Pharmacology

Consolidated mail outpatient pharmacy (CMOP) is an automated prescription order processing and delivery system developed by the US Department of Veterans Affairs (VA) in 1994 to provide medications to VA patients.¹ In fiscal year (FY) 2016, CMOP filled about 80% of VA outpatient prescriptions.²

Formalized by the 2010 Memorandum of Understanding between Indian Health Service (IHS) and VA, CMOP is a partnership undertaken to improve the delivery of care to patients by both agencies.³ The number of prescriptions filled by CMOP for IHS patients increased from 1,972 in FY 2010 to 840,109 in FY 2018.⁴ In the fourth quarter of FY 2018, there were 94 CMOP-enrolled IHS federal and tribal sites.⁵ It is only appropriate that a growing number of IHS sites are adopting CMOP considering the evidence for mail-order pharmacy on better patient adherence, improved health outcomes, and potential cost savings.^6-9 Furthermore, using a centralized pharmacy operation, such as CMOP, can lead to better quality services.¹⁰

Crownpoint Health Care Facility (CHCF) serves > 30,000 American Indians and is in Crownpoint, New Mexico, a small community of about 3,000 people.¹¹ Most of the patients served by the facility live in distant places. Many of these underserved patients do not have a stable means of transportation.¹² Therefore, these patients may have difficulty traveling to the facility for their health care needs, including medication pickups. More than 2.5 million American Indians and Alaska Natives IHS beneficiaries face similar challenges due to the rurality of their communities.¹³ CMOP can be a method to increase access to care for this vulnerable population. However, the utilization of CMOP varies significantly among IHS facilities. While some IHS facilities process large numbers of prescriptions through CMOP, other facilities process few, if any. There also are IHS facilities, such as CHCF, which are at the initial stage of implementing CMOP or trying to increase the volume of prescriptions processed through CMOP. Although the utilization of CMOP has grown exponentially among IHS facilities, there is currently no available resource that summarizes the relative advantages and disadvantages, the challenges and opportunities, and the strengths and weaknesses of implementing CMOP for IHS facilities

Methods

A questionnaire encompassing various aspects of CMOP prescription processing was developed and distributed to the primary CMOP contacts for IHS facilities. The questionnaire was first distributed by e-mail on December 19, 2018. It was e-mailed for a second time on January 16, 2019, and the questionnaire was open for responses until the end of January 2019 (Table).

Results

Forty-four of 94 CMOP-enrolled IHS sites responded to the questionnaire. Most sites train the majority of their pharmacists in CMOP prescription processing. Overall, 310 of 347 pharmacists (89%) in these 44 IHS sites can process prescriptions through CMOP. Thirty-one sites have all their pharmacists trained in CMOP prescription processing. Only 1 facility had less than half (2 of 17 pharmacists) of its pharmacists trained in CMOP prescription processing. More than half the total number of pharmacists, 185 out of 347 (53%), check electronic messages via Resource and Patient Management System (RPMS) MailMan to get information about prescriptions rejected by CMOP. Twenty sites have all their pharmacists check messages about CMOP rejections. However, 2 facilities reported that they do not check the rejection messages at all. Twenty-six of the 44 responding sites (59%) transmit prescriptions to CMOP manually in the electronic system. The rest (18 of 44) rely on the auto-transmission (AT) setup to transmit the CMOP-suspended prescriptions at specified times of the day.

Half the sites (8 of 16) that rely on patients asking for prescriptions to be mailed at the time of refill request do not use any method to designate a CMOP patient. Twenty-four sites use the narrative field on the patient’s profile in RPMS, the health information system used by most IHS facilities, to designate CMOP patients. Eighteen sites use pop-up messages on ScriptPro, a pharmacy automation system, as a designation method. Most of the sites (12 of 15) that use both RPMS and ScriptPro designation methods do not require patients to ask for prescriptions to be mailed at the time of refill request; prescriptions for these patients are routed through CMOP unless patients request otherwise. Only 3 of 44 sites use both methods and rely on patients asking for prescriptions to be mailed at the time of refill request. Some other reported designation methods were using the electronic health record (EHR) posting box, keeping a manual list of CMOP patients, and solely utilizing the Prescription Mail Delivery field in RPMS. Three sites also noted that they keep manual lists to auto-refill prescriptions through CMOP.

Thirty sites (68%) reported that they process every prescription through CMOP even if the patient had prescriptions with specified CMOP quantities. Only 8 sites (18%) said that they used the local mail-out program to keep the same days’ supply for all medication orders. For patients with CMOP-ineligible prescriptions, 34 of the 44 sites (77%) process the eligible prescriptions through CMOP and refill the rest of the prescriptions locally. Six sites (14%) process all medication orders locally for patients with any CMOP-ineligible prescriptions.

Only 12 of 44 sites (27%) involve pharmacy technicians in CMOP prescription processing. Five sites have technicians process prescription refills through CMOP. Two of these sites mentioned the strategy of technicians suspending the prescriptions to be sent to CMOP on the refill due date. Other technician roles included tracking CMOP packages, checking electronic messages for CMOP rejections, and signing up patients for CMOP.

Only 3 of the 44 sites (7%) have measured patient satisfaction with the CMOP program. One of these 3 sites reported that the overall satisfaction was high with CMOP. This site administered the survey to patients who came to the clinic for appointments. The second facility called patients and asked for their feedback. The third site conducted the survey by using student pharmacists. Two sites reported that they use the survey results from the CMOP-conducted patient satisfaction surveys, although they have not measured patient satisfaction at their specific facilities.

Most sites have not assessed CMOP’s impact on their insurance (point of sale) collections. However, 13 sites (30%) reported that they believe they are losing on collections by utilizing CMOP. The use of repackaged products by CMOP, which are usually nonreimbursable, is an issue that was mentioned multiple times. In contrast, 2 sites mentioned that CMOP has led to increased insurance collections for their facilities.

Discussion

The utility of CMOP among the responding IHS sites varies quite significantly. Some sites appreciate the convenience of CMOP while acknowledging its limitations, such as the possible decrease in insurance collections, lengthy prescription processing time, or medication backorders. However, some sites have reserved CMOP for special circumstances (eg, mailing refrigerated items to the patient’s street address) due to various complexities that may come with CMOP. One site reported that it compares IHS contract drug prices with VA contract drug prices quarterly to determine which prescriptions should be sent through CMOP.

Most of the IHS pharmacists (89%) are trained in CMOP prescription processing. If an IHS site wants to increase its volume of CMOP prescriptions, it is sensible to train as many pharmacists as possible so that the responsibility does not fall on a few pharmacists. Newly hired pharmacists can receive guidance from trained pharmacists. Designation methods for CMOP patients can be beneficial for these pharmacists to identify CMOP-enrolled patients, especially if the site does not require patients to ask for prescriptions to be mailed at the time of refill request. Only 3 sites (7%) use multiple designation methods in addition to relying on patients to ask for prescriptions to be mailed. Proper implementation of designation methods can remove this extra burden on patients. Conversely, requiring patients to ask for prescriptions to be sent through CMOP can prevent spontaneous mail-outs if a CMOP-designated patient wants to pick up prescriptions locally. Overall, 16 sites (36%) rely on patients asking for prescriptions to be mailed.

One of the main benefits of CMOP is the ability to mail refrigerated items. Local pharmacy mail-out programs may not have this ability. Patients at rural locations often use post office (PO) boxes because they are unable to receive postal services at their physical addresses; however, they may receive packages through United Parcel Service (UPS) at their physical addresses. CMOP uses UPS to send refrigerated items, but UPS does not deliver to PO boxes. Therefore, remotely located sites like CHCF have difficulty in fully optimizing this benefit. One solution is documenting both the physical and mailing addresses on the patient’s EHR, which enables CMOP to send refrigerated items to the patient’s home address via UPS and mail the rest of the prescriptions to the patient’s PO box address with the US Postal Service. The physical address must be listed above the PO box address to ensure that refrigerated items are not rejected by CMOP. Furthermore, both the physical address and the PO box address must be in the same city for this method to work. Two sites noted mailing refrigerated items as one of the major challenges in CMOP prescription processing.

CMOP-enrolled patients must be educated about requesting medications 7 to 10 days before they run out. There is no standard time line for prescriptions filled by CMOP. However, 1 site reported that it may take up to “10 days from time requested to mailbox.” This delay leads to pharmacies facing a dilemma as processing prescriptions too early can lead to insurance rejections, but processing them too late can lead to the patient not receiving the medication by the time they run out of their current supply. However, CMOP provides the ability to track prescriptions sent through CMOP. Pharmacists and technicians need to have access to BestWay Parcel Services Client Portal (genco-mms.bestwayparcel.com) to track CMOP packages. Tracking CMOP prescriptions is a way pharmacy technicians can be involved in CMOP prescription processing. Technicians seem to be underutilized, as only 27% of the responding sites utilize them to some degree in the CMOP process. One site delegated the responsibility of checking CMOP rejection messages to pharmacy technicians. Since 2 of the responding sites do not check CMOP rejection messages at all, this is an excellent opportunity to get pharmacy technicians involved.

A CMOP auto-refill program can potentially be utilized to avoid missed or late medications. In an auto-refill program, a pharmacist can refill prescriptions through CMOP on the due date without a patient request. They may get rejected by insurance the first time they are processed through CMOP for refilling too early if the processing time is taken into account. However, the subsequent refills do not have to consider the CMOP processing time as they would already be synchronized based on the last refill date. Though, if CMOP is out of stock on a medication and it is expected to be available soon, CMOP may take a few extra days to either fill the prescription or reject it if the drug stays unavailable. One of the sites reported “the amount of time [CMOP] holds medications if they are out of stock” as “the hardest thing to work around.” A couple of sites also mentioned the longer than usual delay in processing prescriptions by CMOP during the holidays as one of the major challenges.

CMOP use of repackaged products also may lead insurance companies to deny reimbursement. Repackaged products are usually cheaper to buy.¹⁴ However, most insurances do not reimburse for prescriptions filled with these products.¹⁵ The local drug file on RPMS may have a national drug code (NDC) that is reimbursable by insurance, but CMOP will change it to the repackaged NDC if they are filling the prescription with a repackaged product. One potential solution to this problem would be filling these prescriptions locally. Furthermore, insurance claims are processed when the prescriptions are filled by CMOP. Sites cannot return/cancel the prescription anymore at that point. Therefore, the inability to see real-time rejections as the medication orders are processed on-site makes it challenging to prevent avoidable insurance rejections, such as a refill too soon. One site calculated that it lost $26,386.45 by utilizing CMOP from January 9, 2018 to December 12, 2018. However, it is unclear whether this loss was representative of other sites. It is also worth noting that IHS sites can save a substantial amount of money on certain products by utilizing CMOP because VA buys these products at a reduced price.¹⁶

CMOP-transmitted prescriptions can be rejected for various reasons, such as CMOP manufacturer’s backorder, a different quantity from CMOP stock size, etc. Information about these rejected prescriptions is accessed through electronic messages on RPMS. CMOP does not dispense less than a full, unopened package for most over-the-counter (OTC) medications. The quantity on these prescriptions must be equal to or multiples of the package size for them to be filled by CMOP. This can lead to a patient having prescriptions with different days’ supplies, which results in various refill due dates. If a site has a local mail-out program available, it can potentially keep the same days’ supply for all prescriptions by mailing these OTC medications locally rather than utilizing CMOP. However, this can partially negate CMOP’s benefit of reduced workload.

CMOP also has specified quantities on some prescription medications. One survey respondent viewed “the quantity and day supply required by CMOP” as a negative influence on the site’s insurance collection. It is possible that CMOP does not carry all the medications that a CMOP-enrolled patient is prescribed. Most sites (77%) still send eligible prescriptions through CMOP for the patients who also have CMOP-ineligible prescriptions. There are a small number of sites (14%) that utilize local mail-out program for the patients with any CMOP-ineligible prescriptions, possibly to simplify the process. Schedule II controlled substances cannot be processed through CMOP either; however, facilities may have local policies that prohibit mailing any controlled substances.

Prescriptions can be manually transmitted to CMOP, or they can be automatically transmitted based on the run time and frequency of the auto-transmission setup. The prescriptions that are waiting to be transmitted to CMOP must be in the “suspended” status. The apparent advantage of relying on auto-transmission is that you do not have to complete the steps manually to transmit suspended CMOP prescriptions, thereby making the process more convenient. However, the manual transmission can be utilized as a checkpoint to verify that prescriptions were properly suspended for CMOP, as the prescription status changes from “S” (suspended) to “AT” once the transmission is completed. If a prescription is not properly suspended for CMOP, the status will remain as S even after manual transmission. More than half (59%) of the responding sites must find the manual transmission feature useful as they use it either over or in addition to the auto-transmission setup.

Despite the challenges, many IHS sites process thousands of monthly prescriptions through CMOP. Of the 94 CMOP-enrolled IHS sites, 17 processed > 1,000 prescriptions from March 27, 2019 to April 25, 2019.¹⁷ Five sites processed > 5,000 prescriptions.¹⁷ At the rate of > 5,000 prescriptions per month, the yearly CMOP prescription count will be > 60,000. That is more than one-third of the prescriptions processed by CHCF in 2018. By handling these prescriptions through CMOP, it can decrease pharmacy filling and dispensing workload, thereby freeing pharmacists to participate in other services.¹⁸ Furthermore, implementing CMOP does not incur any cost for the IHS site. There is a nondrug cost for each prescription that is filled through CMOP. This cost was $2.67 during FY 2016.¹⁹ The fee covers prescription vial, label, packaging for mail, postage, personnel, building overhead, and equipment capitalization.¹⁹ The nondrug cost of filling a prescription locally at the site can potentially exceed the cost charged by CMOP.¹⁹

A lack of objective data exists to assess the net impact of CMOP on patients. Different theoretical assumptions can be made, such as CMOP resulting in better patient adherence. However, there is no objective information about how much CMOP improves patient adherence if it does at all. Though J.D. Power US Pharmacy Study ranks CMOP as “among the best” mail-order pharmacies in customer satisfaction, only 3 of the 44 responding sites have measured patient satisfaction locally.²⁰ Only 1 site had objective data about CMOP’s impact on the point of sale. Therefore, it is currently difficult to perform a cost-benefit analysis of the CMOP program. There are opportunities for further studies on these topics.

Limitations

One limitation of this study is that < 50% of the CMOP-enrolled sites (44 of 94) responded to the questionnaire. It is possible that the facilities that had a significantly positive or negative experience with CMOP were more inclined to share their views. Therefore, it is difficult to conclude whether the responding sites are an accurate representative sample. Another limitation of the study was the questionnaire design and the reliance on free-text responses as opposed to structured data. The free-text responses had to be analyzed manually to determine whether they fall in the same category, thereby increasing the risk of interpretation error.

Conclusion

CMOP has its unique challenges but provides many benefits that local pharmacy mail-out programs may not possess, such as the abilities to mail refrigerated items and track packages. One must be familiar with CMOP’s various idiosyncrasies to make the best use of the program. Extensive staff education and orientation for new staff members must be done to familiarize them with the program. Nevertheless, the successful implementation of CMOP can lead to reduced pharmacy workload while increasing access to care for patients with transportation issues.

