later in the course of the disease.”

Of the 734 patients, 296 received heparin within 5 days of the onset of symptoms or a positive COVID-19 test. Of the remaining 438 patients, 196 received LMWH treatment later during the disease course, and the rest never received LMWH.

All patients who received early heparin were treated with LMWH 4,000 IU, or 6,000 IU if their body mass index was above 30 kg/m². This was reduced to 2,000 IU if estimated glomerular filtration rate (eGFR) dropped below 30 mL/min. None of the patients had previously received heparin.

Median age was slightly younger for patients who received early heparin than for those who did not (76.8 vs. 78.5 years).

Other demographic characteristics, such as sex and BMI, were similar in the two groups, as were rates of comorbidities, such as hypertension, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, kidney disease, and neurologic conditions. Also similar were the frequency of symptoms (such as fever, cough, and shortness of breath) and rates of treatment with remdesivir or steroids.

Rates of hospital admission were not significantly different between patients who received early heparin and those who did not (65% vs. 61%). There was also no significant difference in use of a venturi mask (35% vs. 28%), noninvasive ventilation (13% vs. 14%), or intubation (5% vs. 8%).

However, rates of death were significantly lower in patients who received early heparin than in those who did not (13% vs. 25%; P < .0001).

There was a trend toward shorter hospital stays for patients treated with early heparin, but the difference was not significant (median, 10 vs. 13 days; P = .08).

Researchers also conducted a separate analysis of 219 COVID-19 patients who received LMWH at home, regardless of when during their disease course they received it. These patients were significantly less likely to be hospitalized than were patients who did not receive LMWH at home (odds ratio, 0.2; P < .0001).

Comparatively, early heparin treatment had a greater effect on the risk for death and the risk for hospitalization than did other factors.

“Thromboemboli are a major complication of COVID. There is good consensus that hospitalized patients with COVID should receive anticoagulants prophylactically, although the best dose is being studied,” said Judy Stone, MD, an infectious disease physician and journalist who was not involved in the study.

“This study extends those findings of benefit from anticoagulants to nonhospitalized patients, with fewer deaths in those treated with low-molecular-weight heparin,” Dr. Stone told this news organization. “The major limitation is that the study is retrospective and observational. The next step would be to confirm these findings prospectively, randomizing a similar group to LMWH or no anticoagulation.”

Another limitation of the study is that some of the patients lived in nursing homes and might have received care from nurses that eliminated the need for hospitalization, Dr. De Vito added.

The study did not note any external funding. The authors have disclosed no relevant financial relationships. Dr. Stone is a member of the advisory committee for the C-Path CURE Drug Repurposing Collaboratory (CDRC) program and has written for Medscape.

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

Early treatment with low-molecular-weight heparin (LMWH) reduces the risk for death in patients with COVID-19, a retrospective cohort study shows.

Heparin could reduce the risk for blood clots, Andrea De Vito, MD, of the unit of infectious diseases at the University of Sassari, Italy, said during his online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.

“Several studies try to describe the role played by coagulopathies in COVID-19 death,” but the mechanism causing them is still unclear, Dr. De Vito explained.

Some guidelines have suggested heparin as a treatment for hospitalized COVID-19 patients, but few have looked at nonhospitalized patients. In fact, the National Institutes of Health discourages the use of heparin in nonhospitalized COVID-19 patients, and guidance for the home care of COVID-19 patients from the World Health Organization doesn’t mention heparin treatment at all, he said.

To examine the benefits of early heparin – whether administered at home or in the hospital – Dr. De Vito and colleagues looked at a cohort of older adults with COVID-19 who were evaluated or treated at an Italian university hospital.

“Some patients were hospitalized immediately after symptoms onset; other people preferred to call their general practitioner and started the treatment at home,” Dr. De Vito said in an interview. “Other people were hospitalized for worsening of symptoms later in the course of the disease.”

Of the 734 patients, 296 received heparin within 5 days of the onset of symptoms or a positive COVID-19 test. Of the remaining 438 patients, 196 received LMWH treatment later during the disease course, and the rest never received LMWH.

All patients who received early heparin were treated with LMWH 4,000 IU, or 6,000 IU if their body mass index was above 30 kg/m². This was reduced to 2,000 IU if estimated glomerular filtration rate (eGFR) dropped below 30 mL/min. None of the patients had previously received heparin.

Median age was slightly younger for patients who received early heparin than for those who did not (76.8 vs. 78.5 years).