Acknowledgments
The authors thank LCDR Karsten Smith, PharmD, BCGP, the IHS CMOP Coordinator for providing the list of primary CMOP contacts and CDR Kendall Van Tyle, PharmD, BCPS, for proofreading the article.

Consolidated mail outpatient pharmacy (CMOP) is an automated prescription order processing and delivery system developed by the US Department of Veterans Affairs (VA) in 1994 to provide medications to VA patients.¹ In fiscal year (FY) 2016, CMOP filled about 80% of VA outpatient prescriptions.²

Formalized by the 2010 Memorandum of Understanding between Indian Health Service (IHS) and VA, CMOP is a partnership undertaken to improve the delivery of care to patients by both agencies.³ The number of prescriptions filled by CMOP for IHS patients increased from 1,972 in FY 2010 to 840,109 in FY 2018.⁴ In the fourth quarter of FY 2018, there were 94 CMOP-enrolled IHS federal and tribal sites.⁵ It is only appropriate that a growing number of IHS sites are adopting CMOP considering the evidence for mail-order pharmacy on better patient adherence, improved health outcomes, and potential cost savings.^6-9 Furthermore, using a centralized pharmacy operation, such as CMOP, can lead to better quality services.¹⁰

Crownpoint Health Care Facility (CHCF) serves > 30,000 American Indians and is in Crownpoint, New Mexico, a small community of about 3,000 people.¹¹ Most of the patients served by the facility live in distant places. Many of these underserved patients do not have a stable means of transportation.¹² Therefore, these patients may have difficulty traveling to the facility for their health care needs, including medication pickups. More than 2.5 million American Indians and Alaska Natives IHS beneficiaries face similar challenges due to the rurality of their communities.¹³ CMOP can be a method to increase access to care for this vulnerable population. However, the utilization of CMOP varies significantly among IHS facilities. While some IHS facilities process large numbers of prescriptions through CMOP, other facilities process few, if any. There also are IHS facilities, such as CHCF, which are at the initial stage of implementing CMOP or trying to increase the volume of prescriptions processed through CMOP. Although the utilization of CMOP has grown exponentially among IHS facilities, there is currently no available resource that summarizes the relative advantages and disadvantages, the challenges and opportunities, and the strengths and weaknesses of implementing CMOP for IHS facilities

Methods

A questionnaire encompassing various aspects of CMOP prescription processing was developed and distributed to the primary CMOP contacts for IHS facilities. The questionnaire was first distributed by e-mail on December 19, 2018. It was e-mailed for a second time on January 16, 2019, and the questionnaire was open for responses until the end of January 2019 (Table).

Results

Forty-four of 94 CMOP-enrolled IHS sites responded to the questionnaire. Most sites train the majority of their pharmacists in CMOP prescription processing. Overall, 310 of 347 pharmacists (89%) in these 44 IHS sites can process prescriptions through CMOP. Thirty-one sites have all their pharmacists trained in CMOP prescription processing. Only 1 facility had less than half (2 of 17 pharmacists) of its pharmacists trained in CMOP prescription processing. More than half the total number of pharmacists, 185 out of 347 (53%), check electronic messages via Resource and Patient Management System (RPMS) MailMan to get information about prescriptions rejected by CMOP. Twenty sites have all their pharmacists check messages about CMOP rejections. However, 2 facilities reported that they do not check the rejection messages at all. Twenty-six of the 44 responding sites (59%) transmit prescriptions to CMOP manually in the electronic system. The rest (18 of 44) rely on the auto-transmission (AT) setup to transmit the CMOP-suspended prescriptions at specified times of the day.

Half the sites (8 of 16) that rely on patients asking for prescriptions to be mailed at the time of refill request do not use any method to designate a CMOP patient. Twenty-four sites use the narrative field on the patient’s profile in RPMS, the health information system used by most IHS facilities, to designate CMOP patients. Eighteen sites use pop-up messages on ScriptPro, a pharmacy automation system, as a designation method. Most of the sites (12 of 15) that use both RPMS and ScriptPro designation methods do not require patients to ask for prescriptions to be mailed at the time of refill request; prescriptions for these patients are routed through CMOP unless patients request otherwise. Only 3 of 44 sites use both methods and rely on patients asking for prescriptions to be mailed at the time of refill request. Some other reported designation methods were using the electronic health record (EHR) posting box, keeping a manual list of CMOP patients, and solely utilizing the Prescription Mail Delivery field in RPMS. Three sites also noted that they keep manual lists to auto-refill prescriptions through CMOP.

Thirty sites (68%) reported that they process every prescription through CMOP even if the patient had prescriptions with specified CMOP quantities. Only 8 sites (18%) said that they used the local mail-out program to keep the same days’ supply for all medication orders. For patients with CMOP-ineligible prescriptions, 34 of the 44 sites (77%) process the eligible prescriptions through CMOP and refill the rest of the prescriptions locally. Six sites (14%) process all medication orders locally for patients with any CMOP-ineligible prescriptions.

Only 12 of 44 sites (27%) involve pharmacy technicians in CMOP prescription processing. Five sites have technicians process prescription refills through CMOP. Two of these sites mentioned the strategy of technicians suspending the prescriptions to be sent to CMOP on the refill due date. Other technician roles included tracking CMOP packages, checking electronic messages for CMOP rejections, and signing up patients for CMOP.

Only 3 of the 44 sites (7%) have measured patient satisfaction with the CMOP program. One of these 3 sites reported that the overall satisfaction was high with CMOP. This site administered the survey to patients who came to the clinic for appointments. The second facility called patients and asked for their feedback. The third site conducted the survey by using student pharmacists. Two sites reported that they use the survey results from the CMOP-conducted patient satisfaction surveys, although they have not measured patient satisfaction at their specific facilities.

Most sites have not assessed CMOP’s impact on their insurance (point of sale) collections. However, 13 sites (30%) reported that they believe they are losing on collections by utilizing CMOP. The use of repackaged products by CMOP, which are usually nonreimbursable, is an issue that was mentioned multiple times. In contrast, 2 sites mentioned that CMOP has led to increased insurance collections for their facilities.

Discussion

The utility of CMOP among the responding IHS sites varies quite significantly. Some sites appreciate the convenience of CMOP while acknowledging its limitations, such as the possible decrease in insurance collections, lengthy prescription processing time, or medication backorders. However, some sites have reserved CMOP for special circumstances (eg, mailing refrigerated items to the patient’s street address) due to various complexities that may come with CMOP. One site reported that it compares IHS contract drug prices with VA contract drug prices quarterly to determine which prescriptions should be sent through CMOP.

Most of the IHS pharmacists (89%) are trained in CMOP prescription processing. If an IHS site wants to increase its volume of CMOP prescriptions, it is sensible to train as many pharmacists as possible so that the responsibility does not fall on a few pharmacists. Newly hired pharmacists can receive guidance from trained pharmacists. Designation methods for CMOP patients can be beneficial for these pharmacists to identify CMOP-enrolled patients, especially if the site does not require patients to ask for prescriptions to be mailed at the time of refill request. Only 3 sites (7%) use multiple designation methods in addition to relying on patients to ask for prescriptions to be mailed. Proper implementation of designation methods can remove this extra burden on patients. Conversely, requiring patients to ask for prescriptions to be sent through CMOP can prevent spontaneous mail-outs if a CMOP-designated patient wants to pick up prescriptions locally. Overall, 16 sites (36%) rely on patients asking for prescriptions to be mailed.

One of the main benefits of CMOP is the ability to mail refrigerated items. Local pharmacy mail-out programs may not have this ability. Patients at rural locations often use post office (PO) boxes because they are unable to receive postal services at their physical addresses; however, they may receive packages through United Parcel Service (UPS) at their physical addresses. CMOP uses UPS to send refrigerated items, but UPS does not deliver to PO boxes. Therefore, remotely located sites like CHCF have difficulty in fully optimizing this benefit. One solution is documenting both the physical and mailing addresses on the patient’s EHR, which enables CMOP to send refrigerated items to the patient’s home address via UPS and mail the rest of the prescriptions to the patient’s PO box address with the US Postal Service. The physical address must be listed above the PO box address to ensure that refrigerated items are not rejected by CMOP. Furthermore, both the physical address and the PO box address must be in the same city for this method to work. Two sites noted mailing refrigerated items as one of the major challenges in CMOP prescription processing.

CMOP-enrolled patients must be educated about requesting medications 7 to 10 days before they run out. There is no standard time line for prescriptions filled by CMOP. However, 1 site reported that it may take up to “10 days from time requested to mailbox.” This delay leads to pharmacies facing a dilemma as processing prescriptions too early can lead to insurance rejections, but processing them too late can lead to the patient not receiving the medication by the time they run out of their current supply. However, CMOP provides the ability to track prescriptions sent through CMOP. Pharmacists and technicians need to have access to BestWay Parcel Services Client Portal (genco-mms.bestwayparcel.com) to track CMOP packages. Tracking CMOP prescriptions is a way pharmacy technicians can be involved in CMOP prescription processing. Technicians seem to be underutilized, as only 27% of the responding sites utilize them to some degree in the CMOP process. One site delegated the responsibility of checking CMOP rejection messages to pharmacy technicians. Since 2 of the responding sites do not check CMOP rejection messages at all, this is an excellent opportunity to get pharmacy technicians involved.

A CMOP auto-refill program can potentially be utilized to avoid missed or late medications. In an auto-refill program, a pharmacist can refill prescriptions through CMOP on the due date without a patient request. They may get rejected by insurance the first time they are processed through CMOP for refilling too early if the processing time is taken into account. However, the subsequent refills do not have to consider the CMOP processing time as they would already be synchronized based on the last refill date. Though, if CMOP is out of stock on a medication and it is expected to be available soon, CMOP may take a few extra days to either fill the prescription or reject it if the drug stays unavailable. One of the sites reported “the amount of time [CMOP] holds medications if they are out of stock” as “the hardest thing to work around.” A couple of sites also mentioned the longer than usual delay in processing prescriptions by CMOP during the holidays as one of the major challenges.

CMOP use of repackaged products also may lead insurance companies to deny reimbursement. Repackaged products are usually cheaper to buy.¹⁴ However, most insurances do not reimburse for prescriptions filled with these products.¹⁵ The local drug file on RPMS may have a national drug code (NDC) that is reimbursable by insurance, but CMOP will change it to the repackaged NDC if they are filling the prescription with a repackaged product. One potential solution to this problem would be filling these prescriptions locally. Furthermore, insurance claims are processed when the prescriptions are filled by CMOP. Sites cannot return/cancel the prescription anymore at that point. Therefore, the inability to see real-time rejections as the medication orders are processed on-site makes it challenging to prevent avoidable insurance rejections, such as a refill too soon. One site calculated that it lost $26,386.45 by utilizing CMOP from January 9, 2018 to December 12, 2018. However, it is unclear whether this loss was representative of other sites. It is also worth noting that IHS sites can save a substantial amount of money on certain products by utilizing CMOP because VA buys these products at a reduced price.¹⁶

CMOP-transmitted prescriptions can be rejected for various reasons, such as CMOP manufacturer’s backorder, a different quantity from CMOP stock size, etc. Information about these rejected prescriptions is accessed through electronic messages on RPMS. CMOP does not dispense less than a full, unopened package for most over-the-counter (OTC) medications. The quantity on these prescriptions must be equal to or multiples of the package size for them to be filled by CMOP. This can lead to a patient having prescriptions with different days’ supplies, which results in various refill due dates. If a site has a local mail-out program available, it can potentially keep the same days’ supply for all prescriptions by mailing these OTC medications locally rather than utilizing CMOP. However, this can partially negate CMOP’s benefit of reduced workload.

CMOP also has specified quantities on some prescription medications. One survey respondent viewed “the quantity and day supply required by CMOP” as a negative influence on the site’s insurance collection. It is possible that CMOP does not carry all the medications that a CMOP-enrolled patient is prescribed. Most sites (77%) still send eligible prescriptions through CMOP for the patients who also have CMOP-ineligible prescriptions. There are a small number of sites (14%) that utilize local mail-out program for the patients with any CMOP-ineligible prescriptions, possibly to simplify the process. Schedule II controlled substances cannot be processed through CMOP either; however, facilities may have local policies that prohibit mailing any controlled substances.

Prescriptions can be manually transmitted to CMOP, or they can be automatically transmitted based on the run time and frequency of the auto-transmission setup. The prescriptions that are waiting to be transmitted to CMOP must be in the “suspended” status. The apparent advantage of relying on auto-transmission is that you do not have to complete the steps manually to transmit suspended CMOP prescriptions, thereby making the process more convenient. However, the manual transmission can be utilized as a checkpoint to verify that prescriptions were properly suspended for CMOP, as the prescription status changes from “S” (suspended) to “AT” once the transmission is completed. If a prescription is not properly suspended for CMOP, the status will remain as S even after manual transmission. More than half (59%) of the responding sites must find the manual transmission feature useful as they use it either over or in addition to the auto-transmission setup.

Despite the challenges, many IHS sites process thousands of monthly prescriptions through CMOP. Of the 94 CMOP-enrolled IHS sites, 17 processed > 1,000 prescriptions from March 27, 2019 to April 25, 2019.¹⁷ Five sites processed > 5,000 prescriptions.¹⁷ At the rate of > 5,000 prescriptions per month, the yearly CMOP prescription count will be > 60,000. That is more than one-third of the prescriptions processed by CHCF in 2018. By handling these prescriptions through CMOP, it can decrease pharmacy filling and dispensing workload, thereby freeing pharmacists to participate in other services.¹⁸ Furthermore, implementing CMOP does not incur any cost for the IHS site. There is a nondrug cost for each prescription that is filled through CMOP. This cost was $2.67 during FY 2016.¹⁹ The fee covers prescription vial, label, packaging for mail, postage, personnel, building overhead, and equipment capitalization.¹⁹ The nondrug cost of filling a prescription locally at the site can potentially exceed the cost charged by CMOP.¹⁹

A lack of objective data exists to assess the net impact of CMOP on patients. Different theoretical assumptions can be made, such as CMOP resulting in better patient adherence. However, there is no objective information about how much CMOP improves patient adherence if it does at all. Though J.D. Power US Pharmacy Study ranks CMOP as “among the best” mail-order pharmacies in customer satisfaction, only 3 of the 44 responding sites have measured patient satisfaction locally.²⁰ Only 1 site had objective data about CMOP’s impact on the point of sale. Therefore, it is currently difficult to perform a cost-benefit analysis of the CMOP program. There are opportunities for further studies on these topics.

Limitations

One limitation of this study is that < 50% of the CMOP-enrolled sites (44 of 94) responded to the questionnaire. It is possible that the facilities that had a significantly positive or negative experience with CMOP were more inclined to share their views. Therefore, it is difficult to conclude whether the responding sites are an accurate representative sample. Another limitation of the study was the questionnaire design and the reliance on free-text responses as opposed to structured data. The free-text responses had to be analyzed manually to determine whether they fall in the same category, thereby increasing the risk of interpretation error.

Conclusion

CMOP has its unique challenges but provides many benefits that local pharmacy mail-out programs may not possess, such as the abilities to mail refrigerated items and track packages. One must be familiar with CMOP’s various idiosyncrasies to make the best use of the program. Extensive staff education and orientation for new staff members must be done to familiarize them with the program. Nevertheless, the successful implementation of CMOP can lead to reduced pharmacy workload while increasing access to care for patients with transportation issues.

Acknowledgments
The authors thank LCDR Karsten Smith, PharmD, BCGP, the IHS CMOP Coordinator for providing the list of primary CMOP contacts and CDR Kendall Van Tyle, PharmD, BCPS, for proofreading the article.

Consolidated mail outpatient pharmacy (CMOP) is an automated prescription order processing and delivery system developed by the US Department of Veterans Affairs (VA) in 1994 to provide medications to VA patients.¹ In fiscal year (FY) 2016, CMOP filled about 80% of VA outpatient prescriptions.²

Formalized by the 2010 Memorandum of Understanding between Indian Health Service (IHS) and VA, CMOP is a partnership undertaken to improve the delivery of care to patients by both agencies.³ The number of prescriptions filled by CMOP for IHS patients increased from 1,972 in FY 2010 to 840,109 in FY 2018.⁴ In the fourth quarter of FY 2018, there were 94 CMOP-enrolled IHS federal and tribal sites.⁵ It is only appropriate that a growing number of IHS sites are adopting CMOP considering the evidence for mail-order pharmacy on better patient adherence, improved health outcomes, and potential cost savings.^6-9 Furthermore, using a centralized pharmacy operation, such as CMOP, can lead to better quality services.¹⁰

Crownpoint Health Care Facility (CHCF) serves > 30,000 American Indians and is in Crownpoint, New Mexico, a small community of about 3,000 people.¹¹ Most of the patients served by the facility live in distant places. Many of these underserved patients do not have a stable means of transportation.¹² Therefore, these patients may have difficulty traveling to the facility for their health care needs, including medication pickups. More than 2.5 million American Indians and Alaska Natives IHS beneficiaries face similar challenges due to the rurality of their communities.¹³ CMOP can be a method to increase access to care for this vulnerable population. However, the utilization of CMOP varies significantly among IHS facilities. While some IHS facilities process large numbers of prescriptions through CMOP, other facilities process few, if any. There also are IHS facilities, such as CHCF, which are at the initial stage of implementing CMOP or trying to increase the volume of prescriptions processed through CMOP. Although the utilization of CMOP has grown exponentially among IHS facilities, there is currently no available resource that summarizes the relative advantages and disadvantages, the challenges and opportunities, and the strengths and weaknesses of implementing CMOP for IHS facilities

Methods

A questionnaire encompassing various aspects of CMOP prescription processing was developed and distributed to the primary CMOP contacts for IHS facilities. The questionnaire was first distributed by e-mail on December 19, 2018. It was e-mailed for a second time on January 16, 2019, and the questionnaire was open for responses until the end of January 2019 (Table).

Results

Forty-four of 94 CMOP-enrolled IHS sites responded to the questionnaire. Most sites train the majority of their pharmacists in CMOP prescription processing. Overall, 310 of 347 pharmacists (89%) in these 44 IHS sites can process prescriptions through CMOP. Thirty-one sites have all their pharmacists trained in CMOP prescription processing. Only 1 facility had less than half (2 of 17 pharmacists) of its pharmacists trained in CMOP prescription processing. More than half the total number of pharmacists, 185 out of 347 (53%), check electronic messages via Resource and Patient Management System (RPMS) MailMan to get information about prescriptions rejected by CMOP. Twenty sites have all their pharmacists check messages about CMOP rejections. However, 2 facilities reported that they do not check the rejection messages at all. Twenty-six of the 44 responding sites (59%) transmit prescriptions to CMOP manually in the electronic system. The rest (18 of 44) rely on the auto-transmission (AT) setup to transmit the CMOP-suspended prescriptions at specified times of the day.

Half the sites (8 of 16) that rely on patients asking for prescriptions to be mailed at the time of refill request do not use any method to designate a CMOP patient. Twenty-four sites use the narrative field on the patient’s profile in RPMS, the health information system used by most IHS facilities, to designate CMOP patients. Eighteen sites use pop-up messages on ScriptPro, a pharmacy automation system, as a designation method. Most of the sites (12 of 15) that use both RPMS and ScriptPro designation methods do not require patients to ask for prescriptions to be mailed at the time of refill request; prescriptions for these patients are routed through CMOP unless patients request otherwise. Only 3 of 44 sites use both methods and rely on patients asking for prescriptions to be mailed at the time of refill request. Some other reported designation methods were using the electronic health record (EHR) posting box, keeping a manual list of CMOP patients, and solely utilizing the Prescription Mail Delivery field in RPMS. Three sites also noted that they keep manual lists to auto-refill prescriptions through CMOP.

Thirty sites (68%) reported that they process every prescription through CMOP even if the patient had prescriptions with specified CMOP quantities. Only 8 sites (18%) said that they used the local mail-out program to keep the same days’ supply for all medication orders. For patients with CMOP-ineligible prescriptions, 34 of the 44 sites (77%) process the eligible prescriptions through CMOP and refill the rest of the prescriptions locally. Six sites (14%) process all medication orders locally for patients with any CMOP-ineligible prescriptions.

Only 12 of 44 sites (27%) involve pharmacy technicians in CMOP prescription processing. Five sites have technicians process prescription refills through CMOP. Two of these sites mentioned the strategy of technicians suspending the prescriptions to be sent to CMOP on the refill due date. Other technician roles included tracking CMOP packages, checking electronic messages for CMOP rejections, and signing up patients for CMOP.

Only 3 of the 44 sites (7%) have measured patient satisfaction with the CMOP program. One of these 3 sites reported that the overall satisfaction was high with CMOP. This site administered the survey to patients who came to the clinic for appointments. The second facility called patients and asked for their feedback. The third site conducted the survey by using student pharmacists. Two sites reported that they use the survey results from the CMOP-conducted patient satisfaction surveys, although they have not measured patient satisfaction at their specific facilities.

Most sites have not assessed CMOP’s impact on their insurance (point of sale) collections. However, 13 sites (30%) reported that they believe they are losing on collections by utilizing CMOP. The use of repackaged products by CMOP, which are usually nonreimbursable, is an issue that was mentioned multiple times. In contrast, 2 sites mentioned that CMOP has led to increased insurance collections for their facilities.

Discussion

The utility of CMOP among the responding IHS sites varies quite significantly. Some sites appreciate the convenience of CMOP while acknowledging its limitations, such as the possible decrease in insurance collections, lengthy prescription processing time, or medication backorders. However, some sites have reserved CMOP for special circumstances (eg, mailing refrigerated items to the patient’s street address) due to various complexities that may come with CMOP. One site reported that it compares IHS contract drug prices with VA contract drug prices quarterly to determine which prescriptions should be sent through CMOP.

Most of the IHS pharmacists (89%) are trained in CMOP prescription processing. If an IHS site wants to increase its volume of CMOP prescriptions, it is sensible to train as many pharmacists as possible so that the responsibility does not fall on a few pharmacists. Newly hired pharmacists can receive guidance from trained pharmacists. Designation methods for CMOP patients can be beneficial for these pharmacists to identify CMOP-enrolled patients, especially if the site does not require patients to ask for prescriptions to be mailed at the time of refill request. Only 3 sites (7%) use multiple designation methods in addition to relying on patients to ask for prescriptions to be mailed. Proper implementation of designation methods can remove this extra burden on patients. Conversely, requiring patients to ask for prescriptions to be sent through CMOP can prevent spontaneous mail-outs if a CMOP-designated patient wants to pick up prescriptions locally. Overall, 16 sites (36%) rely on patients asking for prescriptions to be mailed.

One of the main benefits of CMOP is the ability to mail refrigerated items. Local pharmacy mail-out programs may not have this ability. Patients at rural locations often use post office (PO) boxes because they are unable to receive postal services at their physical addresses; however, they may receive packages through United Parcel Service (UPS) at their physical addresses. CMOP uses UPS to send refrigerated items, but UPS does not deliver to PO boxes. Therefore, remotely located sites like CHCF have difficulty in fully optimizing this benefit. One solution is documenting both the physical and mailing addresses on the patient’s EHR, which enables CMOP to send refrigerated items to the patient’s home address via UPS and mail the rest of the prescriptions to the patient’s PO box address with the US Postal Service. The physical address must be listed above the PO box address to ensure that refrigerated items are not rejected by CMOP. Furthermore, both the physical address and the PO box address must be in the same city for this method to work. Two sites noted mailing refrigerated items as one of the major challenges in CMOP prescription processing.

CMOP-enrolled patients must be educated about requesting medications 7 to 10 days before they run out. There is no standard time line for prescriptions filled by CMOP. However, 1 site reported that it may take up to “10 days from time requested to mailbox.” This delay leads to pharmacies facing a dilemma as processing prescriptions too early can lead to insurance rejections, but processing them too late can lead to the patient not receiving the medication by the time they run out of their current supply. However, CMOP provides the ability to track prescriptions sent through CMOP. Pharmacists and technicians need to have access to BestWay Parcel Services Client Portal (genco-mms.bestwayparcel.com) to track CMOP packages. Tracking CMOP prescriptions is a way pharmacy technicians can be involved in CMOP prescription processing. Technicians seem to be underutilized, as only 27% of the responding sites utilize them to some degree in the CMOP process. One site delegated the responsibility of checking CMOP rejection messages to pharmacy technicians. Since 2 of the responding sites do not check CMOP rejection messages at all, this is an excellent opportunity to get pharmacy technicians involved.

A CMOP auto-refill program can potentially be utilized to avoid missed or late medications. In an auto-refill program, a pharmacist can refill prescriptions through CMOP on the due date without a patient request. They may get rejected by insurance the first time they are processed through CMOP for refilling too early if the processing time is taken into account. However, the subsequent refills do not have to consider the CMOP processing time as they would already be synchronized based on the last refill date. Though, if CMOP is out of stock on a medication and it is expected to be available soon, CMOP may take a few extra days to either fill the prescription or reject it if the drug stays unavailable. One of the sites reported “the amount of time [CMOP] holds medications if they are out of stock” as “the hardest thing to work around.” A couple of sites also mentioned the longer than usual delay in processing prescriptions by CMOP during the holidays as one of the major challenges.

CMOP use of repackaged products also may lead insurance companies to deny reimbursement. Repackaged products are usually cheaper to buy.¹⁴ However, most insurances do not reimburse for prescriptions filled with these products.¹⁵ The local drug file on RPMS may have a national drug code (NDC) that is reimbursable by insurance, but CMOP will change it to the repackaged NDC if they are filling the prescription with a repackaged product. One potential solution to this problem would be filling these prescriptions locally. Furthermore, insurance claims are processed when the prescriptions are filled by CMOP. Sites cannot return/cancel the prescription anymore at that point. Therefore, the inability to see real-time rejections as the medication orders are processed on-site makes it challenging to prevent avoidable insurance rejections, such as a refill too soon. One site calculated that it lost $26,386.45 by utilizing CMOP from January 9, 2018 to December 12, 2018. However, it is unclear whether this loss was representative of other sites. It is also worth noting that IHS sites can save a substantial amount of money on certain products by utilizing CMOP because VA buys these products at a reduced price.¹⁶

CMOP-transmitted prescriptions can be rejected for various reasons, such as CMOP manufacturer’s backorder, a different quantity from CMOP stock size, etc. Information about these rejected prescriptions is accessed through electronic messages on RPMS. CMOP does not dispense less than a full, unopened package for most over-the-counter (OTC) medications. The quantity on these prescriptions must be equal to or multiples of the package size for them to be filled by CMOP. This can lead to a patient having prescriptions with different days’ supplies, which results in various refill due dates. If a site has a local mail-out program available, it can potentially keep the same days’ supply for all prescriptions by mailing these OTC medications locally rather than utilizing CMOP. However, this can partially negate CMOP’s benefit of reduced workload.

CMOP also has specified quantities on some prescription medications. One survey respondent viewed “the quantity and day supply required by CMOP” as a negative influence on the site’s insurance collection. It is possible that CMOP does not carry all the medications that a CMOP-enrolled patient is prescribed. Most sites (77%) still send eligible prescriptions through CMOP for the patients who also have CMOP-ineligible prescriptions. There are a small number of sites (14%) that utilize local mail-out program for the patients with any CMOP-ineligible prescriptions, possibly to simplify the process. Schedule II controlled substances cannot be processed through CMOP either; however, facilities may have local policies that prohibit mailing any controlled substances.

Prescriptions can be manually transmitted to CMOP, or they can be automatically transmitted based on the run time and frequency of the auto-transmission setup. The prescriptions that are waiting to be transmitted to CMOP must be in the “suspended” status. The apparent advantage of relying on auto-transmission is that you do not have to complete the steps manually to transmit suspended CMOP prescriptions, thereby making the process more convenient. However, the manual transmission can be utilized as a checkpoint to verify that prescriptions were properly suspended for CMOP, as the prescription status changes from “S” (suspended) to “AT” once the transmission is completed. If a prescription is not properly suspended for CMOP, the status will remain as S even after manual transmission. More than half (59%) of the responding sites must find the manual transmission feature useful as they use it either over or in addition to the auto-transmission setup.

Despite the challenges, many IHS sites process thousands of monthly prescriptions through CMOP. Of the 94 CMOP-enrolled IHS sites, 17 processed > 1,000 prescriptions from March 27, 2019 to April 25, 2019.¹⁷ Five sites processed > 5,000 prescriptions.¹⁷ At the rate of > 5,000 prescriptions per month, the yearly CMOP prescription count will be > 60,000. That is more than one-third of the prescriptions processed by CHCF in 2018. By handling these prescriptions through CMOP, it can decrease pharmacy filling and dispensing workload, thereby freeing pharmacists to participate in other services.¹⁸ Furthermore, implementing CMOP does not incur any cost for the IHS site. There is a nondrug cost for each prescription that is filled through CMOP. This cost was $2.67 during FY 2016.¹⁹ The fee covers prescription vial, label, packaging for mail, postage, personnel, building overhead, and equipment capitalization.¹⁹ The nondrug cost of filling a prescription locally at the site can potentially exceed the cost charged by CMOP.¹⁹

A lack of objective data exists to assess the net impact of CMOP on patients. Different theoretical assumptions can be made, such as CMOP resulting in better patient adherence. However, there is no objective information about how much CMOP improves patient adherence if it does at all. Though J.D. Power US Pharmacy Study ranks CMOP as “among the best” mail-order pharmacies in customer satisfaction, only 3 of the 44 responding sites have measured patient satisfaction locally.²⁰ Only 1 site had objective data about CMOP’s impact on the point of sale. Therefore, it is currently difficult to perform a cost-benefit analysis of the CMOP program. There are opportunities for further studies on these topics.