Other demographic characteristics, such as sex and BMI, were similar in the two groups, as were rates of comorbidities, such as hypertension, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, kidney disease, and neurologic conditions. Also similar were the frequency of symptoms (such as fever, cough, and shortness of breath) and rates of treatment with remdesivir or steroids.

Rates of hospital admission were not significantly different between patients who received early heparin and those who did not (65% vs. 61%). There was also no significant difference in use of a venturi mask (35% vs. 28%), noninvasive ventilation (13% vs. 14%), or intubation (5% vs. 8%).

However, rates of death were significantly lower in patients who received early heparin than in those who did not (13% vs. 25%; P < .0001).

There was a trend toward shorter hospital stays for patients treated with early heparin, but the difference was not significant (median, 10 vs. 13 days; P = .08).

Researchers also conducted a separate analysis of 219 COVID-19 patients who received LMWH at home, regardless of when during their disease course they received it. These patients were significantly less likely to be hospitalized than were patients who did not receive LMWH at home (odds ratio, 0.2; P < .0001).

Comparatively, early heparin treatment had a greater effect on the risk for death and the risk for hospitalization than did other factors.

“Thromboemboli are a major complication of COVID. There is good consensus that hospitalized patients with COVID should receive anticoagulants prophylactically, although the best dose is being studied,” said Judy Stone, MD, an infectious disease physician and journalist who was not involved in the study.

“This study extends those findings of benefit from anticoagulants to nonhospitalized patients, with fewer deaths in those treated with low-molecular-weight heparin,” Dr. Stone told this news organization. “The major limitation is that the study is retrospective and observational. The next step would be to confirm these findings prospectively, randomizing a similar group to LMWH or no anticoagulation.”

Another limitation of the study is that some of the patients lived in nursing homes and might have received care from nurses that eliminated the need for hospitalization, Dr. De Vito added.

The study did not note any external funding. The authors have disclosed no relevant financial relationships. Dr. Stone is a member of the advisory committee for the C-Path CURE Drug Repurposing Collaboratory (CDRC) program and has written for Medscape.

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

Early treatment with low-molecular-weight heparin (LMWH) reduces the risk for death in patients with COVID-19, a retrospective cohort study shows.

Heparin could reduce the risk for blood clots, Andrea De Vito, MD, of the unit of infectious diseases at the University of Sassari, Italy, said during his online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.

“Several studies try to describe the role played by coagulopathies in COVID-19 death,” but the mechanism causing them is still unclear, Dr. De Vito explained.

Some guidelines have suggested heparin as a treatment for hospitalized COVID-19 patients, but few have looked at nonhospitalized patients. In fact, the National Institutes of Health discourages the use of heparin in nonhospitalized COVID-19 patients, and guidance for the home care of COVID-19 patients from the World Health Organization doesn’t mention heparin treatment at all, he said.

To examine the benefits of early heparin – whether administered at home or in the hospital – Dr. De Vito and colleagues looked at a cohort of older adults with COVID-19 who were evaluated or treated at an Italian university hospital.

“Some patients were hospitalized immediately after symptoms onset; other people preferred to call their general practitioner and started the treatment at home,” Dr. De Vito said in an interview. “Other people were hospitalized for worsening of symptoms later in the course of the disease.”

Of the 734 patients, 296 received heparin within 5 days of the onset of symptoms or a positive COVID-19 test. Of the remaining 438 patients, 196 received LMWH treatment later during the disease course, and the rest never received LMWH.

All patients who received early heparin were treated with LMWH 4,000 IU, or 6,000 IU if their body mass index was above 30 kg/m². This was reduced to 2,000 IU if estimated glomerular filtration rate (eGFR) dropped below 30 mL/min. None of the patients had previously received heparin.

Median age was slightly younger for patients who received early heparin than for those who did not (76.8 vs. 78.5 years).

Other demographic characteristics, such as sex and BMI, were similar in the two groups, as were rates of comorbidities, such as hypertension, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, kidney disease, and neurologic conditions. Also similar were the frequency of symptoms (such as fever, cough, and shortness of breath) and rates of treatment with remdesivir or steroids.

Rates of hospital admission were not significantly different between patients who received early heparin and those who did not (65% vs. 61%). There was also no significant difference in use of a venturi mask (35% vs. 28%), noninvasive ventilation (13% vs. 14%), or intubation (5% vs. 8%).

However, rates of death were significantly lower in patients who received early heparin than in those who did not (13% vs. 25%; P < .0001).

There was a trend toward shorter hospital stays for patients treated with early heparin, but the difference was not significant (median, 10 vs. 13 days; P = .08).

Researchers also conducted a separate analysis of 219 COVID-19 patients who received LMWH at home, regardless of when during their disease course they received it. These patients were significantly less likely to be hospitalized than were patients who did not receive LMWH at home (odds ratio, 0.2; P < .0001).

Comparatively, early heparin treatment had a greater effect on the risk for death and the risk for hospitalization than did other factors.

“Thromboemboli are a major complication of COVID. There is good consensus that hospitalized patients with COVID should receive anticoagulants prophylactically, although the best dose is being studied,” said Judy Stone, MD, an infectious disease physician and journalist who was not involved in the study.

“This study extends those findings of benefit from anticoagulants to nonhospitalized patients, with fewer deaths in those treated with low-molecular-weight heparin,” Dr. Stone told this news organization. “The major limitation is that the study is retrospective and observational. The next step would be to confirm these findings prospectively, randomizing a similar group to LMWH or no anticoagulation.”

Another limitation of the study is that some of the patients lived in nursing homes and might have received care from nurses that eliminated the need for hospitalization, Dr. De Vito added.

The study did not note any external funding. The authors have disclosed no relevant financial relationships. Dr. Stone is a member of the advisory committee for the C-Path CURE Drug Repurposing Collaboratory (CDRC) program and has written for Medscape.

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

A 46-year-old woman presents with fatigue. She reports that she has had unusually heavy periods for the past 6 months. Her blood work shows a hematocrit level of 32, a mean corpuscular volume of 77, a platelet count of 390,000, and a ferritin level of 5.

What would you recommend for iron replacement?

A. FeSO₄ 325 mg three times a day with vitamin C

B. FeSO₄ 325 mg daily with vitamin C

C. FeSO₄ 325 mg every other day

Recommendations and supporting research

I think I would start with choice C, FeSO₄ every other day.

Treatment of iron deficiency with oral iron has traditionally been done by giving 150-200 mg of elemental iron (which is equal to three 325 mg tablets of iron sulfate).¹ This dosing regimen has considerable gastrointestinal side effects. Recent evidence has shown that iron absorption is diminished the more frequently it is given.

Stoffel and colleagues found that fractional iron absorption was higher in iron-deficient women who were given iron every other day, compared with those who received daily iron.² They also found that the more frequently iron was administered, the higher the hepcidin levels were, and the lower the iron absorption.

Karacok and colleagues studied every other day iron versus daily iron for the treatment of iron-deficiency anemia of pregnancy.³ A total of 217 women completed randomization and participated in the study, with all women receiving 100 mg of elemental iron, either daily (111) or every other day (106). There was no significant difference in increase in ferritin levels, or hemoglobin increase between the groups. The daily iron group had more gastrointestinal symptoms (41.4%) than the every other day iron group (15.1%) (P < .0057).

Düzen Oflas and colleagues looked at the same question in nonpregnant women with iron deficiency anemia.⁴ Study patients either received 80 mg iron sulfate twice a day, 80 mg once a day, or 80 mg every other day. There was no statistically significant difference in hemoglobin improvement between groups, but the group that received twice a day dosing of iron had statistically significantly higher ferritin levels than the daily or every other day iron groups. This improvement in ferritin levels came at a cost, though, as 68% of patients in the twice daily iron group had gastrointestinal symptoms, compared with only 10% in the every other day iron group (P < .01).

Vitamin C is often recommended to be taken with iron to promote absorption. The evidence for this practice is scant, and dates back almost 50 years.^5,6

Cook and Reddy found there was no significant difference in mean iron absorption among the three dietary periods studied in 12 patients despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d.⁷

Hunt and colleagues studied 25 non pregnant, healthy women with low ferritin levels.⁸ The women’s meals were supplemented with vitamin C (500 mg, three times a day) for 5 of the 10 weeks, in a double-blind, crossover design. Vitamin C supplementation did not lead to a difference in iron absorption, lab indices of iron deficiency, or the biological half-life of iron.

Li and colleagues looked at the effect of vitamin C supplementation on iron levels in women with iron deficiency anemia.⁹ A total of 440 women were recruited, with 432 completing the trial. Women were randomized to receive iron supplements plus vitamin C or iron supplements only. Their findings were that oral iron supplements alone were equivalent to oral iron supplements plus vitamin C in improving hemoglobin recovery and iron absorption.
 

Bottom line

Less frequent administration of iron supplements (every other day) is as effective as more frequent administration, with less GI symptoms. Also, adding vitamin C does not appear to improve absorption of iron supplements.