Limitations

One limitation of this study is that < 50% of the CMOP-enrolled sites (44 of 94) responded to the questionnaire. It is possible that the facilities that had a significantly positive or negative experience with CMOP were more inclined to share their views. Therefore, it is difficult to conclude whether the responding sites are an accurate representative sample. Another limitation of the study was the questionnaire design and the reliance on free-text responses as opposed to structured data. The free-text responses had to be analyzed manually to determine whether they fall in the same category, thereby increasing the risk of interpretation error.

Conclusion

CMOP has its unique challenges but provides many benefits that local pharmacy mail-out programs may not possess, such as the abilities to mail refrigerated items and track packages. One must be familiar with CMOP’s various idiosyncrasies to make the best use of the program. Extensive staff education and orientation for new staff members must be done to familiarize them with the program. Nevertheless, the successful implementation of CMOP can lead to reduced pharmacy workload while increasing access to care for patients with transportation issues.

Acknowledgments
The authors thank LCDR Karsten Smith, PharmD, BCGP, the IHS CMOP Coordinator for providing the list of primary CMOP contacts and CDR Kendall Van Tyle, PharmD, BCPS, for proofreading the article.

The US Food and Drug Administration has approved fostemsavir (Rukobia, ViiV Healthcare), a first-in-class attachment inhibitor for the treatment of HIV-1 infection in adults.

Fostemsavir is indicated for use in combination with other antiretroviral (ARV) agents in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who fail to achieve viral suppression on other regimens due to resistance, intolerance, or safety considerations.

“This approval marks a new class of antiretroviral medications that may benefit patients who have run out of HIV treatment options,” Jeff Murray, MD, deputy director of the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced patients living with multidrug resistant HIV infection — helping people living with hard-to-treat HIV who are at greater risk for HIV-related complications to potentially live longer, healthier lives,” he said.

Fostemsavir 600 mg extended-release tablets are taken twice daily.

In the phase 3 BRIGHTE study, 60% of adults who added fostemsavir to optimized background ARV therapy achieved and maintained viral suppression through 96 weeks and saw clinically meaningful improvements in CD4+ T cells.

Most of the 371 participants in the study had been on anti-HIV therapy for more than 15 years (71%), had been exposed to five or more different HIV treatment regimens (85%), and/or had a history of AIDS (86%).

The most common adverse reactions with fostemsavir are nausea, fatigue, and diarrhea. Serious drug reactions included liver enzyme elevations in patients co-infected with hepatitis B or C virus and three cases of severe immune reconstitution inflammatory syndrome. 

“Exciting” Advance

“There is a small group of heavily treatment-experienced adults living with HIV who are not able to maintain viral suppression with currently available medication and, without effective new options, are at great risk of progressing to AIDS,” Deborah Waterhouse, CEO of ViiV Healthcare, said in a news release.

“The approval of Rukobia is a culmination of incredibly complex research, development, and manufacturing efforts to ensure we leave no person living with HIV behind,” she said.

“As a novel HIV attachment inhibitor, fostemsavir targets the first step of the viral lifecycle offering a new mechanism of action to treat people living with HIV,” Jacob P. Lalezari, MD, chief executive officer and director of Quest Clinical Research, commented in the release.

Fostemsavir is an “exciting” advance for the heavily treatment-experienced population and “an advancement the HIV community has long been waiting for. As an activist as well as researcher, I am very grateful to ViiV Healthcare for their commitment to heavily-treatment experienced people living with HIV,” he added.

Fostemsavir was reviewed and approved under the FDA’s fast track and breakthrough therapy designations, which are intended to facilitate and expedite the development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition.

Full prescribing information is available online.
 

This article first appeared on Medscape.com.

The US Food and Drug Administration has approved fostemsavir (Rukobia, ViiV Healthcare), a first-in-class attachment inhibitor for the treatment of HIV-1 infection in adults.

Fostemsavir is indicated for use in combination with other antiretroviral (ARV) agents in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who fail to achieve viral suppression on other regimens due to resistance, intolerance, or safety considerations.

“This approval marks a new class of antiretroviral medications that may benefit patients who have run out of HIV treatment options,” Jeff Murray, MD, deputy director of the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced patients living with multidrug resistant HIV infection — helping people living with hard-to-treat HIV who are at greater risk for HIV-related complications to potentially live longer, healthier lives,” he said.

Fostemsavir 600 mg extended-release tablets are taken twice daily.

In the phase 3 BRIGHTE study, 60% of adults who added fostemsavir to optimized background ARV therapy achieved and maintained viral suppression through 96 weeks and saw clinically meaningful improvements in CD4+ T cells.

Most of the 371 participants in the study had been on anti-HIV therapy for more than 15 years (71%), had been exposed to five or more different HIV treatment regimens (85%), and/or had a history of AIDS (86%).

The most common adverse reactions with fostemsavir are nausea, fatigue, and diarrhea. Serious drug reactions included liver enzyme elevations in patients co-infected with hepatitis B or C virus and three cases of severe immune reconstitution inflammatory syndrome. 

“Exciting” Advance

“There is a small group of heavily treatment-experienced adults living with HIV who are not able to maintain viral suppression with currently available medication and, without effective new options, are at great risk of progressing to AIDS,” Deborah Waterhouse, CEO of ViiV Healthcare, said in a news release.

“The approval of Rukobia is a culmination of incredibly complex research, development, and manufacturing efforts to ensure we leave no person living with HIV behind,” she said.

“As a novel HIV attachment inhibitor, fostemsavir targets the first step of the viral lifecycle offering a new mechanism of action to treat people living with HIV,” Jacob P. Lalezari, MD, chief executive officer and director of Quest Clinical Research, commented in the release.

Fostemsavir is an “exciting” advance for the heavily treatment-experienced population and “an advancement the HIV community has long been waiting for. As an activist as well as researcher, I am very grateful to ViiV Healthcare for their commitment to heavily-treatment experienced people living with HIV,” he added.

Fostemsavir was reviewed and approved under the FDA’s fast track and breakthrough therapy designations, which are intended to facilitate and expedite the development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition.

Full prescribing information is available online.
 

This article first appeared on Medscape.com.

The US Food and Drug Administration has approved fostemsavir (Rukobia, ViiV Healthcare), a first-in-class attachment inhibitor for the treatment of HIV-1 infection in adults.

Fostemsavir is indicated for use in combination with other antiretroviral (ARV) agents in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who fail to achieve viral suppression on other regimens due to resistance, intolerance, or safety considerations.

“This approval marks a new class of antiretroviral medications that may benefit patients who have run out of HIV treatment options,” Jeff Murray, MD, deputy director of the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced patients living with multidrug resistant HIV infection — helping people living with hard-to-treat HIV who are at greater risk for HIV-related complications to potentially live longer, healthier lives,” he said.

Fostemsavir 600 mg extended-release tablets are taken twice daily.

In the phase 3 BRIGHTE study, 60% of adults who added fostemsavir to optimized background ARV therapy achieved and maintained viral suppression through 96 weeks and saw clinically meaningful improvements in CD4+ T cells.

Most of the 371 participants in the study had been on anti-HIV therapy for more than 15 years (71%), had been exposed to five or more different HIV treatment regimens (85%), and/or had a history of AIDS (86%).

The most common adverse reactions with fostemsavir are nausea, fatigue, and diarrhea. Serious drug reactions included liver enzyme elevations in patients co-infected with hepatitis B or C virus and three cases of severe immune reconstitution inflammatory syndrome. 

“Exciting” Advance

“There is a small group of heavily treatment-experienced adults living with HIV who are not able to maintain viral suppression with currently available medication and, without effective new options, are at great risk of progressing to AIDS,” Deborah Waterhouse, CEO of ViiV Healthcare, said in a news release.

“The approval of Rukobia is a culmination of incredibly complex research, development, and manufacturing efforts to ensure we leave no person living with HIV behind,” she said.

“As a novel HIV attachment inhibitor, fostemsavir targets the first step of the viral lifecycle offering a new mechanism of action to treat people living with HIV,” Jacob P. Lalezari, MD, chief executive officer and director of Quest Clinical Research, commented in the release.

Fostemsavir is an “exciting” advance for the heavily treatment-experienced population and “an advancement the HIV community has long been waiting for. As an activist as well as researcher, I am very grateful to ViiV Healthcare for their commitment to heavily-treatment experienced people living with HIV,” he added.

Fostemsavir was reviewed and approved under the FDA’s fast track and breakthrough therapy designations, which are intended to facilitate and expedite the development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition.

Full prescribing information is available online.
 

This article first appeared on Medscape.com.

Captopril appears to be associated with a higher rate of pulmonary adverse reactions in patients with diabetes than that of other ACE inhibitors or angiotensin receptor blockers (ARBs) and therefore may not be the best choice for patients with diabetes and COVID-19, a new study suggests.

The study was published online in the Journal of the American Pharmacists Association.

The authors, led by Emma G. Stafford, PharmD, University of Missouri-Kansas City School of Pharmacy, note that diabetes seems to confer a higher risk of adverse outcomes in COVID-19 infection and there is conflicting data on the contribution of ACE inhibitors and ARBs, commonly used medications in diabetes, on the mortality and morbidity of COVID-19.

“In light of the recent COVID-19 outbreak, more research is needed to understand the effects that diabetes (and its medications) may have on the respiratory system and how that could affect the management of diseases such as COVID-19,” they say.

“Although ACE inhibitors and ARBs are generally considered to have similar adverse event profiles, evaluation of postmarketing adverse events may shed light on minute differences that could have important clinical impacts,” they add.

For the current study, the researchers analyzed data from multiple publicly available data sources on adverse drug reactions in patients with diabetes taking ACE inhibitors or ARBs. The data included all adverse drug events (ADEs) reported nationally to the US Food and Drug Administration and internationally to the Medical Dictionary for Regulatory Activities (MedDRA).

Results showed that captopril, the first ACE inhibitor approved back in 1981, has a higher incidence of pulmonary ADEs in patients with diabetes as compared with other ACE-inhibitor drugs (P = .005) as well as a statistically significant difference in pulmonary events compared with ARBs (P = .012).

“These analyses suggest that pharmacists and clinicians will need to consider the specific medication’s adverse event profile, particularly captopril, on how it may affect infections and other acute disease states that alter pulmonary function, such as COVID-19,” the authors conclude.

They say that the high incidence of pulmonary adverse drug effects with captopril “highlights the fact that the drugs belonging in one class are not identical and that its pharmacokinetics and pharmacodynamics can affect the patients’ health especially during acute processes like COVID-19.”

“This is especially important as current observational studies of COVID-19 patients tend to group drugs within a class and are not analyzing the potential differences within each class,” they add.

They note that ACE inhibitors can be broadly classified into 3 structural classes: sulfhydryl-, dicarboxyl-, and phosphorous- containing molecules. Notably, captopril is the only currently available ACE inhibitor belonging to the sulfhydryl-containing class and may explain the higher incidence of adverse drug effects observed, they comment.

“Health care providers have been left with many questions when treating patients with COVID-19, including how ACE inhibitors or ARBs may affect their clinical course. Results from this study may be helpful when prescribing or continuing ACE inhibitors or ARBs for patients with diabetes and infections or illnesses that may affect pulmonary function, such as COVID-19,” they conclude.

Questioning safety in COVID-19 an “overreach”

Commenting for Medscape Medical News, Michael A. Weber, MD, professor of medicine at State University of New York, said he thought the current article appears to overreach in questioning captopril’s safety in the COVID-19 setting.

“Captopril was the first ACE inhibitor available for clinical use. In early prescribing its dosage was not well understood and it might have been administered in excessive amounts,” Weber notes.

“There were some renal and other adverse effects reported that at first were attributed to the fact that captopril, unlike any other popular ACE inhibitors, contained a sulfhydryl (SH) group in its molecule,” he said. “It is not clear whether this feature could be responsible for the increased pulmonary side effects and potential danger to COVID-19 patients now reported with captopril in this new pharmacy article.”

But he adds: “The article contains no evidence that the effect of captopril or any other ACE inhibitor on the pulmonary ACE-2 enzyme has a deleterious effect on outcomes of COVID-19 disease. In any case, captopril — which should be prescribed in a twice-daily dose — is not frequently prescribed these days since newer ACE inhibitors are effective with just once-daily dosing.”

This article first appeared on Medscape.com.

Captopril appears to be associated with a higher rate of pulmonary adverse reactions in patients with diabetes than that of other ACE inhibitors or angiotensin receptor blockers (ARBs) and therefore may not be the best choice for patients with diabetes and COVID-19, a new study suggests.

The study was published online in the Journal of the American Pharmacists Association.

The authors, led by Emma G. Stafford, PharmD, University of Missouri-Kansas City School of Pharmacy, note that diabetes seems to confer a higher risk of adverse outcomes in COVID-19 infection and there is conflicting data on the contribution of ACE inhibitors and ARBs, commonly used medications in diabetes, on the mortality and morbidity of COVID-19.

“In light of the recent COVID-19 outbreak, more research is needed to understand the effects that diabetes (and its medications) may have on the respiratory system and how that could affect the management of diseases such as COVID-19,” they say.

“Although ACE inhibitors and ARBs are generally considered to have similar adverse event profiles, evaluation of postmarketing adverse events may shed light on minute differences that could have important clinical impacts,” they add.

For the current study, the researchers analyzed data from multiple publicly available data sources on adverse drug reactions in patients with diabetes taking ACE inhibitors or ARBs. The data included all adverse drug events (ADEs) reported nationally to the US Food and Drug Administration and internationally to the Medical Dictionary for Regulatory Activities (MedDRA).

Results showed that captopril, the first ACE inhibitor approved back in 1981, has a higher incidence of pulmonary ADEs in patients with diabetes as compared with other ACE-inhibitor drugs (P = .005) as well as a statistically significant difference in pulmonary events compared with ARBs (P = .012).

“These analyses suggest that pharmacists and clinicians will need to consider the specific medication’s adverse event profile, particularly captopril, on how it may affect infections and other acute disease states that alter pulmonary function, such as COVID-19,” the authors conclude.

They say that the high incidence of pulmonary adverse drug effects with captopril “highlights the fact that the drugs belonging in one class are not identical and that its pharmacokinetics and pharmacodynamics can affect the patients’ health especially during acute processes like COVID-19.”

“This is especially important as current observational studies of COVID-19 patients tend to group drugs within a class and are not analyzing the potential differences within each class,” they add.

They note that ACE inhibitors can be broadly classified into 3 structural classes: sulfhydryl-, dicarboxyl-, and phosphorous- containing molecules. Notably, captopril is the only currently available ACE inhibitor belonging to the sulfhydryl-containing class and may explain the higher incidence of adverse drug effects observed, they comment.

“Health care providers have been left with many questions when treating patients with COVID-19, including how ACE inhibitors or ARBs may affect their clinical course. Results from this study may be helpful when prescribing or continuing ACE inhibitors or ARBs for patients with diabetes and infections or illnesses that may affect pulmonary function, such as COVID-19,” they conclude.

Questioning safety in COVID-19 an “overreach”

Commenting for Medscape Medical News, Michael A. Weber, MD, professor of medicine at State University of New York, said he thought the current article appears to overreach in questioning captopril’s safety in the COVID-19 setting.

“Captopril was the first ACE inhibitor available for clinical use. In early prescribing its dosage was not well understood and it might have been administered in excessive amounts,” Weber notes.

“There were some renal and other adverse effects reported that at first were attributed to the fact that captopril, unlike any other popular ACE inhibitors, contained a sulfhydryl (SH) group in its molecule,” he said. “It is not clear whether this feature could be responsible for the increased pulmonary side effects and potential danger to COVID-19 patients now reported with captopril in this new pharmacy article.”

But he adds: “The article contains no evidence that the effect of captopril or any other ACE inhibitor on the pulmonary ACE-2 enzyme has a deleterious effect on outcomes of COVID-19 disease. In any case, captopril — which should be prescribed in a twice-daily dose — is not frequently prescribed these days since newer ACE inhibitors are effective with just once-daily dosing.”

This article first appeared on Medscape.com.

Captopril appears to be associated with a higher rate of pulmonary adverse reactions in patients with diabetes than that of other ACE inhibitors or angiotensin receptor blockers (ARBs) and therefore may not be the best choice for patients with diabetes and COVID-19, a new study suggests.

The study was published online in the Journal of the American Pharmacists Association.

The authors, led by Emma G. Stafford, PharmD, University of Missouri-Kansas City School of Pharmacy, note that diabetes seems to confer a higher risk of adverse outcomes in COVID-19 infection and there is conflicting data on the contribution of ACE inhibitors and ARBs, commonly used medications in diabetes, on the mortality and morbidity of COVID-19.

“In light of the recent COVID-19 outbreak, more research is needed to understand the effects that diabetes (and its medications) may have on the respiratory system and how that could affect the management of diseases such as COVID-19,” they say.

“Although ACE inhibitors and ARBs are generally considered to have similar adverse event profiles, evaluation of postmarketing adverse events may shed light on minute differences that could have important clinical impacts,” they add.

For the current study, the researchers analyzed data from multiple publicly available data sources on adverse drug reactions in patients with diabetes taking ACE inhibitors or ARBs. The data included all adverse drug events (ADEs) reported nationally to the US Food and Drug Administration and internationally to the Medical Dictionary for Regulatory Activities (MedDRA).

Results showed that captopril, the first ACE inhibitor approved back in 1981, has a higher incidence of pulmonary ADEs in patients with diabetes as compared with other ACE-inhibitor drugs (P = .005) as well as a statistically significant difference in pulmonary events compared with ARBs (P = .012).

“These analyses suggest that pharmacists and clinicians will need to consider the specific medication’s adverse event profile, particularly captopril, on how it may affect infections and other acute disease states that alter pulmonary function, such as COVID-19,” the authors conclude.

They say that the high incidence of pulmonary adverse drug effects with captopril “highlights the fact that the drugs belonging in one class are not identical and that its pharmacokinetics and pharmacodynamics can affect the patients’ health especially during acute processes like COVID-19.”

“This is especially important as current observational studies of COVID-19 patients tend to group drugs within a class and are not analyzing the potential differences within each class,” they add.

They note that ACE inhibitors can be broadly classified into 3 structural classes: sulfhydryl-, dicarboxyl-, and phosphorous- containing molecules. Notably, captopril is the only currently available ACE inhibitor belonging to the sulfhydryl-containing class and may explain the higher incidence of adverse drug effects observed, they comment.

“Health care providers have been left with many questions when treating patients with COVID-19, including how ACE inhibitors or ARBs may affect their clinical course. Results from this study may be helpful when prescribing or continuing ACE inhibitors or ARBs for patients with diabetes and infections or illnesses that may affect pulmonary function, such as COVID-19,” they conclude.

Questioning safety in COVID-19 an “overreach”

Commenting for Medscape Medical News, Michael A. Weber, MD, professor of medicine at State University of New York, said he thought the current article appears to overreach in questioning captopril’s safety in the COVID-19 setting.

“Captopril was the first ACE inhibitor available for clinical use. In early prescribing its dosage was not well understood and it might have been administered in excessive amounts,” Weber notes.

“There were some renal and other adverse effects reported that at first were attributed to the fact that captopril, unlike any other popular ACE inhibitors, contained a sulfhydryl (SH) group in its molecule,” he said. “It is not clear whether this feature could be responsible for the increased pulmonary side effects and potential danger to COVID-19 patients now reported with captopril in this new pharmacy article.”

But he adds: “The article contains no evidence that the effect of captopril or any other ACE inhibitor on the pulmonary ACE-2 enzyme has a deleterious effect on outcomes of COVID-19 disease. In any case, captopril — which should be prescribed in a twice-daily dose — is not frequently prescribed these days since newer ACE inhibitors are effective with just once-daily dosing.”

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

A new article in the Journal of Clinical Endocrinology & Metabolism (JCEM) addresses unique concerns and considerations regarding diabetic ketoacidosis (DKA) in the setting of COVID-19.

Corresponding author Marie E. McDonnell, MD, director of the diabetes program at Brigham and Women’s Hospital, Boston, Massachusetts, discussed the recommendations with Medscape Medical News and also spoke about the news this week that the corticosteroid dexamethasone reduced death rates in severely ill patients with COVID-19.

The full JCEM article, by lead author Nadine E. Palermo, DO, Division of Endocrinology, Diabetes, and Hypertension, also at Brigham and Women’s Hospital, covers DKA diagnosis and triage, and emphasizes that usual hospital protocols for DKA management may need to be adjusted during COVID-19 to help preserve personal protective equipment and ICU beds.

“Hospitals and clinicians need to be able to quickly identify and manage DKA in COVID patients to save lives. This involves determining the options for management, including when less intensive subcutaneous insulin is indicated, and understanding how to guide patients on avoiding this serious complication,” McDonnell said in an Endocrine Society statement.
 

What about dexamethasone for severe COVID-19 in diabetes?

The new article briefly touches on the fact that upward adjustments to intensive intravenous insulin therapy for DKA may be necessary in patients with COVID-19 who are receiving concomitant corticosteroids or vasopressors.

But it was written prior to the June 16 announcement of the “RECOVERY” trial results with dexamethasone. The UK National Health Service immediately approved the drug’s use in the COVID-19 setting, despite the fact that there has been no published article on the findings yet.

McDonnell told Medscape Medical News that she would need to see formal results to better understand exactly which patients were studied and which ones benefited.

“The peer review will be critical. It looks as if it only benefits people who need respiratory support, but I want to understand that in much more detail,” she said. “If they all had acute respiratory distress syndrome [ARDS],” that’s different.

“There are already some data supporting steroid use in ARDS,” she noted, but added that not all of it suggests benefit.

She pointed to one of several studies now showing that diabetes, and hyperglycemia among people without a prior diabetes diagnosis, are both strong predictors of mortality in hospitalized patients with COVID-19.

“There was a very clear relationship between hyperglycemia and outcomes. We really shouldn’t put people at risk until we have clear data,” she said.

If, once the data are reviewed and appropriate dexamethasone becomes an established treatment for severe COVID-19, hyperglycemia would be a concern among all patients, not just those with previously diagnosed diabetes, she noted.

“We know a good number of people with prediabetes develop hyperglycemia when put on steroids. They can push people over the edge. We’re not going to miss anybody, but treating steroid-induced hyperglycemia is really hard,” McDonnell explained.

She also recommended 2014 guidance from Diabetes UK and the Association of British Clinical Diabetologists, which addresses management of inpatient steroid-induced DKA in patients with and without pre-existing diabetes.

Another major concern, she said, is “patients trying to get dexamethasone when they start to get sick” because this is not the right population to use this agent.

“We worry about people who do not need this drug. If they have diabetes, they put themselves at risk of hyperglycemia, which then increases the risk of severe COVID-19. And then they’re also putting themselves at risk of DKA. It would just be bad medicine,” she said.

Managing DKA in the face of COVID-19: Flexibility is key

In the JCEM article, Palermo and colleagues emphasize that the usual hospital protocols for DKA management may need to be adjusted during COVID-19 in the interest of reducing transmission risk and preserving scare resources.

They provide evidence for alternative treatment strategies, such as the use of subcutaneous rather than intravenous insulin when appropriate.

“We wanted to outline when exactly you should consider nonintensive management strategies for DKA,” McDonnell further explained to Medscape Medical News.

“That would include those with mild or some with moderate DKA. ... The idea is to remind our colleagues about that because hospitals tend to operate on a protocol-driven algorithmic methodology, they can forget to step off the usual care pathway even if evidence supports that,” she said.   

But on the other hand, she also said that, in some very complex or severely ill patients with COVID-19, classical intravenous insulin therapy makes the most sense even if their DKA is mild.
 

The outpatient setting: Prevention and preparation

The new article also addresses several concerns regarding DKA prevention in the outpatient setting.

As with other guidelines, it includes a reminder that patients with diabetes should be advised to discontinue sodium-glucose cotransporter 2 (SGLT2) inhibitors if they become ill with COVID-19, especially if they’re not eating or drinking normally, because they raise the risk for DKA.

Also, for patients with type 1 diabetes, particularly those with a history of repeated DKA, “this is the time to make sure we reach out to patients to refill their insulin prescriptions and address issues related to cost and other access difficulties,” McDonnell said.

The authors also emphasize that insulin starts and education should not be postponed during the pandemic. “Patients identified as meeting criteria to start insulin should be referred for urgent education, either in person or, whenever possible and practical, via video teleconferencing,” they urge.

McDonnell has reported receiving research funding from Novo Nordisk. The other two authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

A new article in the Journal of Clinical Endocrinology & Metabolism (JCEM) addresses unique concerns and considerations regarding diabetic ketoacidosis (DKA) in the setting of COVID-19.

Corresponding author Marie E. McDonnell, MD, director of the diabetes program at Brigham and Women’s Hospital, Boston, Massachusetts, discussed the recommendations with Medscape Medical News and also spoke about the news this week that the corticosteroid dexamethasone reduced death rates in severely ill patients with COVID-19.

The full JCEM article, by lead author Nadine E. Palermo, DO, Division of Endocrinology, Diabetes, and Hypertension, also at Brigham and Women’s Hospital, covers DKA diagnosis and triage, and emphasizes that usual hospital protocols for DKA management may need to be adjusted during COVID-19 to help preserve personal protective equipment and ICU beds.

“Hospitals and clinicians need to be able to quickly identify and manage DKA in COVID patients to save lives. This involves determining the options for management, including when less intensive subcutaneous insulin is indicated, and understanding how to guide patients on avoiding this serious complication,” McDonnell said in an Endocrine Society statement.
 

What about dexamethasone for severe COVID-19 in diabetes?

The new article briefly touches on the fact that upward adjustments to intensive intravenous insulin therapy for DKA may be necessary in patients with COVID-19 who are receiving concomitant corticosteroids or vasopressors.

But it was written prior to the June 16 announcement of the “RECOVERY” trial results with dexamethasone. The UK National Health Service immediately approved the drug’s use in the COVID-19 setting, despite the fact that there has been no published article on the findings yet.

McDonnell told Medscape Medical News that she would need to see formal results to better understand exactly which patients were studied and which ones benefited.

“The peer review will be critical. It looks as if it only benefits people who need respiratory support, but I want to understand that in much more detail,” she said. “If they all had acute respiratory distress syndrome [ARDS],” that’s different.

“There are already some data supporting steroid use in ARDS,” she noted, but added that not all of it suggests benefit.

She pointed to one of several studies now showing that diabetes, and hyperglycemia among people without a prior diabetes diagnosis, are both strong predictors of mortality in hospitalized patients with COVID-19.

“There was a very clear relationship between hyperglycemia and outcomes. We really shouldn’t put people at risk until we have clear data,” she said.

If, once the data are reviewed and appropriate dexamethasone becomes an established treatment for severe COVID-19, hyperglycemia would be a concern among all patients, not just those with previously diagnosed diabetes, she noted.

“We know a good number of people with prediabetes develop hyperglycemia when put on steroids. They can push people over the edge. We’re not going to miss anybody, but treating steroid-induced hyperglycemia is really hard,” McDonnell explained.

She also recommended 2014 guidance from Diabetes UK and the Association of British Clinical Diabetologists, which addresses management of inpatient steroid-induced DKA in patients with and without pre-existing diabetes.

Another major concern, she said, is “patients trying to get dexamethasone when they start to get sick” because this is not the right population to use this agent.

“We worry about people who do not need this drug. If they have diabetes, they put themselves at risk of hyperglycemia, which then increases the risk of severe COVID-19. And then they’re also putting themselves at risk of DKA. It would just be bad medicine,” she said.

Managing DKA in the face of COVID-19: Flexibility is key

In the JCEM article, Palermo and colleagues emphasize that the usual hospital protocols for DKA management may need to be adjusted during COVID-19 in the interest of reducing transmission risk and preserving scare resources.

They provide evidence for alternative treatment strategies, such as the use of subcutaneous rather than intravenous insulin when appropriate.

“We wanted to outline when exactly you should consider nonintensive management strategies for DKA,” McDonnell further explained to Medscape Medical News.

“That would include those with mild or some with moderate DKA. ... The idea is to remind our colleagues about that because hospitals tend to operate on a protocol-driven algorithmic methodology, they can forget to step off the usual care pathway even if evidence supports that,” she said.   

But on the other hand, she also said that, in some very complex or severely ill patients with COVID-19, classical intravenous insulin therapy makes the most sense even if their DKA is mild.
 

The outpatient setting: Prevention and preparation

The new article also addresses several concerns regarding DKA prevention in the outpatient setting.

As with other guidelines, it includes a reminder that patients with diabetes should be advised to discontinue sodium-glucose cotransporter 2 (SGLT2) inhibitors if they become ill with COVID-19, especially if they’re not eating or drinking normally, because they raise the risk for DKA.

Also, for patients with type 1 diabetes, particularly those with a history of repeated DKA, “this is the time to make sure we reach out to patients to refill their insulin prescriptions and address issues related to cost and other access difficulties,” McDonnell said.

The authors also emphasize that insulin starts and education should not be postponed during the pandemic. “Patients identified as meeting criteria to start insulin should be referred for urgent education, either in person or, whenever possible and practical, via video teleconferencing,” they urge.

McDonnell has reported receiving research funding from Novo Nordisk. The other two authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

A new article in the Journal of Clinical Endocrinology & Metabolism (JCEM) addresses unique concerns and considerations regarding diabetic ketoacidosis (DKA) in the setting of COVID-19.

Corresponding author Marie E. McDonnell, MD, director of the diabetes program at Brigham and Women’s Hospital, Boston, Massachusetts, discussed the recommendations with Medscape Medical News and also spoke about the news this week that the corticosteroid dexamethasone reduced death rates in severely ill patients with COVID-19.

The full JCEM article, by lead author Nadine E. Palermo, DO, Division of Endocrinology, Diabetes, and Hypertension, also at Brigham and Women’s Hospital, covers DKA diagnosis and triage, and emphasizes that usual hospital protocols for DKA management may need to be adjusted during COVID-19 to help preserve personal protective equipment and ICU beds.

“Hospitals and clinicians need to be able to quickly identify and manage DKA in COVID patients to save lives. This involves determining the options for management, including when less intensive subcutaneous insulin is indicated, and understanding how to guide patients on avoiding this serious complication,” McDonnell said in an Endocrine Society statement.
 