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

References

1. 1. Fairbanks VF and Beutler E. Iron deficiency, in “Williams Textbook of Hematology, 6th ed.” (New York: McGraw-Hill, 2001).

2. Stoffel N et al. Lancet Haematology. 2017;4: e524-33.

3. Karakoc G et al. J Matern Fetal Neonatal Med. 2021 Apr 18:1-5

4. Düzen Oflas N et al. Intern Med J. 2020 Jul;50(7):854-8

5. Cook JD and Monsen ER. Am J Clin Nutr. 1977;30:235-41.

6. Hallberg L etal. Hum Nutr Appl Nutr. 1986;40: 97-113.

7. Cook JD and Reddy M. Am J Clin Nutr. 2001;73:93-8.

8. Hunt JR et al. Am J Clin Nutr. 1994 Jun;59(6):1381-5.

9. Li N et al. JAMA Netw Open. 2020 Nov 2;3(11):e2023644.

A 46-year-old woman presents with fatigue. She reports that she has had unusually heavy periods for the past 6 months. Her blood work shows a hematocrit level of 32, a mean corpuscular volume of 77, a platelet count of 390,000, and a ferritin level of 5.

What would you recommend for iron replacement?

A. FeSO₄ 325 mg three times a day with vitamin C

B. FeSO₄ 325 mg daily with vitamin C

C. FeSO₄ 325 mg every other day

Recommendations and supporting research

I think I would start with choice C, FeSO₄ every other day.

Treatment of iron deficiency with oral iron has traditionally been done by giving 150-200 mg of elemental iron (which is equal to three 325 mg tablets of iron sulfate).¹ This dosing regimen has considerable gastrointestinal side effects. Recent evidence has shown that iron absorption is diminished the more frequently it is given.

Stoffel and colleagues found that fractional iron absorption was higher in iron-deficient women who were given iron every other day, compared with those who received daily iron.² They also found that the more frequently iron was administered, the higher the hepcidin levels were, and the lower the iron absorption.

Karacok and colleagues studied every other day iron versus daily iron for the treatment of iron-deficiency anemia of pregnancy.³ A total of 217 women completed randomization and participated in the study, with all women receiving 100 mg of elemental iron, either daily (111) or every other day (106). There was no significant difference in increase in ferritin levels, or hemoglobin increase between the groups. The daily iron group had more gastrointestinal symptoms (41.4%) than the every other day iron group (15.1%) (P < .0057).

Düzen Oflas and colleagues looked at the same question in nonpregnant women with iron deficiency anemia.⁴ Study patients either received 80 mg iron sulfate twice a day, 80 mg once a day, or 80 mg every other day. There was no statistically significant difference in hemoglobin improvement between groups, but the group that received twice a day dosing of iron had statistically significantly higher ferritin levels than the daily or every other day iron groups. This improvement in ferritin levels came at a cost, though, as 68% of patients in the twice daily iron group had gastrointestinal symptoms, compared with only 10% in the every other day iron group (P < .01).

Vitamin C is often recommended to be taken with iron to promote absorption. The evidence for this practice is scant, and dates back almost 50 years.^5,6

Cook and Reddy found there was no significant difference in mean iron absorption among the three dietary periods studied in 12 patients despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d.⁷

Hunt and colleagues studied 25 non pregnant, healthy women with low ferritin levels.⁸ The women’s meals were supplemented with vitamin C (500 mg, three times a day) for 5 of the 10 weeks, in a double-blind, crossover design. Vitamin C supplementation did not lead to a difference in iron absorption, lab indices of iron deficiency, or the biological half-life of iron.

Li and colleagues looked at the effect of vitamin C supplementation on iron levels in women with iron deficiency anemia.⁹ A total of 440 women were recruited, with 432 completing the trial. Women were randomized to receive iron supplements plus vitamin C or iron supplements only. Their findings were that oral iron supplements alone were equivalent to oral iron supplements plus vitamin C in improving hemoglobin recovery and iron absorption.
 

Bottom line

Less frequent administration of iron supplements (every other day) is as effective as more frequent administration, with less GI symptoms. Also, adding vitamin C does not appear to improve absorption of iron supplements.

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

References

1. 1. Fairbanks VF and Beutler E. Iron deficiency, in “Williams Textbook of Hematology, 6th ed.” (New York: McGraw-Hill, 2001).