What about dexamethasone for severe COVID-19 in diabetes?

The new article briefly touches on the fact that upward adjustments to intensive intravenous insulin therapy for DKA may be necessary in patients with COVID-19 who are receiving concomitant corticosteroids or vasopressors.

But it was written prior to the June 16 announcement of the “RECOVERY” trial results with dexamethasone. The UK National Health Service immediately approved the drug’s use in the COVID-19 setting, despite the fact that there has been no published article on the findings yet.

McDonnell told Medscape Medical News that she would need to see formal results to better understand exactly which patients were studied and which ones benefited.

“The peer review will be critical. It looks as if it only benefits people who need respiratory support, but I want to understand that in much more detail,” she said. “If they all had acute respiratory distress syndrome [ARDS],” that’s different.

“There are already some data supporting steroid use in ARDS,” she noted, but added that not all of it suggests benefit.

She pointed to one of several studies now showing that diabetes, and hyperglycemia among people without a prior diabetes diagnosis, are both strong predictors of mortality in hospitalized patients with COVID-19.

“There was a very clear relationship between hyperglycemia and outcomes. We really shouldn’t put people at risk until we have clear data,” she said.

If, once the data are reviewed and appropriate dexamethasone becomes an established treatment for severe COVID-19, hyperglycemia would be a concern among all patients, not just those with previously diagnosed diabetes, she noted.

“We know a good number of people with prediabetes develop hyperglycemia when put on steroids. They can push people over the edge. We’re not going to miss anybody, but treating steroid-induced hyperglycemia is really hard,” McDonnell explained.

She also recommended 2014 guidance from Diabetes UK and the Association of British Clinical Diabetologists, which addresses management of inpatient steroid-induced DKA in patients with and without pre-existing diabetes.

Another major concern, she said, is “patients trying to get dexamethasone when they start to get sick” because this is not the right population to use this agent.

“We worry about people who do not need this drug. If they have diabetes, they put themselves at risk of hyperglycemia, which then increases the risk of severe COVID-19. And then they’re also putting themselves at risk of DKA. It would just be bad medicine,” she said.

Managing DKA in the face of COVID-19: Flexibility is key

In the JCEM article, Palermo and colleagues emphasize that the usual hospital protocols for DKA management may need to be adjusted during COVID-19 in the interest of reducing transmission risk and preserving scare resources.

They provide evidence for alternative treatment strategies, such as the use of subcutaneous rather than intravenous insulin when appropriate.

“We wanted to outline when exactly you should consider nonintensive management strategies for DKA,” McDonnell further explained to Medscape Medical News.

“That would include those with mild or some with moderate DKA. ... The idea is to remind our colleagues about that because hospitals tend to operate on a protocol-driven algorithmic methodology, they can forget to step off the usual care pathway even if evidence supports that,” she said.   

But on the other hand, she also said that, in some very complex or severely ill patients with COVID-19, classical intravenous insulin therapy makes the most sense even if their DKA is mild.
 

The outpatient setting: Prevention and preparation

The new article also addresses several concerns regarding DKA prevention in the outpatient setting.

As with other guidelines, it includes a reminder that patients with diabetes should be advised to discontinue sodium-glucose cotransporter 2 (SGLT2) inhibitors if they become ill with COVID-19, especially if they’re not eating or drinking normally, because they raise the risk for DKA.

Also, for patients with type 1 diabetes, particularly those with a history of repeated DKA, “this is the time to make sure we reach out to patients to refill their insulin prescriptions and address issues related to cost and other access difficulties,” McDonnell said.

The authors also emphasize that insulin starts and education should not be postponed during the pandemic. “Patients identified as meeting criteria to start insulin should be referred for urgent education, either in person or, whenever possible and practical, via video teleconferencing,” they urge.

McDonnell has reported receiving research funding from Novo Nordisk. The other two authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Magrolimab plus azacitidine (AZA) improved outcomes in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients according to the results of a phase 1b study (NCT03248479) presented at the virtual ASCO meeting. The combo especially was promising for the underserved patient population that have the TP53 (p53) mutation.

Magrolimab is a first-in-kind IgG anti-CD47 monoclonal antibody that promotes the elimination of tumor cells through macrophage phagocytosis. CD47 is a “do not eat me” signal on cancer cells that allows the cells to evade macrophages. Its increased expression is predictive of a worse outcome in AML patients, according to David A. Sallman, MD, of the Moffitt Cancer Center, Tampa, Fla., and colleagues.

Dr. Sallman presented the results of a study examining whether magrolimab would provide a synergistic benefit when combined with AZA (which induces other prophagocytic “eat me” signals such as calreticulin on cancer cells). The primary objectives of the study were to examine the safety of magrolimab alone or with AZA, and to assess the efficacy of the magrolimab/AZA combo in 29 untreated AML patients and 39 untreated MDS patients. The majority of both the MDS and AML patients were poor cytogenetic risk at 64% and 72%, respectively. Mutant p53 was present in 13% of the MDS patients and 45% of the AML patients.

No deaths occurred in the first 60 days of the study among either the MDS or AML patients and discontinuation of treatment because of drug-related adverse events was seen in only one of the patients (1.5%) treated with magrolimab/AZA. There was no significant neutropenia or thrombocytopenia caused by the therapy seen, and the majority of the patients improved their neutrophil and platelet counts while on therapy.

Anemia from CD47 blockade was mitigated by the use of a priming dose of magrolimab coupled to a maintenance-dose regimen, resulting in a mild hemoglobin drop on the first dose, which returned to baseline with a majority of patients experiencing significant hemoglobin improvement and a decrease in transfusion frequency over time, according to Dr. Sallman and his colleagues.

The results showed that magrolimab/AZA induced a 91% overall response rate (ORR), with a 42% complete remission (CR) that increased to 56% at 6 months, in the MDS patients. AML patients experienced a 64% ORR (56% CR/CRi [CR with incomplete hematological remission]). These results compare favorably with the CR rate of 6%-17% rate seen for AZA monotherapy, according to Dr. Sallman.

Red blood cell transfusion independence was achieved in 58% of the MDS patients and 64% of the AML patients, and a complete cytogenetic response was seen in 35% and 50% of the MDS and AML patients, respectively.

The combined treatment was especially effective in the patients with p53 mutations, with an overall response rate of 75% for both MDS and AML, and a complete response of 42% and 50%, respectively. During the reported time of the study, the median survival was not reached, which compares favorably with current therapies, according to Dr. Sallman.

“Specifically looking at a very-high-risk p53-mutant subset, complete remissions have been observed in the majority of patients. And again, these have been durable. Based on all of these data, expansion cohorts both in MDS and p53 and AML continue to accrue with registrational studies in progress for MDS and planned for p53-mutant AML,” Dr. Sallman concluded.

The trial was sponsored by Gilead Sciences, and funding was obtained from the California Institute for Regenerative Medicine. Dr. Sallman disclosed that he received research funding from Celgene and has acted in a consulting or advisory role for Agios, argenx, and Celyad. He was also on the speaker’s bureau for a variety of pharmaceutical/biotech companies.

[email protected]

SOURCE: Sallman DA et al. ASCO 2020, Abstract 7507.

Magrolimab plus azacitidine (AZA) improved outcomes in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients according to the results of a phase 1b study (NCT03248479) presented at the virtual ASCO meeting. The combo especially was promising for the underserved patient population that have the TP53 (p53) mutation.

Magrolimab is a first-in-kind IgG anti-CD47 monoclonal antibody that promotes the elimination of tumor cells through macrophage phagocytosis. CD47 is a “do not eat me” signal on cancer cells that allows the cells to evade macrophages. Its increased expression is predictive of a worse outcome in AML patients, according to David A. Sallman, MD, of the Moffitt Cancer Center, Tampa, Fla., and colleagues.

Dr. Sallman presented the results of a study examining whether magrolimab would provide a synergistic benefit when combined with AZA (which induces other prophagocytic “eat me” signals such as calreticulin on cancer cells). The primary objectives of the study were to examine the safety of magrolimab alone or with AZA, and to assess the efficacy of the magrolimab/AZA combo in 29 untreated AML patients and 39 untreated MDS patients. The majority of both the MDS and AML patients were poor cytogenetic risk at 64% and 72%, respectively. Mutant p53 was present in 13% of the MDS patients and 45% of the AML patients.

No deaths occurred in the first 60 days of the study among either the MDS or AML patients and discontinuation of treatment because of drug-related adverse events was seen in only one of the patients (1.5%) treated with magrolimab/AZA. There was no significant neutropenia or thrombocytopenia caused by the therapy seen, and the majority of the patients improved their neutrophil and platelet counts while on therapy.

Anemia from CD47 blockade was mitigated by the use of a priming dose of magrolimab coupled to a maintenance-dose regimen, resulting in a mild hemoglobin drop on the first dose, which returned to baseline with a majority of patients experiencing significant hemoglobin improvement and a decrease in transfusion frequency over time, according to Dr. Sallman and his colleagues.

The results showed that magrolimab/AZA induced a 91% overall response rate (ORR), with a 42% complete remission (CR) that increased to 56% at 6 months, in the MDS patients. AML patients experienced a 64% ORR (56% CR/CRi [CR with incomplete hematological remission]). These results compare favorably with the CR rate of 6%-17% rate seen for AZA monotherapy, according to Dr. Sallman.

Red blood cell transfusion independence was achieved in 58% of the MDS patients and 64% of the AML patients, and a complete cytogenetic response was seen in 35% and 50% of the MDS and AML patients, respectively.

The combined treatment was especially effective in the patients with p53 mutations, with an overall response rate of 75% for both MDS and AML, and a complete response of 42% and 50%, respectively. During the reported time of the study, the median survival was not reached, which compares favorably with current therapies, according to Dr. Sallman.

“Specifically looking at a very-high-risk p53-mutant subset, complete remissions have been observed in the majority of patients. And again, these have been durable. Based on all of these data, expansion cohorts both in MDS and p53 and AML continue to accrue with registrational studies in progress for MDS and planned for p53-mutant AML,” Dr. Sallman concluded.

The trial was sponsored by Gilead Sciences, and funding was obtained from the California Institute for Regenerative Medicine. Dr. Sallman disclosed that he received research funding from Celgene and has acted in a consulting or advisory role for Agios, argenx, and Celyad. He was also on the speaker’s bureau for a variety of pharmaceutical/biotech companies.

[email protected]

SOURCE: Sallman DA et al. ASCO 2020, Abstract 7507.

Magrolimab plus azacitidine (AZA) improved outcomes in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients according to the results of a phase 1b study (NCT03248479) presented at the virtual ASCO meeting. The combo especially was promising for the underserved patient population that have the TP53 (p53) mutation.

Magrolimab is a first-in-kind IgG anti-CD47 monoclonal antibody that promotes the elimination of tumor cells through macrophage phagocytosis. CD47 is a “do not eat me” signal on cancer cells that allows the cells to evade macrophages. Its increased expression is predictive of a worse outcome in AML patients, according to David A. Sallman, MD, of the Moffitt Cancer Center, Tampa, Fla., and colleagues.

Dr. Sallman presented the results of a study examining whether magrolimab would provide a synergistic benefit when combined with AZA (which induces other prophagocytic “eat me” signals such as calreticulin on cancer cells). The primary objectives of the study were to examine the safety of magrolimab alone or with AZA, and to assess the efficacy of the magrolimab/AZA combo in 29 untreated AML patients and 39 untreated MDS patients. The majority of both the MDS and AML patients were poor cytogenetic risk at 64% and 72%, respectively. Mutant p53 was present in 13% of the MDS patients and 45% of the AML patients.

No deaths occurred in the first 60 days of the study among either the MDS or AML patients and discontinuation of treatment because of drug-related adverse events was seen in only one of the patients (1.5%) treated with magrolimab/AZA. There was no significant neutropenia or thrombocytopenia caused by the therapy seen, and the majority of the patients improved their neutrophil and platelet counts while on therapy.

Anemia from CD47 blockade was mitigated by the use of a priming dose of magrolimab coupled to a maintenance-dose regimen, resulting in a mild hemoglobin drop on the first dose, which returned to baseline with a majority of patients experiencing significant hemoglobin improvement and a decrease in transfusion frequency over time, according to Dr. Sallman and his colleagues.

The results showed that magrolimab/AZA induced a 91% overall response rate (ORR), with a 42% complete remission (CR) that increased to 56% at 6 months, in the MDS patients. AML patients experienced a 64% ORR (56% CR/CRi [CR with incomplete hematological remission]). These results compare favorably with the CR rate of 6%-17% rate seen for AZA monotherapy, according to Dr. Sallman.

Red blood cell transfusion independence was achieved in 58% of the MDS patients and 64% of the AML patients, and a complete cytogenetic response was seen in 35% and 50% of the MDS and AML patients, respectively.

The combined treatment was especially effective in the patients with p53 mutations, with an overall response rate of 75% for both MDS and AML, and a complete response of 42% and 50%, respectively. During the reported time of the study, the median survival was not reached, which compares favorably with current therapies, according to Dr. Sallman.

“Specifically looking at a very-high-risk p53-mutant subset, complete remissions have been observed in the majority of patients. And again, these have been durable. Based on all of these data, expansion cohorts both in MDS and p53 and AML continue to accrue with registrational studies in progress for MDS and planned for p53-mutant AML,” Dr. Sallman concluded.

The trial was sponsored by Gilead Sciences, and funding was obtained from the California Institute for Regenerative Medicine. Dr. Sallman disclosed that he received research funding from Celgene and has acted in a consulting or advisory role for Agios, argenx, and Celyad. He was also on the speaker’s bureau for a variety of pharmaceutical/biotech companies.

[email protected]

SOURCE: Sallman DA et al. ASCO 2020, Abstract 7507.

Dapagliflozin treatment of patients with heart failure but without diabetes in the DAPA-HF trial led to a one-third cut in the relative incidence of new-onset diabetes over a median follow-up of 18 months in a prespecified analysis from the multicenter trial that included 2,605 heart failure patients without diabetes at baseline.

The findings represented the first evidence that a drug from dapagliflozin’s class, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, could prevent or slow the onset of type 2 diabetes. It represents “an additional benefit” that dapagliflozin (Farxiga) offers to patients with heart failure with reduced ejection fraction (HFrEF) like those enrolled in the DAPA-HF trial, Silvio E. Inzucchi, MD, said at the virtual annual scientific sessions of the American Diabetes Association. DAPA-HF had previously proved that treatment with this drug significantly reduced the study’s primary endpoint of cardiovascular death or heart failure worsening.

During 18 months of follow-up, 7.1% of patients in the placebo arm developed type 2 diabetes, compared with 4.9% in those who received dapagliflozin, a 2.2% absolute difference and a 32% relative risk reduction that was statistically significant for this prespecified but “exploratory” endpoint, reported Dr. Inzucchi, an endocrinologist and professor of medicine at Yale University, New Haven, Conn.

For this analysis, a hemoglobin A1c level of at least 6.5% measured in two consecutive assessments was the criterion for diagnosing incident diabetes. The 2,605 enrolled patients without diabetes in the DAPA-HF trial represented 55% of the entire trial cohort of 4,744 patients with HFrEF.

The 32% relative risk reduction for incident diabetes was primarily relevant to enrolled patients with prediabetes at entry, who constituted 67% of the enrolled cohort based on the usual definition of prediabetes, an A1c of 5.7%-6.4%.

Among all 157 (6%) of the DAPA-HF patients who developed diabetes during the trial, 150 (96%) occurred in patients with prediabetes by the usual definition; 136 of the incident cases (87%) had prediabetes by a more stringent criterion of an A1c of 6.0%-6.4%.

To put the preventive efficacy of dapagliflozin into more context, Dr. Inzucchi cited the 31% relative protection rate exerted by metformin in the Diabetes Prevention Program study (N Engl J Med. 2002 Feb 7;346[6]:393-403).

The findings showed that “dapagliflozin is the first medication demonstrated to reduce both incident type 2 diabetes and mortality in a single trial,” as well as the first agent from the SGLT2 inhibitor class to show a diabetes prevention effect, Dr. Inzucchi noted. Patients with both heart failure and diabetes are known to have a substantially increased mortality risk, compared with patients with just one of these diseases, and the potent risk posed by the confluence of both was confirmed in the results Dr. Inzucchi reported.

The 157 HFrEF patients in the trial who developed diabetes had a statistically significant 70% increased incidence of all-cause mortality during the trial’s follow-up, compared with similar HFrEF patients who remained free from a diabetes diagnosis, and they also had a significant 77% relative increase in their incidence of cardiovascular death. This analysis failed to show that incident diabetes had a significant impact on hospitalizations for heart failure coupled with cardiovascular death, another endpoint of the trial.

Mitchel L. Zoler/Frontline Medical News

“This is a tremendously important analysis. We recognize that diabetes is an important factor that can forecast heart failure risk, even over relatively short follow-up. A drug that targets both diseases can be quite beneficial,” commented Muthiah Vaduganathan, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

The impact of dapagliflozin on average A1c levels during the DAPA-HF trial was minimal, reducing levels by an average of 0.04% among those who entered with prediabetes and by 0.05% among the other patients. This suggests that the mechanisms by which dapagliflozin reduced incident diabetes was by routes that did not involve simply reducing hyperglycemia, and the observed decrease in incident diabetes was not apparently caused by “masking” of hyperglycemia by dapagliflozin, said Dr. Inzucchi.

One possibility is that dapagliflozin, which also improved quality of life and reduced hospitalizations in the DAPA-HF trial, led to improved function and mobility among patients that had beneficial effects on their insulin sensitivity, Dr. Vaduganathan speculated in an interview.

The new finding of dapagliflozin’s benefit “is great news,” commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif. “It’s an impressive and important result, and another reason to use dapagliflozin in patients with HFrEF, a group of patients whom you want to prevent from having worse outcomes” by developing diabetes.

The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial enrolled HFrEF patients at 410 centers in 20 countries during February 2017–August 2018. The study’s primary endpoint was the composite incidence of cardiovascular death or worsening heart failure, which occurred in 16.3% of patients randomized to receive dapagliflozin and in 21.2% of control patients on standard care but on placebo instead of the study drug, a statistically significant relative risk reduction of 26% (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). In the 2,605-patient subgroup without type 2 diabetes at baseline the primary endpoint fell by a statistically significant 27% with dapagliflozin treatment, the first time an SGLT2 inhibitor drug was shown effective for reducing this endpoint in patients with HFrEF but without diabetes. DAPA-HF did not enroll any patients with type 1 diabetes.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Inzucchi has been a consultant to AstraZeneca and to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Vaduganathan has been an adviser to AstraZeneca and to Amgen, Baxter, Bayer, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including AstraZeneca.

[email protected]

SOURCE: Inzucchi SE et al. ADA 2020, abstract 271-OR.

Dapagliflozin treatment of patients with heart failure but without diabetes in the DAPA-HF trial led to a one-third cut in the relative incidence of new-onset diabetes over a median follow-up of 18 months in a prespecified analysis from the multicenter trial that included 2,605 heart failure patients without diabetes at baseline.

The findings represented the first evidence that a drug from dapagliflozin’s class, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, could prevent or slow the onset of type 2 diabetes. It represents “an additional benefit” that dapagliflozin (Farxiga) offers to patients with heart failure with reduced ejection fraction (HFrEF) like those enrolled in the DAPA-HF trial, Silvio E. Inzucchi, MD, said at the virtual annual scientific sessions of the American Diabetes Association. DAPA-HF had previously proved that treatment with this drug significantly reduced the study’s primary endpoint of cardiovascular death or heart failure worsening.

During 18 months of follow-up, 7.1% of patients in the placebo arm developed type 2 diabetes, compared with 4.9% in those who received dapagliflozin, a 2.2% absolute difference and a 32% relative risk reduction that was statistically significant for this prespecified but “exploratory” endpoint, reported Dr. Inzucchi, an endocrinologist and professor of medicine at Yale University, New Haven, Conn.

For this analysis, a hemoglobin A1c level of at least 6.5% measured in two consecutive assessments was the criterion for diagnosing incident diabetes. The 2,605 enrolled patients without diabetes in the DAPA-HF trial represented 55% of the entire trial cohort of 4,744 patients with HFrEF.

The 32% relative risk reduction for incident diabetes was primarily relevant to enrolled patients with prediabetes at entry, who constituted 67% of the enrolled cohort based on the usual definition of prediabetes, an A1c of 5.7%-6.4%.

Among all 157 (6%) of the DAPA-HF patients who developed diabetes during the trial, 150 (96%) occurred in patients with prediabetes by the usual definition; 136 of the incident cases (87%) had prediabetes by a more stringent criterion of an A1c of 6.0%-6.4%.

To put the preventive efficacy of dapagliflozin into more context, Dr. Inzucchi cited the 31% relative protection rate exerted by metformin in the Diabetes Prevention Program study (N Engl J Med. 2002 Feb 7;346[6]:393-403).

The findings showed that “dapagliflozin is the first medication demonstrated to reduce both incident type 2 diabetes and mortality in a single trial,” as well as the first agent from the SGLT2 inhibitor class to show a diabetes prevention effect, Dr. Inzucchi noted. Patients with both heart failure and diabetes are known to have a substantially increased mortality risk, compared with patients with just one of these diseases, and the potent risk posed by the confluence of both was confirmed in the results Dr. Inzucchi reported.

The 157 HFrEF patients in the trial who developed diabetes had a statistically significant 70% increased incidence of all-cause mortality during the trial’s follow-up, compared with similar HFrEF patients who remained free from a diabetes diagnosis, and they also had a significant 77% relative increase in their incidence of cardiovascular death. This analysis failed to show that incident diabetes had a significant impact on hospitalizations for heart failure coupled with cardiovascular death, another endpoint of the trial.

Mitchel L. Zoler/Frontline Medical News

“This is a tremendously important analysis. We recognize that diabetes is an important factor that can forecast heart failure risk, even over relatively short follow-up. A drug that targets both diseases can be quite beneficial,” commented Muthiah Vaduganathan, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

The impact of dapagliflozin on average A1c levels during the DAPA-HF trial was minimal, reducing levels by an average of 0.04% among those who entered with prediabetes and by 0.05% among the other patients. This suggests that the mechanisms by which dapagliflozin reduced incident diabetes was by routes that did not involve simply reducing hyperglycemia, and the observed decrease in incident diabetes was not apparently caused by “masking” of hyperglycemia by dapagliflozin, said Dr. Inzucchi.

One possibility is that dapagliflozin, which also improved quality of life and reduced hospitalizations in the DAPA-HF trial, led to improved function and mobility among patients that had beneficial effects on their insulin sensitivity, Dr. Vaduganathan speculated in an interview.

The new finding of dapagliflozin’s benefit “is great news,” commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif. “It’s an impressive and important result, and another reason to use dapagliflozin in patients with HFrEF, a group of patients whom you want to prevent from having worse outcomes” by developing diabetes.

The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial enrolled HFrEF patients at 410 centers in 20 countries during February 2017–August 2018. The study’s primary endpoint was the composite incidence of cardiovascular death or worsening heart failure, which occurred in 16.3% of patients randomized to receive dapagliflozin and in 21.2% of control patients on standard care but on placebo instead of the study drug, a statistically significant relative risk reduction of 26% (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). In the 2,605-patient subgroup without type 2 diabetes at baseline the primary endpoint fell by a statistically significant 27% with dapagliflozin treatment, the first time an SGLT2 inhibitor drug was shown effective for reducing this endpoint in patients with HFrEF but without diabetes. DAPA-HF did not enroll any patients with type 1 diabetes.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Inzucchi has been a consultant to AstraZeneca and to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Vaduganathan has been an adviser to AstraZeneca and to Amgen, Baxter, Bayer, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including AstraZeneca.

[email protected]

SOURCE: Inzucchi SE et al. ADA 2020, abstract 271-OR.

Dapagliflozin treatment of patients with heart failure but without diabetes in the DAPA-HF trial led to a one-third cut in the relative incidence of new-onset diabetes over a median follow-up of 18 months in a prespecified analysis from the multicenter trial that included 2,605 heart failure patients without diabetes at baseline.

The findings represented the first evidence that a drug from dapagliflozin’s class, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, could prevent or slow the onset of type 2 diabetes. It represents “an additional benefit” that dapagliflozin (Farxiga) offers to patients with heart failure with reduced ejection fraction (HFrEF) like those enrolled in the DAPA-HF trial, Silvio E. Inzucchi, MD, said at the virtual annual scientific sessions of the American Diabetes Association. DAPA-HF had previously proved that treatment with this drug significantly reduced the study’s primary endpoint of cardiovascular death or heart failure worsening.

During 18 months of follow-up, 7.1% of patients in the placebo arm developed type 2 diabetes, compared with 4.9% in those who received dapagliflozin, a 2.2% absolute difference and a 32% relative risk reduction that was statistically significant for this prespecified but “exploratory” endpoint, reported Dr. Inzucchi, an endocrinologist and professor of medicine at Yale University, New Haven, Conn.

For this analysis, a hemoglobin A1c level of at least 6.5% measured in two consecutive assessments was the criterion for diagnosing incident diabetes. The 2,605 enrolled patients without diabetes in the DAPA-HF trial represented 55% of the entire trial cohort of 4,744 patients with HFrEF.

The 32% relative risk reduction for incident diabetes was primarily relevant to enrolled patients with prediabetes at entry, who constituted 67% of the enrolled cohort based on the usual definition of prediabetes, an A1c of 5.7%-6.4%.

Among all 157 (6%) of the DAPA-HF patients who developed diabetes during the trial, 150 (96%) occurred in patients with prediabetes by the usual definition; 136 of the incident cases (87%) had prediabetes by a more stringent criterion of an A1c of 6.0%-6.4%.

To put the preventive efficacy of dapagliflozin into more context, Dr. Inzucchi cited the 31% relative protection rate exerted by metformin in the Diabetes Prevention Program study (N Engl J Med. 2002 Feb 7;346[6]:393-403).

The findings showed that “dapagliflozin is the first medication demonstrated to reduce both incident type 2 diabetes and mortality in a single trial,” as well as the first agent from the SGLT2 inhibitor class to show a diabetes prevention effect, Dr. Inzucchi noted. Patients with both heart failure and diabetes are known to have a substantially increased mortality risk, compared with patients with just one of these diseases, and the potent risk posed by the confluence of both was confirmed in the results Dr. Inzucchi reported.

The 157 HFrEF patients in the trial who developed diabetes had a statistically significant 70% increased incidence of all-cause mortality during the trial’s follow-up, compared with similar HFrEF patients who remained free from a diabetes diagnosis, and they also had a significant 77% relative increase in their incidence of cardiovascular death. This analysis failed to show that incident diabetes had a significant impact on hospitalizations for heart failure coupled with cardiovascular death, another endpoint of the trial.

Mitchel L. Zoler/Frontline Medical News

“This is a tremendously important analysis. We recognize that diabetes is an important factor that can forecast heart failure risk, even over relatively short follow-up. A drug that targets both diseases can be quite beneficial,” commented Muthiah Vaduganathan, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

The impact of dapagliflozin on average A1c levels during the DAPA-HF trial was minimal, reducing levels by an average of 0.04% among those who entered with prediabetes and by 0.05% among the other patients. This suggests that the mechanisms by which dapagliflozin reduced incident diabetes was by routes that did not involve simply reducing hyperglycemia, and the observed decrease in incident diabetes was not apparently caused by “masking” of hyperglycemia by dapagliflozin, said Dr. Inzucchi.

One possibility is that dapagliflozin, which also improved quality of life and reduced hospitalizations in the DAPA-HF trial, led to improved function and mobility among patients that had beneficial effects on their insulin sensitivity, Dr. Vaduganathan speculated in an interview.

The new finding of dapagliflozin’s benefit “is great news,” commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif. “It’s an impressive and important result, and another reason to use dapagliflozin in patients with HFrEF, a group of patients whom you want to prevent from having worse outcomes” by developing diabetes.

The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial enrolled HFrEF patients at 410 centers in 20 countries during February 2017–August 2018. The study’s primary endpoint was the composite incidence of cardiovascular death or worsening heart failure, which occurred in 16.3% of patients randomized to receive dapagliflozin and in 21.2% of control patients on standard care but on placebo instead of the study drug, a statistically significant relative risk reduction of 26% (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). In the 2,605-patient subgroup without type 2 diabetes at baseline the primary endpoint fell by a statistically significant 27% with dapagliflozin treatment, the first time an SGLT2 inhibitor drug was shown effective for reducing this endpoint in patients with HFrEF but without diabetes. DAPA-HF did not enroll any patients with type 1 diabetes.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Inzucchi has been a consultant to AstraZeneca and to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Vaduganathan has been an adviser to AstraZeneca and to Amgen, Baxter, Bayer, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including AstraZeneca.

[email protected]

SOURCE: Inzucchi SE et al. ADA 2020, abstract 271-OR.

The U.S. Food and Drug Administration revoked its decision from March 28 allowing use of hydroxychloroquine and chloroquine to treat people hospitalized with COVID-19 under an emergency use authorization (EUA).

“Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that chloroquine and hydroxychloroquine are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA,” the agency announced in a June 15 statement.

The FDA also warned today that the use of hydroxychloroquine or chloroquine may have a potential drug interaction with the investigational antiviral drug remdesivir that limits its effectiveness against COVID-19.

Remdesivir was granted emergency use authorization by the FDA on May 1.

“Based on a recently completed nonclinical laboratory study, the FDA is revising the fact sheet for healthcare providers that accompanies the drug to state that coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended as it may result in reduced antiviral activity of remdesivir. The agency is not aware of instances of this reduced activity occurring in the clinical setting but is continuing to evaluate all data related to remdesivir,” the FDA said in a news release.
 

Controversy over hydroxychloroquine

Even with such federal permission, since late March the use of these two agents has been mired in controversy.