2. Stoffel N et al. Lancet Haematology. 2017;4: e524-33.

3. Karakoc G et al. J Matern Fetal Neonatal Med. 2021 Apr 18:1-5

4. Düzen Oflas N et al. Intern Med J. 2020 Jul;50(7):854-8

5. Cook JD and Monsen ER. Am J Clin Nutr. 1977;30:235-41.

6. Hallberg L etal. Hum Nutr Appl Nutr. 1986;40: 97-113.

7. Cook JD and Reddy M. Am J Clin Nutr. 2001;73:93-8.

8. Hunt JR et al. Am J Clin Nutr. 1994 Jun;59(6):1381-5.

9. Li N et al. JAMA Netw Open. 2020 Nov 2;3(11):e2023644.

A 46-year-old woman presents with fatigue. She reports that she has had unusually heavy periods for the past 6 months. Her blood work shows a hematocrit level of 32, a mean corpuscular volume of 77, a platelet count of 390,000, and a ferritin level of 5.

What would you recommend for iron replacement?

A. FeSO₄ 325 mg three times a day with vitamin C

B. FeSO₄ 325 mg daily with vitamin C

C. FeSO₄ 325 mg every other day

Recommendations and supporting research

I think I would start with choice C, FeSO₄ every other day.

Treatment of iron deficiency with oral iron has traditionally been done by giving 150-200 mg of elemental iron (which is equal to three 325 mg tablets of iron sulfate).¹ This dosing regimen has considerable gastrointestinal side effects. Recent evidence has shown that iron absorption is diminished the more frequently it is given.

Stoffel and colleagues found that fractional iron absorption was higher in iron-deficient women who were given iron every other day, compared with those who received daily iron.² They also found that the more frequently iron was administered, the higher the hepcidin levels were, and the lower the iron absorption.

Karacok and colleagues studied every other day iron versus daily iron for the treatment of iron-deficiency anemia of pregnancy.³ A total of 217 women completed randomization and participated in the study, with all women receiving 100 mg of elemental iron, either daily (111) or every other day (106). There was no significant difference in increase in ferritin levels, or hemoglobin increase between the groups. The daily iron group had more gastrointestinal symptoms (41.4%) than the every other day iron group (15.1%) (P < .0057).

Düzen Oflas and colleagues looked at the same question in nonpregnant women with iron deficiency anemia.⁴ Study patients either received 80 mg iron sulfate twice a day, 80 mg once a day, or 80 mg every other day. There was no statistically significant difference in hemoglobin improvement between groups, but the group that received twice a day dosing of iron had statistically significantly higher ferritin levels than the daily or every other day iron groups. This improvement in ferritin levels came at a cost, though, as 68% of patients in the twice daily iron group had gastrointestinal symptoms, compared with only 10% in the every other day iron group (P < .01).

Vitamin C is often recommended to be taken with iron to promote absorption. The evidence for this practice is scant, and dates back almost 50 years.^5,6

Cook and Reddy found there was no significant difference in mean iron absorption among the three dietary periods studied in 12 patients despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d.⁷

Hunt and colleagues studied 25 non pregnant, healthy women with low ferritin levels.⁸ The women’s meals were supplemented with vitamin C (500 mg, three times a day) for 5 of the 10 weeks, in a double-blind, crossover design. Vitamin C supplementation did not lead to a difference in iron absorption, lab indices of iron deficiency, or the biological half-life of iron.

Li and colleagues looked at the effect of vitamin C supplementation on iron levels in women with iron deficiency anemia.⁹ A total of 440 women were recruited, with 432 completing the trial. Women were randomized to receive iron supplements plus vitamin C or iron supplements only. Their findings were that oral iron supplements alone were equivalent to oral iron supplements plus vitamin C in improving hemoglobin recovery and iron absorption.
 

Bottom line

Less frequent administration of iron supplements (every other day) is as effective as more frequent administration, with less GI symptoms. Also, adding vitamin C does not appear to improve absorption of iron supplements.

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

References

1. 1. Fairbanks VF and Beutler E. Iron deficiency, in “Williams Textbook of Hematology, 6th ed.” (New York: McGraw-Hill, 2001).

2. Stoffel N et al. Lancet Haematology. 2017;4: e524-33.

3. Karakoc G et al. J Matern Fetal Neonatal Med. 2021 Apr 18:1-5

4. Düzen Oflas N et al. Intern Med J. 2020 Jul;50(7):854-8

5. Cook JD and Monsen ER. Am J Clin Nutr. 1977;30:235-41.

6. Hallberg L etal. Hum Nutr Appl Nutr. 1986;40: 97-113.

7. Cook JD and Reddy M. Am J Clin Nutr. 2001;73:93-8.

8. Hunt JR et al. Am J Clin Nutr. 1994 Jun;59(6):1381-5.

9. Li N et al. JAMA Netw Open. 2020 Nov 2;3(11):e2023644.

Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.

FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.

Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
 

Major bleeds

A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.

The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.

“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.

They reported having no conflicts of interest.

mlesney@mdedge.com

Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.

FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.

Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
 

Major bleeds

A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.

The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.

“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.

They reported having no conflicts of interest.

mlesney@mdedge.com

Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.

FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.

Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
 

Major bleeds

A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.

The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.

“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.

They reported having no conflicts of interest.

mlesney@mdedge.com

Adults with sickle cell disease who experienced a vaso-occlusive crisis had substantially better outcomes when they were treated at specialty infusion centers than those treated in emergency departments (EDs), a prospective observational study shows.

At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.

“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”

To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.

The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.

The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs. 

Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.

The investigators used propensity score methodology to balance patient characteristics in the study groups.
 

Quick, effective pain reduction is beneficial

The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write. 

Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.

The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note. 

“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write. 

“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.

Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote. 

The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study. 

“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
 

Infusion centers are scarce

“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.

“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.” 

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.

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

Adults with sickle cell disease who experienced a vaso-occlusive crisis had substantially better outcomes when they were treated at specialty infusion centers than those treated in emergency departments (EDs), a prospective observational study shows.

At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.

“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”

To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.

The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.

The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs. 

Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.

The investigators used propensity score methodology to balance patient characteristics in the study groups.
 

Quick, effective pain reduction is beneficial

The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write. 

Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.

The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note. 

“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write. 

“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.

Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote. 

The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study. 

“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
 

Infusion centers are scarce

“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.

“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.” 

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.

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

Adults with sickle cell disease who experienced a vaso-occlusive crisis had substantially better outcomes when they were treated at specialty infusion centers than those treated in emergency departments (EDs), a prospective observational study shows.

At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.

“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”

To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.

The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.

The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs. 

Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.

The investigators used propensity score methodology to balance patient characteristics in the study groups.
 

Quick, effective pain reduction is beneficial

The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write. 

Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.

The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note. 

“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write. 

“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.

Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote. 

The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study. 

“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
 

Infusion centers are scarce

“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.

“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.” 

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.

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

Breast and cervical cancer screenings declined sharply in the early months of the COVID-19 pandemic, particularly among certain racial and ethnic minority groups and rural populations, notes the U.S. Centers for Disease Control and Prevention.

The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.

The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.

The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.

In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.

The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.

“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.

Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.

Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.

The findings were published online June 30 in Preventive Medicine.

“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.

The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.

The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.

A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.

Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.

“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”

Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.

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

Breast and cervical cancer screenings declined sharply in the early months of the COVID-19 pandemic, particularly among certain racial and ethnic minority groups and rural populations, notes the U.S. Centers for Disease Control and Prevention.

The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.

The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.

The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.

In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.

The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.

“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.

Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.

Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.

The findings were published online June 30 in Preventive Medicine.

“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.

The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.

The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.

A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.

Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.

“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”

Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.

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

Breast and cervical cancer screenings declined sharply in the early months of the COVID-19 pandemic, particularly among certain racial and ethnic minority groups and rural populations, notes the U.S. Centers for Disease Control and Prevention.

The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.

The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.

The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.

In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.

The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.

“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.

Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.

Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.

The findings were published online June 30 in Preventive Medicine.

“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.

The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.

The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.

A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.

Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.

“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”

Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.

For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.

Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
 

Specialized care

The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.

Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.

In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.

Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”

They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”

The authors reported that they had no competing interests.

mlesney@mdedge.com

To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.

For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.

Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
 

Specialized care

The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.

Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.

In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.

Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”

They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”

The authors reported that they had no competing interests.

mlesney@mdedge.com

To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.

For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.

Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
 

Specialized care

The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.

Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.

In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.

Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”

They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”

The authors reported that they had no competing interests.

mlesney@mdedge.com

Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).

Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.

The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.

The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
 

Promising results

In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.

“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
 

Problems remain

In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.

“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.

The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.

mlesney@mdedge.com

Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).

Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.

The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.

The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
 

Promising results

In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.

“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
 

Problems remain

In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.

“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.

The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.

mlesney@mdedge.com

Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).

Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.

The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.

The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
 

Promising results

In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.

“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
 

Problems remain

In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.

“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.

The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.

mlesney@mdedge.com