President Donald J. Trump promoted the use of hydroxychloroquine and chloroquine to treat Americans with COVID-19, while scientific studies raised questions about their safety and effectiveness. Recent research, for example, pointed to elevated cardiovascular risks, as reported by Medscape Medical News.

The FDA acknowledged this recent evidence. “Additionally, in light of ongoing serious cardiac adverse events and other potential serious side effects, the known and potential benefits of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use.”

The full suspension of the EUA follows a warning the agency issued on April 24. The FDA’s Safety Communication cautioned against use of the two agents outside of a hospital setting, citing an increase in outpatient prescriptions and “reports of serious heart rhythm problems.”

“While additional clinical trials continue to evaluate the potential benefit of these drugs in treating or preventing COVID-19, we determined the emergency use authorization was no longer appropriate,” based on a rigorous assessment by scientists in our Center for Drug Evaluation and Research,” Patrizia Cavazzoni, MD, acting director of CDER, noted in the FDA statement.

This article first appeared on Medscape.com.

The U.S. Food and Drug Administration revoked its decision from March 28 allowing use of hydroxychloroquine and chloroquine to treat people hospitalized with COVID-19 under an emergency use authorization (EUA).

“Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that chloroquine and hydroxychloroquine are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA,” the agency announced in a June 15 statement.

The FDA also warned today that the use of hydroxychloroquine or chloroquine may have a potential drug interaction with the investigational antiviral drug remdesivir that limits its effectiveness against COVID-19.

Remdesivir was granted emergency use authorization by the FDA on May 1.

“Based on a recently completed nonclinical laboratory study, the FDA is revising the fact sheet for healthcare providers that accompanies the drug to state that coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended as it may result in reduced antiviral activity of remdesivir. The agency is not aware of instances of this reduced activity occurring in the clinical setting but is continuing to evaluate all data related to remdesivir,” the FDA said in a news release.
 

Controversy over hydroxychloroquine

Even with such federal permission, since late March the use of these two agents has been mired in controversy.

President Donald J. Trump promoted the use of hydroxychloroquine and chloroquine to treat Americans with COVID-19, while scientific studies raised questions about their safety and effectiveness. Recent research, for example, pointed to elevated cardiovascular risks, as reported by Medscape Medical News.

The FDA acknowledged this recent evidence. “Additionally, in light of ongoing serious cardiac adverse events and other potential serious side effects, the known and potential benefits of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use.”

The full suspension of the EUA follows a warning the agency issued on April 24. The FDA’s Safety Communication cautioned against use of the two agents outside of a hospital setting, citing an increase in outpatient prescriptions and “reports of serious heart rhythm problems.”

“While additional clinical trials continue to evaluate the potential benefit of these drugs in treating or preventing COVID-19, we determined the emergency use authorization was no longer appropriate,” based on a rigorous assessment by scientists in our Center for Drug Evaluation and Research,” Patrizia Cavazzoni, MD, acting director of CDER, noted in the FDA statement.

This article first appeared on Medscape.com.

The U.S. Food and Drug Administration revoked its decision from March 28 allowing use of hydroxychloroquine and chloroquine to treat people hospitalized with COVID-19 under an emergency use authorization (EUA).

“Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that chloroquine and hydroxychloroquine are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA,” the agency announced in a June 15 statement.

The FDA also warned today that the use of hydroxychloroquine or chloroquine may have a potential drug interaction with the investigational antiviral drug remdesivir that limits its effectiveness against COVID-19.

Remdesivir was granted emergency use authorization by the FDA on May 1.

“Based on a recently completed nonclinical laboratory study, the FDA is revising the fact sheet for healthcare providers that accompanies the drug to state that coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended as it may result in reduced antiviral activity of remdesivir. The agency is not aware of instances of this reduced activity occurring in the clinical setting but is continuing to evaluate all data related to remdesivir,” the FDA said in a news release.
 

Controversy over hydroxychloroquine

Even with such federal permission, since late March the use of these two agents has been mired in controversy.

President Donald J. Trump promoted the use of hydroxychloroquine and chloroquine to treat Americans with COVID-19, while scientific studies raised questions about their safety and effectiveness. Recent research, for example, pointed to elevated cardiovascular risks, as reported by Medscape Medical News.

The FDA acknowledged this recent evidence. “Additionally, in light of ongoing serious cardiac adverse events and other potential serious side effects, the known and potential benefits of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use.”

The full suspension of the EUA follows a warning the agency issued on April 24. The FDA’s Safety Communication cautioned against use of the two agents outside of a hospital setting, citing an increase in outpatient prescriptions and “reports of serious heart rhythm problems.”

“While additional clinical trials continue to evaluate the potential benefit of these drugs in treating or preventing COVID-19, we determined the emergency use authorization was no longer appropriate,” based on a rigorous assessment by scientists in our Center for Drug Evaluation and Research,” Patrizia Cavazzoni, MD, acting director of CDER, noted in the FDA statement.

This article first appeared on Medscape.com.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

[email protected]

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

[email protected]

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

[email protected]

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

High-dose oral famotidine might improve cardinal symptoms of COVID-19 infection, according to the findings of a small outpatient case series and a subsequent retrospective study.

After developing COVID-19 symptoms, the 10 patients in the case series began self-medicating with 60-240 mg famotidine daily over a median of 11 days. “All patients reported marked improvements of disease-related symptoms after starting famotidine,” first author Tobias Janowitz, MD, PhD, of Cold Spring Harbor Laboratory, N.Y., and associates wrote in Gut.

Improvements began within 24-48 hours of starting on the histamine-2 receptor antagonist. By 14 days after treatment initiation, all patients reported near-normalization of both respiratory and systemic symptoms, the researchers reported.

The patients were 23-71 years old. Seven tested positive for COVID-19, two had antibodies to COVID-19, and one had a clinical diagnosis of COVID-19 without laboratory confirmation. Over a median of 11 days (range, 5-21 days), six patients self-administered 80 mg famotidine three times daily and four self-administered lower amounts – from 60 to 150 mg of famotidine daily, divided into two or three doses. Patients started on famotidine between 2 and 26 days after symptom onset.

Through phone interviews and questionnaires, the researchers ascertained changes in cough, dyspnea, fatigue, headache, anosmia, and general unwellness by using a modified four-point Eastern Cooperative Oncology Group (ECOG) performance status scale. Improvements were seen across all symptom categories, and respiratory symptoms improved faster than systemic symptoms. Apart from two cases of persistent anosmia, symptoms resolved completely within 14 days of starting famotidine.

Seven patients reported no side effects of famotidine; one reported grade 1 dizziness and infrequent perceptions of tachycardia; one reported grade 1 dizziness, dry skin, and insomnia; and one reported grade 1 gastrointestinal symptoms and temporary forgetfulness. “Other than forgetfulness, all of these side effects are listed in the prescription information for famotidine, and all side effects resolved on discontinuation of famotidine,” the investigators wrote.

While the findings are intriguing, Dr. Janowitz and associates cautioned against overinterpretation of them. Another expert agreed: “This is a preliminary study based on a hypothesized antiviral effect. It’s important to know that it doesn’t really prove it works,” said Amesh Adalja, MD, senior scholar at the Johns Hopkins University Center for Health Security, Baltimore, and a spokesperson for the Infectious Diseases Society of America, during an interview with MDedge.

These patients might have improved anyway, without self-administering famotidine, said Dr. Adalja, who was not involved in the study.

Furthermore, the mechanism by which famotidine might act on COVID-19 remains unclear. The drug “could have a viral target, for example, one of the viral proteases, or a host target, resulting, for example, in modulation of the immunological response to the virus,” Dr. Janowitz and associates wrote.

Dr. Adalja noted that many compounds show effects against COVID-19 that are not well understood. He called for randomized trials to evaluate the biological plausibility of famotidine use, and its potential efficacy.

“This is a cheap, over-the-counter drug, but no drug is without side effects,” he added. “We need to know whether it works.”

Based on the case series findings, researchers conducted another retrospective study of patients hospitalized with COVID-19 infection. Those who were incidentally taking famotidine before or at hospitalization had a significantly reduced risk of intubation or death, with a hazard ratio of 0.43 (Gastroenterology. 2020 May 22. doi: 10.1053/j.gastro.2020.05.053)

The National Institutes of Health provided partial support. The investigators reported having no conflicts of interest.

SOURCE: Janowitz T et al. Gut. 2020 Jun 4. doi: 10.1136/gutjnl-2020-321852.

High-dose oral famotidine might improve cardinal symptoms of COVID-19 infection, according to the findings of a small outpatient case series and a subsequent retrospective study.

After developing COVID-19 symptoms, the 10 patients in the case series began self-medicating with 60-240 mg famotidine daily over a median of 11 days. “All patients reported marked improvements of disease-related symptoms after starting famotidine,” first author Tobias Janowitz, MD, PhD, of Cold Spring Harbor Laboratory, N.Y., and associates wrote in Gut.

Improvements began within 24-48 hours of starting on the histamine-2 receptor antagonist. By 14 days after treatment initiation, all patients reported near-normalization of both respiratory and systemic symptoms, the researchers reported.

The patients were 23-71 years old. Seven tested positive for COVID-19, two had antibodies to COVID-19, and one had a clinical diagnosis of COVID-19 without laboratory confirmation. Over a median of 11 days (range, 5-21 days), six patients self-administered 80 mg famotidine three times daily and four self-administered lower amounts – from 60 to 150 mg of famotidine daily, divided into two or three doses. Patients started on famotidine between 2 and 26 days after symptom onset.

Through phone interviews and questionnaires, the researchers ascertained changes in cough, dyspnea, fatigue, headache, anosmia, and general unwellness by using a modified four-point Eastern Cooperative Oncology Group (ECOG) performance status scale. Improvements were seen across all symptom categories, and respiratory symptoms improved faster than systemic symptoms. Apart from two cases of persistent anosmia, symptoms resolved completely within 14 days of starting famotidine.

Seven patients reported no side effects of famotidine; one reported grade 1 dizziness and infrequent perceptions of tachycardia; one reported grade 1 dizziness, dry skin, and insomnia; and one reported grade 1 gastrointestinal symptoms and temporary forgetfulness. “Other than forgetfulness, all of these side effects are listed in the prescription information for famotidine, and all side effects resolved on discontinuation of famotidine,” the investigators wrote.

While the findings are intriguing, Dr. Janowitz and associates cautioned against overinterpretation of them. Another expert agreed: “This is a preliminary study based on a hypothesized antiviral effect. It’s important to know that it doesn’t really prove it works,” said Amesh Adalja, MD, senior scholar at the Johns Hopkins University Center for Health Security, Baltimore, and a spokesperson for the Infectious Diseases Society of America, during an interview with MDedge.

These patients might have improved anyway, without self-administering famotidine, said Dr. Adalja, who was not involved in the study.

Furthermore, the mechanism by which famotidine might act on COVID-19 remains unclear. The drug “could have a viral target, for example, one of the viral proteases, or a host target, resulting, for example, in modulation of the immunological response to the virus,” Dr. Janowitz and associates wrote.

Dr. Adalja noted that many compounds show effects against COVID-19 that are not well understood. He called for randomized trials to evaluate the biological plausibility of famotidine use, and its potential efficacy.

“This is a cheap, over-the-counter drug, but no drug is without side effects,” he added. “We need to know whether it works.”

Based on the case series findings, researchers conducted another retrospective study of patients hospitalized with COVID-19 infection. Those who were incidentally taking famotidine before or at hospitalization had a significantly reduced risk of intubation or death, with a hazard ratio of 0.43 (Gastroenterology. 2020 May 22. doi: 10.1053/j.gastro.2020.05.053)

The National Institutes of Health provided partial support. The investigators reported having no conflicts of interest.

SOURCE: Janowitz T et al. Gut. 2020 Jun 4. doi: 10.1136/gutjnl-2020-321852.

High-dose oral famotidine might improve cardinal symptoms of COVID-19 infection, according to the findings of a small outpatient case series and a subsequent retrospective study.

After developing COVID-19 symptoms, the 10 patients in the case series began self-medicating with 60-240 mg famotidine daily over a median of 11 days. “All patients reported marked improvements of disease-related symptoms after starting famotidine,” first author Tobias Janowitz, MD, PhD, of Cold Spring Harbor Laboratory, N.Y., and associates wrote in Gut.

Improvements began within 24-48 hours of starting on the histamine-2 receptor antagonist. By 14 days after treatment initiation, all patients reported near-normalization of both respiratory and systemic symptoms, the researchers reported.

The patients were 23-71 years old. Seven tested positive for COVID-19, two had antibodies to COVID-19, and one had a clinical diagnosis of COVID-19 without laboratory confirmation. Over a median of 11 days (range, 5-21 days), six patients self-administered 80 mg famotidine three times daily and four self-administered lower amounts – from 60 to 150 mg of famotidine daily, divided into two or three doses. Patients started on famotidine between 2 and 26 days after symptom onset.

Through phone interviews and questionnaires, the researchers ascertained changes in cough, dyspnea, fatigue, headache, anosmia, and general unwellness by using a modified four-point Eastern Cooperative Oncology Group (ECOG) performance status scale. Improvements were seen across all symptom categories, and respiratory symptoms improved faster than systemic symptoms. Apart from two cases of persistent anosmia, symptoms resolved completely within 14 days of starting famotidine.

Seven patients reported no side effects of famotidine; one reported grade 1 dizziness and infrequent perceptions of tachycardia; one reported grade 1 dizziness, dry skin, and insomnia; and one reported grade 1 gastrointestinal symptoms and temporary forgetfulness. “Other than forgetfulness, all of these side effects are listed in the prescription information for famotidine, and all side effects resolved on discontinuation of famotidine,” the investigators wrote.

While the findings are intriguing, Dr. Janowitz and associates cautioned against overinterpretation of them. Another expert agreed: “This is a preliminary study based on a hypothesized antiviral effect. It’s important to know that it doesn’t really prove it works,” said Amesh Adalja, MD, senior scholar at the Johns Hopkins University Center for Health Security, Baltimore, and a spokesperson for the Infectious Diseases Society of America, during an interview with MDedge.

These patients might have improved anyway, without self-administering famotidine, said Dr. Adalja, who was not involved in the study.

Furthermore, the mechanism by which famotidine might act on COVID-19 remains unclear. The drug “could have a viral target, for example, one of the viral proteases, or a host target, resulting, for example, in modulation of the immunological response to the virus,” Dr. Janowitz and associates wrote.

Dr. Adalja noted that many compounds show effects against COVID-19 that are not well understood. He called for randomized trials to evaluate the biological plausibility of famotidine use, and its potential efficacy.

“This is a cheap, over-the-counter drug, but no drug is without side effects,” he added. “We need to know whether it works.”

Based on the case series findings, researchers conducted another retrospective study of patients hospitalized with COVID-19 infection. Those who were incidentally taking famotidine before or at hospitalization had a significantly reduced risk of intubation or death, with a hazard ratio of 0.43 (Gastroenterology. 2020 May 22. doi: 10.1053/j.gastro.2020.05.053)

The National Institutes of Health provided partial support. The investigators reported having no conflicts of interest.

SOURCE: Janowitz T et al. Gut. 2020 Jun 4. doi: 10.1136/gutjnl-2020-321852.